Instructions for Zavicefta powder for concentrate for solution for infusion 2000 mg + 500 mg vial No. 10
Composition
active ingredients: ceftazidime, avibactam;
1 vial contains 2329.7 mg of ceftazidime pentahydrate, equivalent to 2000 mg of ceftazidime, and 543.5 mg of avibactam sodium, equivalent to 500 mg of avibactam;
excipient: sodium carbonate anhydrous.
Dosage form
Powder for concentrate for solution for infusion.
Main physicochemical properties: white to pale yellow powder.
Pharmacotherapeutic group
Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. ATX code J01D D52.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
Ceftazidime inhibits the synthesis of bacterial cell wall peptidoglycan by binding to penicillin-binding proteins (PBPs), resulting in lysis and death of bacterial cells. Avibactam is a non-beta-lactamase inhibitor. Avibactam forms a covalent bond with the enzyme that is not hydrolyzed. It inhibits class A and C beta-lactamases and some class D beta-lactamases according to the Ambler classification, including extended-spectrum beta-lactamases (ESBLs), KRS and OXA-48 carbapenemases, as well as AmpC enzymes. Avibactam does not inhibit class B beta-lactamases (metallo-beta-lactamases) and is unable to inhibit many class D beta-lactamases.
Resistance
Mechanisms of bacterial resistance that could potentially affect the activity of ceftazidime/avibactam include mutant or acquired PBZs, reduced permeability of the outer cell membrane to avibactam or ceftazidime, active efflux of avibactam or ceftazidime, and beta-lactamases that are resistant to inhibition by avibactam and capable of hydrolyzing ceftazidime.
Antibacterial activity in interaction with other antibacterial agents
No synergism or antagonism was observed in in vitro studies of the co-administration of ceftazidime/avibactam with metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistin and tigecycline.
Sensitivity testing criteria
The minimum inhibitory concentration (MIC) breakpoints determined in clinical studies by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for ceftazidime/avibactam are:
| Microorganisms | Sensitivity | Resistance |
| Enterobacteriales | ≤8 mg/l | >8 mg/l |
| Pseudomonas aeruginosa | ≤8 mg/l | >8 mg/l |
Pharmacokinetics/pharmacodynamics relationship
The antibacterial activity of ceftazidime against selected pathogens correlated best with the time interval (%) during which the concentration of free drug exceeded the MIC of ceftazidime/avibactam during the period between drug administrations (%ƒT > MIC of ceftazidime/avibactam). For avibactam, the pharmacokinetic/pharmacodynamic index is the time interval (%) during which the concentration of free drug was above the threshold during the period between drug administrations (%ƒT > Вт).
Clinical efficacy against selected pathogenic microorganisms
Clinical studies have demonstrated the efficacy of the drug against bacteria that were sensitive to ceftazidime/avibactam in vitro (see their list below by indications for use of the drug).
Complicated intra-abdominal infections
Gram-negative microorganisms:
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
· Pseudomonas aeruginosa
Complicated urinary tract infections
Gram-negative microorganisms:
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Enterobacter cloacae
Pseudomonas aeruginosa
Hospital-acquired pneumonia, including pneumonia associated with mechanical ventilation (MV)
Gram-negative microorganisms:
Enterobacter cloacae
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Serratia marcescens
Pseudomonas aeruginosa
The clinical efficacy of ceftazidime/avibactam against the following pathogens relevant to the approved indications has not been established, however, in vitro studies suggest that they are susceptible to ceftazidime/avibactam in the absence of acquired resistance mechanisms.
Gram-negative microorganisms:
Citrobacter koseri
Enterobacter aerogenes
Morganella morganii
Proteus vulgaris
Providencia rettgeri
The following species of microorganisms are resistant to ceftazidime/avibactam in vitro:
Staphylococcus aureus (methicillin-susceptible and methicillin-resistant)
Anaerobes
Enterococcus spp.
Stenotrophomonas maltophilia
Acinetobacter spp.
The use of Zavicefta in children aged 3 months to < 18 years was investigated in two single-blind, randomized, comparative phase 2 clinical trials, one in patients with complicated intra-abdominal infections and the other in patients with complicated urinary tract infections. The primary objective of each trial was to evaluate the safety and tolerability of ceftazidime/avibactam (+/– metronidazole). Secondary objectives included pharmacokinetics and efficacy; efficacy was the descriptive endpoint of both trials. The clinical cure rate in children with complicated intra-abdominal infection (uIAI) at the cure assessment visit (ITT population) was 91.8% (56/61) for Zavicefta compared to 95.5% (21/22) for meropenem. The microbiological eradication rate in children with complicated urinary tract infections at the cure assessment visit (ITT population) was 79.6% (43/54) with Zavicefta compared to 60.9% (14/23) with cefepime.
The European Medicines Agency has deferred the obligation to submit the results of studies with Zavicefta in one or more subsets of the paediatric population for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, pneumonia and infections caused by Gram-negative bacteria (see section 4.2 for information on paediatric use).
Pharmacokinetics.
Distribution
The extent of binding of ceftazidime and avibactam to plasma proteins is approximately 10% and 8%, respectively. The volumes of distribution of ceftazidime and avibactam at steady state were approximately 17 L and 22 L, respectively, in healthy adult volunteers after multiple administration of ceftazidime/avibactam at a dose of 2000 mg/500 mg as a 2-hour infusion every 8 hours. Ceftazidime and avibactam penetrate the bronchial epithelial lining fluid at concentrations that are 30% of those in plasma, with similar concentration-time profiles in the epithelial lining fluid and plasma.
Penetration of ceftazidime across the intact blood-brain barrier is low. In meningitis, cerebrospinal fluid concentrations reach 4–20 mg/L or more. Clinical studies of avibactam penetration across the blood-brain barrier have not been conducted; however, in rabbits with meningitis, ceftazidime and avibactam exposure in the cerebrospinal fluid were 43% and 38% of the plasma AUC, respectively. Ceftazidime crosses the placenta well and is excreted in breast milk.
Biotransformation
Ceftazidime is not metabolized. No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged avibactam was the major drug component in human plasma and urine following administration of [14C]-avibactam.
Breeding
The elimination half-life (t1/2) of ceftazidime and avibactam after intravenous administration is 2 hours. Ceftazidime is excreted unchanged by the kidneys by glomerular filtration; approximately 80-90% of the dose is excreted by the kidneys within 24 hours. Avibactam is excreted unchanged by the kidneys, with a renal clearance of approximately 158 ml/min, indicating active secretion in the renal tubules in addition to glomerular filtration; approximately 97% of the dose is excreted by the kidneys, 95% within 12 hours. Less than 1% of ceftazidime is excreted by the liver, and less than 0.25% of avibactam is excreted through the intestines.
Linearity/nonlinearity
The pharmacokinetics of ceftazidime and avibactam following single intravenous administration are approximately linear over the dose range studied (50 mg to 2000 mg). After multiple intravenous infusions of ceftazidime/avibactam at a dose of 2000 mg/500 mg every 8 hours for 11 days in healthy adult volunteers with normal renal function, no appreciable accumulation of ceftazidime and avibactam was observed.
Special patient groups
Kidney dysfunction
In patients with moderate and severe renal impairment, the elimination of ceftazidime and avibactam is reduced. The AUC of avibactam in patients with moderate and severe renal impairment is increased on average by 3.8 and 7-fold (see section 4.2).
Liver dysfunction
Mild to moderate hepatic impairment did not affect the pharmacokinetics of ceftazidime in patients receiving 2000 mg intravenously every 8 hours for 5 days, provided that renal function was not impaired. The pharmacokinetics of ceftazidime have not been studied in patients with severe hepatic impairment. The pharmacokinetics of avibactam have not been studied in patients with any degree of hepatic impairment.
Since ceftazidime and avibactam are not significantly metabolized in the liver, the systemic clearance of either active ingredient is not significantly impaired in the presence of hepatic impairment.
A decrease in ceftazidime clearance was observed in elderly patients, mainly due to the decrease in renal clearance of ceftazidime. After intravenous bolus administration of ceftazidime at a dose of 2000 mg every 12 hours to patients ≥ 80 years of age, the mean half-life was 3.5 to 4 hours.
After a single intravenous administration of 500 mg avibactam as an intravenous infusion over 30 minutes, the elimination half-life of avibactam was increased in elderly patients, which may be due to age-related decrease in renal clearance.
Children
The pharmacokinetics of ceftazidime and avibactam were studied in children aged 3 months to < 18 years with confirmed or suspected infections after single administration of ceftazidime 50 mg/kg and avibactam 12.5 mg/kg to patients weighing < 40 kg or Zavicefta 2 g/0.5 g (ceftazidime 2 grams and avibactam 0.5 grams) to patients weighing ≥ 40 kg. Plasma concentrations of ceftazidime and avibactam were similar across the four age groups studied (3 months to < 2 years, 2 to < 6 years, 6 to < 12 years, and 12 to < 18 years). The AUC0–t and Cmax values of ceftazidime and avibactam in two older cohorts (children aged 6 to < 18 years) that underwent a broader pharmacokinetic selection were similar to those observed in healthy adults with normal renal function receiving Zavicefta 2 g/0.5 g. Data from this study and two phase 2 pediatric studies in patients with complicated intra-abdominal infections and complicated urinary tract infections were combined with pharmacokinetic data from adults (phases 1–3) to update the population pharmacokinetic model used to assess the achievement of pharmacokinetic/pharmacodynamic target values. The results of these simulations demonstrated that the recommended dosing regimens for children with complicated intra-abdominal infections, complicated urinary tract infections, nosocomial pneumonia/mechanically-associated pneumonia, including dose adjustments for patients with renal insufficiency, result in target systemic exposure and pharmacokinetic/pharmacodynamic parameters similar to those in adult patients at the approved dose of Zavicefta 2 g/0.5 g administered over 2 hours every 8 hours.
There is limited experience with ceftazidime and avibactam in children aged 3 to < 6 months. The recommended dosing regimens are based on modelling using definitive population pharmacokinetic models. The modelling demonstrated that the recommended dosing regimens result in exposures comparable to those in other age groups, with pharmacokinetic/pharmacodynamic parameter values > 90% of target. Based on data from paediatric clinical trials, there was no evidence of over- or under-exposure in subjects aged 3 to < 6 months at the recommended dosing regimens.
In addition, there are very limited data in children aged 3 months to < 2 years with renal impairment (CrCL ≤ 50 mL/min/1.73 m2) and no data in severe renal impairment from completed clinical studies in children. Population pharmacokinetic models for ceftazidime and avibactam were used to simulate use in patients with renal impairment.
Gender and race
The pharmacokinetics of ceftazidime/avibactam are not significantly affected by gender or race.
Indication
Zavicefta is used to treat the following infections in adults and children aged 3 months and older (see sections “Special instructions for use” and “Pharmacodynamics”):
complicated intra-abdominal infections;
complicated urinary tract infections, including pyelonephritis;
hospital-acquired pneumonia, including ventilator-associated pneumonia.
Treatment of adult patients with bacteremia associated with or suspected of being associated with any of the infections listed above.
Zavicefta is also used to treat infections caused by aerobic Gram-negative microorganisms in adults and children aged 3 months and older who have limited treatment options (see sections “Method of administration and dosage”, “Special instructions for use”, “Pharmacodynamics”).
Official recommendations on the appropriate use of antibacterial drugs should be taken into account.
Contraindication
Hypersensitivity to the active substance or to any of the excipients of the drug.
Hypersensitivity to any other antibacterial agent of the cephalosporin group.
Severe hypersensitivity reactions (e.g. anaphylactic reactions, severe skin reactions) to any other type of beta-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).
Interaction with other medicinal products and other types of interactions
In vitro, avibactam is a substrate for OAT1 and OAT3 transporters, which may promote its active uptake from the bloodstream and thus its excretion. Probenecid (a potent OAT inhibitor) inhibits this uptake by 56–70% in vitro and, therefore, when used in combination with avibactam, may affect the excretion of the latter. Clinical studies of the interaction of avibactam and probenecid have not been conducted, therefore, the use of avibactam in combination with probenecid is not recommended.
Avibactam did not significantly inhibit cytochrome P450 isoenzymes in vitro. Avibactam and ceftazidime did not induce cytochrome P450 isoenzymes in vitro at clinically relevant concentrations. Avibactam and ceftazidime do not inhibit major transporters in the kidney and liver at clinically relevant exposure ranges, therefore the likelihood of drug interactions occurring through these mechanisms is considered low.
Clinical data have demonstrated the absence of interactions between ceftazidime and avibactam, as well as between ceftazidime/avibactam and metronidazole.
Other types of drug interactions
The use of high doses of cephalosporins in combination with nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function (see section "Special warnings and precautions for use").
Chloramphenicol is an in vitro antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is unknown, but due to the possibility of antagonism in vivo, concomitant use of these drugs should be avoided.
Application features
Hypersensitivity reactions
Severe, sometimes fatal hypersensitivity reactions may occur (see sections 4.3 and 4.8). If an allergic reaction occurs, treatment with Zavicefta should be discontinued immediately and appropriate emergency measures should be taken.
Before initiating treatment with Zavicefta, it should be established whether the patient has a history of hypersensitivity reactions to ceftazidime, other cephalosporins, or other beta-lactam antibiotics. Caution should be exercised when prescribing ceftazidime/avibactam to patients with a history of non-severe hypersensitivity reactions to penicillins, monobactams, or carbapenems.
Clostridioides difficile–associated diarrhea
Clostridioides difficile-associated diarrhoea, which can range in severity from mild to life-threatening, has been reported with ceftazidime/avibactam. Therefore, it is important to consider the possibility of this diagnosis in patients who develop diarrhoea during or after the use of Zavicefta (see section 4.8).
Discontinuation of Zavicefta treatment and use of specific treatment directed against Clostridioides difficile should be considered. Medicinal products that inhibit intestinal motility should not be prescribed.
Kidney dysfunction
Ceftazidime and avibactam are excreted by the kidneys, so the dose of the drug should be reduced according to the severity of renal impairment (see section "Method of administration and dosage"). Occasionally, neurological disorders, including tremor, myoclonus, nonconvulsive status epilepticus, seizures, encephalopathy and coma, have been observed in patients with renal impairment treated with ceftazidime at a dose not reduced according to impaired renal function.
In patients with impaired renal function, careful monitoring of estimated creatinine clearance is recommended. In some patients, creatinine clearance, calculated from serum creatinine, may change rapidly, especially at the beginning of treatment for an infection.
Nephrotoxicity
The use of high doses of cephalosporins in combination with nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.
Direct antiglobulin test (PAT or Coombs test) for seroconversion and potential risk of hemolytic anemia
Ceftazidime/avibactam may cause a positive direct antiglobulin test (DAT or Coombs' test), which may interfere with cross-matching and/or cause drug-induced immune haemolytic anaemia (see section 4.8). Although seroconversion to DAT has been reported frequently in clinical trials in patients treated with Zavicefta (estimated seroconversion rates in phase 3 studies ranged from 3.2% to 20.8% in patients with a negative Coombs' test at baseline and at least one follow-up visit), no evidence of haemolysis has been observed in these patients during treatment. However, the possibility of haemolytic anaemia associated with Zavicefta therapy cannot be excluded. Therefore, patients with anaemia developing during or after treatment with Zavicefta should be evaluated for haemolytic anaemia.
Limitations of the clinical database
The clinical efficacy and safety of Zavicefta have been studied in complicated intra-abdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia, including ventilator-associated pneumonia.
In two studies of patients with complicated intra-abdominal infections, the most common diagnosis (approximately 42%) was appendiceal perforation or periappendiceal abscess. Approximately 87% of patients had an APACHE II score ≤ 10 and 4% had bacteremia at baseline. Deaths occurred in 2.1% (18 of 857) of patients receiving Zavicefta plus metronidazole and 1.4% (12 of 863) of patients receiving meropenem.
In the subgroup with baseline creatinine clearance between 30 and 50 mL/min, deaths were reported in 16.7% (9 of 54) of patients receiving Zavicefta and metronidazole and in 6.8% (4 of 59) of patients receiving meropenem. Patients with creatinine clearance between 30 and 50 mL/min received a lower dose of Zavicefta than recommended for this subgroup of patients.
Complicated urinary tract infections in adults
In two studies involving 1091 patients with complicated urinary tract infections, 381 (34.9%) patients with complicated urinary tract infections without pyelonephritis were included, while 710 (65.1%) patients had acute pyelonephritis (mMITT population). A total of 81 patients (7.4%) with complicated urinary tract infections had bacteremia at baseline.
Hospital-acquired pneumonia, including ventilator-associated pneumonia
In one study of adults with hospital-acquired pneumonia, 280 of 808 (34.7%) patients were diagnosed with ventilator-associated pneumonia and 40 of 808 (5%) had bacteremia at baseline.
Patients with limitations in the choice of antibacterial therapy
The use of ceftazidime/avibactam for the treatment of patients with Gram-negative aerobic infections with limited treatment options is based on experience with ceftazidime as monotherapy and an analysis of pharmacokinetic/pharmacodynamic data for ceftazidime/avibactam (see section 5.1).
Spectrum of activity of ceftazidime/avibactam
Ceftazidime has little or no activity against most gram-positive organisms and anaerobes (see sections 4.2 and 4.3). Additional antibacterial agents should be used if these organisms are suspected or confirmed to be involved in the infection.
The spectrum of inhibitory activity of avibactam includes many enzymes that can inactivate ceftazidime, including Ambler class A and C beta-lactamases. Avibactam does not inhibit class B enzymes (metallo-beta-lactamases) and is also unable to inhibit many class D beta-lactamases (see section 5.1).
Non-susceptible microorganisms
Prolonged use may result in overgrowth of non-susceptible organisms (such as enterococci, fungi), which may necessitate discontinuation of treatment or other appropriate measures.
Impact on laboratory test results
Ceftazidime does not affect the results of glycosuria determination by enzymatic methods, but may affect the results of the analysis (pseudo-positive result) when using copper recovery methods (Benedict, Fehling, Clinitest).
Sodium-controlled diet
Each vial of the drug contains approximately 146 mg of sodium, which is equivalent to 7.3% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.
The maximum daily dose of this medicine is equivalent to 22% of the WHO recommended maximum daily intake of sodium. Zavicefta is considered to be a high sodium medicine. This should be taken into consideration when administering Zavicefta to patients on a controlled sodium diet.
Zavicefta can be diluted with sodium-containing solutions (see section 6.2). This should be taken into account when determining the total amount of sodium to be administered to the patient.
Children
There is a potential risk of overdose, especially in children aged 3 to less than 12 months. Care should be taken when calculating the volume of the dose administered (see sections "Overdose" and "Method of administration").
Use during pregnancy or breastfeeding
Pregnancy
Animal studies with ceftazidime indicate no direct or indirect harmful effects with respect to pregnancy, intrauterine development, parturition or postnatal development. Animal studies have shown reproductive toxicity with avibactam, but no teratogenic effects have been observed.
Ceftazidime/avibactam should be used during pregnancy only if the potential benefit outweighs the potential risk.
Breast-feeding
Ceftazidime is excreted in human milk in small amounts. It is not known whether avibactam is excreted in human milk. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceftazidime/avibactam therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
The effect of ceftazidime/avibactam on human fertility has not been studied. There are no animal studies on the effect of ceftazidime on fertility. Animal studies have not shown any harmful effects of avibactam on fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Adverse reactions (e.g. dizziness) that may occur with the use of Zavicefta may affect the ability to drive and use machines (see section "Adverse reactions").
Method of administration and doses
Zavicefta is recommended for the treatment of infections caused by aerobic Gram-negative microorganisms in adults and children aged 3 months and older who have limited treatment options, only after consultation with a physician experienced in the treatment of infectious diseases (see section 4.4).
Dosage
Dose for adult patients with creatinine clearance (CrCL) > 50 mL/min
Table 1 provides recommendations for intravenous dosing in adults with estimated creatinine clearance (CrCL) > 50 mL/min (see sections 4.4 and 5.1).
Table 1
Recommended dosage regimen for adults with estimated CrCL > 50 mL/min1
| Type of infection | Ceftazidime/avibactam dose | Input frequency | Infusion duration | Duration of treatment |
| Complicated intra-abdominal infection2,3 | 2 g/0.5 g | Every 8 hours | 2 hours | 5-14 days |
| Complicated urinary tract infections, including pyelonephritis3 | 2 g/0.5 g | Every 8 hours | 2 hours | 5–10 days4 |
| Hospital-acquired pneumonia, including ventilator-associated pneumonia3 | 2 g/0.5 g | Every 8 hours | 2 hours | 7–14 days |
| Bacteremia resulting from, or suspected to be associated with, any of the above infections | 2 g/0.5 g | Every 8 hours | 2 hours | The duration of treatment depends on the site of infection. |
| Infections caused by gram-negative aerobic microorganisms in patients with limited choice of antibacterial therapy 2,3 | 2 g/0.5 g | Every 8 hours | 2 hours | Depending on the severity of the infection, the pathogen(s), the clinical and bacteriological course of the disease5 |
1 Creatinine clearance is calculated using the Cockcroft–Gault formula.
2 If anaerobic pathogenic microorganisms are confirmed or suspected to be involved in the infectious process, the drug should be used in combination with metronidazole.
3 If the involvement of gram-positive pathogenic microorganisms in the infectious process is confirmed or suspected, the drug should be used in combination with an antibacterial drug effective against these microorganisms.
4 The indicated duration of treatment may include a period of intravenous Zavicefta therapy followed by a transition to the required oral medicinal product.
5 Experience with the use of Zavicefta for more than 14 days is very limited.
Dosage for children with creatinine clearance (CrCL) > 50 mL/min/1.73 m2
Table 2
Recommended dosage regimen for children with estimated CrCL1> 50 mL/min/1.73 m2
| Type of infection | Age group | Ceftazidime dose/ avibactam | Input frequency | Infusion duration | Duration of treatment |
|---|
Complicated intra-abdominal infections2,3 OR Complicated urinary tract infections, including pyelonephritis3, OR Hospital-acquired pneumonia/Ventilator-associated pneumonia3, OR Infections caused by Gram-negative aerobic microorganisms in patients with limited treatment options2,3 | from 6 months to < 18 years | 50 mg/kg/12.5 mg/kg maximum up to 2 g/0.5 g | Every 8 hours | 2 hours | Complicated intra-abdominal infections: 5–14 days Complicated urinary tract infections4: 5–14 days Hospital-acquired pneumonia/ Ventilator-associated pneumonia: 7–14 days Limitations on treatment options: depending on the severity of the infection, pathogen(s), clinical and bacteriological course of the disease5 |
| Every 8 hours | 2 hours |
| From 3 to < 6 months6 | 40 mg/kg/10 mg/kg | Every 8 hours | 2 hours |
1Creatinine clearance is calculated for children using the Schwartz formula.
2If anaerobic pathogenic microorganisms are confirmed or suspected to be involved in the infectious process, the drug should be used in combination with metronidazole.
3If gram-positive pathogenic microorganisms are confirmed or suspected to be involved in the infectious process, the drug should be used in combination with an antibacterial drug effective against these microorganisms.
4The indicated duration of treatment may include intravenous Zavicefta therapy followed by a transition to the required oral medicinal product.
5Experience with the use of Zavicefta for more than 14 days is very limited.
6Experience with Zaviceft in the treatment of children aged 3 to < 6 months is limited (see Pharmacokinetics).
Special patient groups
Elderly patients
There is no need for dose adjustment in elderly patients (see section "Pharmacokinetics").
Kidney dysfunction
Table 3 shows the recommended dose adjustment for adult patients with estimated creatinine clearance ≤ 50 mL/min (see sections 4.4 and 5.2).
Dose for adult patients with CrCL ≤ 50 mL/min
Table 3
Recommended dosage regimen for adults with estimated CrCL1≤ 50 mL/min
| Age group | Estimated CrCL (ml/min) | Ceftazidime dose/ avibactam2 | Frequency | Infusion duration |
|---|
| Adults | 31–50 | 1 g/0.25 g | Every 8 hours | 2 hours |
| 16–30 | 0.75 g/0.1875 g | Every 12 hours |
| 6–15 | Every 24 hours |
| End-stage renal disease, including hemodialysis3 | Every 48 hours |
1Creatinine clearance is calculated using the Cockcroft-Golte formula.
2Dosage recommendations are based on pharmacokinetic modeling (see Pharmacokinetics section).
3Ceftazidime and avibactam are removed by haemodialysis (see sections 4.4 and 4.5). On haemodialysis days, Zavicefta should be administered after the haemodialysis procedure is completed.
Tables 4 and 5 show the recommended dose adjustment for children with estimated CrCL ≤ 50 mL/min/1.73 m2 depending on the different age groups (see sections “Special instructions for use” and “Pharmacokinetics”).
Dosage for children ≥ 2 years of age with CrCl ≤ 50 mL/min/1.73 m2
Table 4
Recommended dosage regimen for children with estimated CrCL1 ≤ 50 mL/min/1.73 m2
| Age group | Estimated CrCL (ml/min/1.73 m2) | Ceftazidime/avibactam dose2 | Frequency | Infusion duration |
|---|
| Children from 2 years to < 18 years | 31–50 | 25 mg/kg/6.25 mg/kg maximum up to 1 g/0.25 g | Every 8 hours | 2 hours |
| 16–30 | 18.75 mg/kg/4.75 mg/kg maximum up to 0.75 g/0.1875 g | Every 12 hours |
| 6–15 | Every 24 hours |
| End-stage renal disease, including hemodialysis3 | Every 48 hours |
1Creatinine clearance is calculated using the Schwartz formula.
2Dosage recommendations are based on pharmacokinetic modeling (see Pharmacokinetics section).
3Ceftazidime and avibactam are removed by hemodialysis (see sections “Overdose” and “Pharmacokinetics”). On hemodialysis days, Zavicefta should be administered after the hemodialysis procedure is completed.
Dosage for children < 2 years of age with CrCl ≤ 50 mL/min/1.73 m2
Table 5
Recommended dosage regimen for children with estimated CrCL1 ≤ 50 mL/min/1.73 m2
| Age group | Estimated CrCL (mL/min/1.73 m2) | Ceftazidime/avibactam dose2 | Frequency | Infusion duration |
|---|
| from 3 to < 6 months | from 31 to 50 | 20 mg/kg/5 mg/kg | Every 8 hours | 2 hours |
| from 6 months to < 2 years | 25 mg/kg/6.25 mg/kg | Every 8 hours |
| from 3 to < 6 months | from 16 to 30 | 15 mg/kg/3.75 mg/kg | Every 12 hours |
| from 6 months to < 2 years | 18.75 mg/kg/4.7 mg/kg | Every 12 hours |
1Calculated using the Schwartz formula. 2Dosage recommendations are based on pharmacokinetic modeling (see Pharmacokinetics section). |
There is insufficient information to recommend a dosing regimen for children < 2 years of age who have a creatinine clearance < 16 mL/min/1.73 m2.
Liver dysfunction
No dose adjustment is necessary in patients with hepatic impairment (see Pharmacokinetics).
Children
The safety and efficacy of Zaviceft in children under 3 months of age have not been established. Data are not available.
Method of application
Zavicefta is administered by intravenous infusion over 120 minutes in the required volume for infusion therapy.
The powder must be reconstituted with water for injection and the resulting concentrate must be diluted immediately before use. The reconstituted solution for infusion is pale yellow in color and free from foreign particles.
Zavicefta (ceftazidime/avibactam) is a combination product; each vial contains 2 g of ceftazidime and 0.5 g of avibactam in a fixed ratio of 4:1. Dosage recommendations are based on the single dose only.
