Leaflet ZAVICEFTA 2g / 0.5g powder for concentrate infusion solution
Indicated for: bacterial infections
Route of administration: infusion
Substance: ceftazidime + avibactam (cephalosporin antibiotic + beta-lactam antibiotic)
ATC: J01DD52 (Antiinfectives for systemic use | Other beta-lactam antibacterials | Third-generation cephalosporins)
The combination of ceftazidime and avibactam is an antibiotic used to treat severe bacterial infections, particularly those caused by bacteria resistant to other antibiotics. Ceftazidime is a third-generation cephalosporin that works by inhibiting bacterial cell wall synthesis, leading to bacterial death. Avibactam is a beta-lactamase inhibitor that protects ceftazidime from enzymatic degradation by beta-lactamases, including some extended-spectrum beta-lactamases (ESBLs) and carbapenemases.
This combination is indicated for the treatment of complicated infections, such as:
- Complicated intra-abdominal infections (in combination with metronidazole).
- Complicated urinary tract infections, including pyelonephritis.
- Nosocomial pneumonia, including ventilator-associated pneumonia.
- Infections caused by resistant Gram-negative bacteria, such as Klebsiella pneumoniae or Pseudomonas aeruginosa.
Common side effects include nausea, diarrhea, headache, injection site reactions, and skin rashes. Rarely, severe allergic reactions such as anaphylaxis or liver dysfunction may occur. Renal function should be monitored, as the dose needs to be adjusted in patients with renal impairment.
Ceftazidime + avibactam is administered intravenously under medical supervision, and the duration of treatment depends on the type and severity of the infection. The use of this antibiotic should be reserved for cases where other therapeutic options are not suitable, to prevent the development of bacterial resistance.
General data about ZAVICEFTA 2g / 0.5g
- Substance: ceftazidime + avibactam
- Date of last drug list: 01-05-2026
- Commercial code: W63728001
- Concentration: 2g / 0.5g
- Pharmaceutical form: powder for concentrate infusion solution
- Quantity: 10
- Product type: original
- Price: 5667.65 RON
- Prescription restrictions: P-RF - Medicines prescription that is retained in the pharmacy (not renewable).
Leaflet ZAVICEFTA 2g/0.5g
Contents of the package leaflet for the medicine ZAVICEFTA 2g / 0.5g powder for concentrate infusion solution
1. NAME OF THE MEDICINAL PRODUCT
Zavicefta 2 g/0.5 g powder for concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains ceftazidime pentahydrate equivalent to 2 g ceftazidime and avibactam sodiumequivalent to 0.5 g avibactam.
After reconstitution, 1 mL of solution contains 167.3 mg of ceftazidime and 41.8 mg of avibactam (seesection 6.6).
Excipient with known effect:Zavicefta contains approximately 146 mg sodium per vial.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion (powder for concentrate).
A white to yellow powder.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Zavicefta is indicated in adults and paediatric patients aged 3 months and older for the treatment of thefollowing infections (see sections 4.4 and 5.1):
- Complicated intra-abdominal infection (cIAI)
- Complicated urinary tract infection (cUTI), including pyelonephritis
- Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP)
Treatment of adult patients with bacteraemia that occurs in association with, or is suspected to beassociated with, any of the infections listed above.
Zavicefta is also indicated for the treatment of infections due to aerobic Gram-negative organisms inadults and paediatric patients aged 3 months and older with limited treatment options (see sections 4.2,4.4 and 5.1).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
It is recommended that Zavicefta should be used to treat infections due to aerobic Gram-negativeorganisms in adults and paediatric patients aged 3 months and older with limited treatment optionsonly after consultation with a physician with appropriate experience in the management of infectiousdiseases (see section 4.4).
PosologyDosage in adults with creatinine clearance (CrCL) > 50 mL/min
Table 1 shows the recommended intravenous dose for adults with estimated creatinine clearance(CrCL) > 50 mL/min (see sections 4.4 and 5.1).
Table 1: Recommended dose for adults with estimated CrCL > 50 mL/min1
Type of infection Dose of Frequency Infusion Duration of treatmentceftazidime/avibactam timecIAI2,3 2 g/0.5 g Every 2 hours 5-14 days8 hourscUTI, including 2 g/0.5 g Every 2 hours 5-10 days4pyelonephritis3 8 hours
HAP/VAP3 2 g/0.5 g Every 2 hours 7-14 days8 hours
Bacteraemia associated 2 g/0.5 g Every 2 hours Duration of treatmentwith, or suspected to be 8 hours should be inassociated with any of accordance with thethe above infections site of infection.
Infections due to 2 g/0.5 g Every 2 hours Guided by the severityaerobic Gram-negative 8 hours of the infection, theorganisms in patients pathogen(s) and thewith limited treatment patient’s clinical andoptions2,3 bacteriologicalprogress51 CrCL estimated using the Cockcroft-Gault formula.2 To be used in combination with metronidazole when anaerobic pathogens are known or suspected tobe contributing to the infectious process.3 To be used in combination with an antibacterial agent active against Gram-positive pathogens whenthese are known or suspected to be contributing to the infectious process.4 The total duration shown may include intravenous Zavicefta followed by appropriate oral therapy.5 There is very limited experience with the use of Zavicefta for more than 14 days.
Dosage in paediatric patients with creatinine clearance (CrCL) > 50 mL/min/1.73 m2
Table 2 shows the recommended intravenous doses for paediatric patients with estimated creatinineclearance (CrCL) > 50 mL/min/1.73 m2 (see sections 4.4 and 5.1).
Table 2: Recommended dose for paediatric patients with estimated CrCL1 > 50 mL/min/1.73 m2
Type of Age group Dose of Frequency Infusion time Duration ofinfection ceftazidime/avibactam7 treatmentcIAI2,350 mg/kg/12.5 mg/kg
OR Every 86 months to 2 hours cIAI: 5 - 14cUTI including to a maximum of hours<18 years dayspyelonephritis32 g/0.5 gcUTI4: 5 - 14
OR Every 8 days2 hourshours
HAP/VAP3 HAP/VAP:7 - 14 days
OR
LTO: Guided
Infections due by the severityto aerobic of the
Gram-negative 3 months to Every 8 infection, theorganisms in 6 40 mg/kg/10 mg/kg 2 hours<6 months hours pathogen(s)patients with and thelimited patient’streatment clinical andoptions bacteriological(LTO)2,3 progress51 CrCL estimated using the Schwartz bedside formula.2 To be used in combination with metronidazole when anaerobic pathogens are known or suspected tobe contributing to the infectious process.3 To be used in combination with an antibacterial agent active against Gram-positive pathogens whenthese are known or suspected to be contributing to the infectious process.4 The total treatment duration shown may include intravenous Zavicefta followed by appropriate oraltherapy.5 There is very limited experience with the use of Zavicefta for more than 14 days.6 There is limited experience with the use of Zavicefta in paediatric patients 3 months to < 6 months(see section 5.2).7 Ceftazidime/avibactam is a combination product in a fixed 4:1 ratio and dosage recommendations arebased on the ceftazidime component only (see section 6.6).
Special populationsElderly
No dosage adjustment is required in elderly patients (see section 5.2).
Renal impairmentNo dosage adjustment is required in patients with mild renal impairment (estimated CrCL> 50 - ≤ 80 mL/min) (see section 5.2).
Table 3 shows the recommended dose adjustments for adults with estimated CrCL ≤ 50 mL/min (seesections 4.4 and 5.2).
Dosage in adults with CrCL ≤ 50 mL/min
Table 3: Recommended dose for adults with estimated CrCL1 ≤ 50 mL/min
Age Group Estimated CrCL Dose of Frequency Infusion(mL/min) ceftazidime/avibactam2,4 time
Adults Every31-50 1 g/0.25 g8 hours
Every16-3012 hours
Every6-15 2 hours0.75 g/0.1875 g 24 hours
End Stage Renal Diseaseincluding on haemodialysis3 Every48 hours1 CrCL estimated using the Cockcroft-Gault formula.2 Dose recommendations are based on pharmacokinetic modelling (see section 5.2).3 Ceftazidime and avibactam are removed by haemodialysis (see sections 4.9 and 5.2). Dosing of
Zavicefta on haemodialysis days should occur after completion of haemodialysis.4 Ceftazidime/avibactam is a combination product in a fixed 4:1 ratio and dosage recommendations arebased on the ceftazidime component only (see section 6.6).
Table 4 and Table 5 show the recommended dose adjustments for paediatric patients with estimated
CrCL ≤ 50 mL/min/1.73 m2 according to different age groups (see sections 4.4 and 5.2).
Dosage in paediatric patients ≥ 2 years of age with CrCl ≤ 50 mL/min/1.73 m2
Table 4: Recommended dose for paediatric patients with estimated CrCL1 ≤ 50 mL/min/1.73 m2
Age Group Estimated CrCL Dose of Frequency Infusion(mL/min/1.73 m2) ceftazidime/avibactam2,4 time25 mg/kg/6.25 mg/kgto a maximum of Every31-508 hours1 g/0.25 g
Every16-30
Paediatric 12 hours2 hourspatients aged 18.75 mg/kg/4.7 mg/kg2 years to<18 years to a maximum of0.75 g/0.1875 g Every6-1524 hours
End Stage Renal Disease Everyincluding on haemodialysis3 48 hours1 CrCL estimated using the Schwartz bedside formula.2 Dose recommendations are based on pharmacokinetic modelling (see section 5.2).3 Ceftazidime and avibactam are removed by haemodialysis (see sections 4.9 and 5.2). Dosing of
Zavicefta on haemodialysis days should occur after completion of haemodialysis.
4 Ceftazidime/avibactam is a combination product in a fixed 4:1 ratio and dosage recommendations arebased on the ceftazidime component only (see section 6.6).
Dosage in paediatric patients <2 years of age with CrCl ≤ 50 mL/min/1.73 m2
Table 5: Recommended dose for paediatric patients with estimated CrCL1 ≤ 50 mL/min/1.73 m2
Age Estimated CrCL Dose of Frequency Infusion
Group (mL/min/1.73 m2) ceftazidime/avibactam2,3 time3 to < 6 Every20 mg/kg/5 mg/kgmonths 8 hours31 to 506 months Everyto < 2 25 mg/kg/6.25 mg/kg8 hoursyears2 hours3 to < 6 Every15 mg/kg/3.75 mg/kgmonths 12 hours16 to 306 months
Everyto < 2 18.75 mg/kg/4.7 mg/kg12 hoursyears1 Calculated using the Schwartz bedside formula2 Dose recommendations are based on pharmacokinetic modelling (see section 5.2).3 Ceftazidime/avibactam is a combination product in a fixed 4:1 ratio and dosage recommendations arebased on the ceftazidime component only (see section 6.6).
There is insufficient information to recommend a dosage regimen for paediatric patients < 2 years ofage that have a CrCL < 16 mL/min/1.73 m2.
Hepatic impairmentNo dosage adjustment is required in patients with hepatic impairment (see section 5.2).
Paediatric populationThe safety and efficacy of Zavicefta in paediatric patients < 3 months old have not been established.
No data are available.
Method of administrationIntravenous use.
Zavicefta is administered by intravenous infusion over 120 minutes in an appropriate infusion volume(see section 6.6).
For instructions on reconstitution and dilution of the medicinal product before administration seesection 6.6.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Hypersensitivity to any cephalosporin antibacterial agent.
Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of β-lactamantibacterial agent (e.g. penicillins, monobactams or carbapenems).
4.4 Special warnings and precautions for use
Serious and occasionally fatal hypersensitivity reactions are possible (see sections 4.3 and 4.8). In caseof hypersensitivity reactions, treatment with Zavicefta must be discontinued immediately and adequateemergency measures must be initiated.
Before beginning treatment, it should be established whether the patient has a history ofhypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactamantibacterial agent. Caution should be used if ceftazidime/avibactam is given to patients with a historyof non-severe hypersensitivity to penicillins, monobactams or carbapenems.
Clostridioides difficile - associated diarrhoea
Clostridioides difficile - associated diarrhoea has been reported with ceftazidime/avibactam, and canrange in severity from mild to life-threatening. This diagnosis should be considered in patients whopresent with diarrhoea during or subsequent to the administration of Zavicefta (see section 4.8).
Discontinuation of therapy with Zavicefta and the administration of specific treatment for
Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not begiven.
Renal impairmentCeftazidime and avibactam are eliminated via the kidneys, therefore, the dose should be reducedaccording to the degree of renal impairment (see section 4.2). Neurological sequelae, including tremor,myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, haveoccasionally been reported with ceftazidime when the dose has not been reduced in patients with renalimpairment.
In patients with renal impairment, close monitoring of estimated creatinine clearance is advised. Insome patients, the creatinine clearance estimated from serum creatinine can change quickly, especiallyearly in the course of treatment for the infection.
NephrotoxicityConcurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such asaminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.
Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of haemolyticanaemia
Ceftazidime/avibactam use may cause development of a positive direct antiglobulin test (DAGT, or
Coombs test), which may interfere with the cross-matching of blood and/or may cause drug inducedimmune haemolytic anaemia (see section 4.8). While DAGT seroconversion in patients receiving
Zavicefta was very common in clinical studies (the estimated range of seroconversion across Phase 3studies was 3.2% to 20.8% in patients with a negative Coombs test at baseline and at least onefollow-up test), there was no evidence of haemolysis in patients who developed a positive DAGT ontreatment. However, the possibility that haemolytic anaemia could occur in association with Zaviceftatreatment cannot be ruled out. Patients experiencing anaemia during or after treatment with Zaviceftashould be investigated for this possibility.
Limitations of the clinical data
Clinical efficacy and safety studies of Zavicefta have been conducted in cIAI, cUTI and HAP(including VAP).
Complicated intra-abdominal infections in adults
In two studies in patients with cIAI, the most common diagnosis (approximately 42%) wasappendiceal perforation or peri-appendiceal abscess. Approximately 87% of patients had APACHE IIscores of ≤ 10 and 4% had bacteraemia at baseline. Death occurred in 2.1% (18/857) of patients whoreceived Zavicefta and metronidazole and in 1.4% (12/863) of patients who received meropenem.
Among a subgroup with baseline CrCL 30 to 50 mL/min death occurred in 16.7% (9/54) of patientswho received Zavicefta and metronidazole and 6.8% (4/59) of patients who received meropenem.
Patients with CrCL 30 to 50 mL/min received a lower dose of Zavicefta than is currentlyrecommended for patients in this sub-group.
Complicated urinary tract infections in adults
In two studies in patients with cUTI, 381/1091 (34.9%) patients were enrolled with cUTI withoutpyelonephritis while 710 (65.1%) were enrolled with acute pyelonephritis (mMITT population). Atotal of 81 cUTI patients (7.4%) had bacteraemia at baseline.
Hospital-acquired pneumonia (including ventilator-associated pneumonia) in adults
In a single study in patients with nosocomial pneumonia 280/808 (34.7%) had VAP and 40/808 (5%)were bacteraemic at baseline.
Patients with limited treatment options
The use of ceftazidime/avibactam to treat patients with infections due to Gram-negative aerobicpathogens who have limited treatment options is based on experience with ceftazidime alone and onanalyses of the pharmacokinetic-pharmacodynamic relationship for ceftazidime/avibactam (seesection 5.1).
Spectrum of activity of ceftazidime/avibactam
Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes(see sections 4.2 and 5.1). Additional antibacterial agents should be used when these pathogens areknown or suspected to be contributing to the infectious process.
The inhibitory spectrum of avibactam includes many of the enzymes that inactivate ceftazidime,including Ambler class A β-lactamases and class C β-lactamases. Avibactam does not inhibit class Benzymes (metallo-β-lactamases) and is not able to inhibit many of the class D enzymes (seesection 5.1).
Non-susceptible organisms
Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. enterococci, fungi),which may require interruption of treatment or other appropriate measures.
Interference with laboratory testsCeftazidime may interfere with copper reduction methods (Benedict's, Fehling's, Clinitest) fordetection of glycosuria leading to false positive results. Ceftazidime does not interfere with enzyme-based tests for glycosuria.
Controlled sodium diet
This medicinal product contains approximately 146 mg sodium per vial, equivalent to 7.3% of the
WHO recommended maximum daily intake (RDI) of 2 g sodium for an adult.
The maximum daily dose of this product is equivalent to 22% of the WHO recommended maximumdaily intake for sodium. Zavicefta is considered high in sodium. This should be considered whenadministering Zavicefta to patients who are on a controlled sodium diet.
Zavicefta may be diluted with sodium-containing solutions (see section 6.6) and this should beconsidered in relation to the total sodium from all sources that will be administered to the patient.
Paediatric populationThere is a potential risk of overdosing, particularly for paediatric patients aged from 3 to less than12 months of age. Care should be taken when calculating the volume of administration of the dose (seesections 4.9 and 6.6).
4.5 Interaction with other medicinal products and other forms of interaction
In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the activeuptake of avibactam from the blood compartment and, therefore, affect its excretion. Probenecid (apotent OAT inhibitor) inhibits this uptake by 56% to 70% in vitro and, therefore, has the potential toalter the elimination of avibactam. Since a clinical interaction study of avibactam and probenecid hasnot been conducted, co-administration of avibactam with probenecid is not recommended.
Avibactam showed no significant inhibition of cytochrome P450 enzymes in vitro. Avibactam andceftazidime showed no in vitro cytochrome P450 induction at clinically relevant concentrations.
Avibactam and ceftazidime do not inhibit the major renal or hepatic transporters in the clinicallyrelevant exposure range, therefore the interaction potential via these mechanisms is considered to below.
Clinical data have demonstrated that there is no interaction between ceftazidime and avibactam, andbetween ceftazidime/avibactam and metronidazole.
Other types of interaction
Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such asaminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function (seesection 4.4).
Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinicalrelevance of this finding is unknown, but due to the possibility of antagonism in vivo this drugcombination should be avoided.
4.6 Fertility, pregnancy and lactation
Animal studies with ceftazidime do not indicate direct or indirect harmful effects with respect topregnancy, embryonal/foetal development, parturition or postnatal development. Animal studies withavibactam have shown reproductive toxicity without evidence of teratogenic effects (see section 5.3).
Ceftazidime/avibactam should only be used during pregnancy if the potential benefit outweighs thepossible risk.
Breast-feedingCeftazidime is excreted in human milk in small quantities. It is unknown whether avibactam isexcreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be madewhether to discontinue breast feeding or to discontinue/abstain from ceftazidime/avibactam therapytaking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
FertilityThe effects of ceftazidime/avibactam on fertility in humans have not been studied. No data areavailable on animal studies with ceftazidime. Animal studies with avibactam do not indicate harmfuleffects with respect to fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
Undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and usemachines following administration of Zavicefta (see section 4.8).
4.8 Undesirable effects
In seven Phase 2 and Phase 3 clinical trials, 2024 adults were treated with Zavicefta. The mostcommon adverse reactions occurring in ≥5% of patients treated with Zavicefta were Coombs directtest positive, nausea, and diarrhoea. Nausea and diarrhoea were usually mild or moderate in intensity.
Tabulated list of adverse reactionsThe following adverse reactions have been reported with ceftazidime alone and/or identified during the
Phase 2 and Phase 3 trials with Zavicefta. Adverse reactions are classified according to frequency and
System Organ Class. Frequency categories are derived from adverse reactions and/or potentiallyclinically significant laboratory abnormalities, and are defined according to the following conventions:
Very common (≥1/10)
Common (≥1/100 and <1/10)
Uncommon (≥1/1,000 and <1/100)
Rare (≥1/10,000 and <1/1000)
Very rare (<1/10,000)
Unknown (cannot be estimated from the available data)
Table 6: Frequency of adverse reactions by system organ class
System Organ Very Common Uncommon Very rare Unknown
Class common
Infections and Candidiasis Clostridioidesinfestations (including difficile colitis
Vulvovaginalcandidiasis and Pseudomembran
Oral candidiasis) ous colitis
Blood and Coombs Eosinophilia Neutropenia Agranulocytosislymphatic direct testsystem positive Thrombocytosis Leukopenia Haemolyticdisorders anaemia
Thrombocytopenia Lymphocytosis
Immune system Anaphylacticdisorders reaction
Nervous system Headache Paraesthesiadisorders
Dizziness
Gastrointestinal Diarrhoea Dysgeusiadisorders
Abdominal pain
System Organ Very Common Uncommon Very rare Unknown
Class common
Nausea
VomitingHepatobiliary Alanine Jaundicedisorders aminotransferaseincreased
Aspartateaminotransferaseincreased
Blood alkalinephosphataseincreased
Gamma-glutamyltransferaseincreased
Blood lactatedehydrogenase
Increased
Skin and Rash maculo- Toxic epidermalsubcutaneous papular necrolysistissue disorders
Urticaria Stevens-Johnsonsyndrome
Pruritus
Erythemamultiforme
AngioedemaDrug Reactionwith Eosinophiliaand Systemic
Symptoms(DRESS)
Renal and Blood creatinine Tubulointerstitialurinary increased nephritisdisorders
Blood ureaincreased
Acute kidneyinjury
System Organ Very Common Uncommon Very rare Unknown
Class common
General Infusion sitedisorders and thrombosisadministrationsite conditions Infusion sitephlebitis
PyrexiaPaediatric population
The safety assessment in paediatric patients is based on the safety data from two trials in which61 patients (aged from 3 years to less than 18 years) with cIAI and 67 patients with cUTI (aged from3 months to less than 18 years) received Zavicefta. Overall, the safety profile in these 128 paediatricpatients was similar to that observed in the adult population with cIAI and cUTI.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
Overdose with ceftazidime/avibactam can lead to neurological sequelae including encephalopathy,convulsions and coma, due to the ceftazidime component.
Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis. During a 4-hourhaemodialysis period, 55% of the avibactam dose was removed.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, other beta-lactam antibacterials,third-generation cephalosporins, ATC code: J01DD52
Mechanism of actionCeftazidime inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin bindingproteins (PBPs), which leads to bacterial cell lysis and death. Avibactam is a non β-lactam,β-lactamase inhibitor that acts by forming a covalent adduct with the enzyme that is stable tohydrolysis. It inhibits both Ambler class A and class C β-lactamases and some class D enzymes,including extended-spectrum β-lactamases (ESBLs), KPC and OXA-48 carbapenemases, and AmpCenzymes. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibitmany class D enzymes.
ResistanceBacterial resistance mechanisms that could potentially affect ceftazidime/avibactam include mutant oracquired PBPs, decreased outer membrane permeability to either compound, active efflux of eithercompound, and β-lactamase enzymes refractory to inhibition by avibactam and able to hydrolyseceftazidime.
Antibacterial activity in combination with other antibacterial agents
No synergy or antagonism was demonstrated in in vitro drug combination studies withceftazidime/avibactam and metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistinand tigecycline.
Susceptibility testing breakpoints
Minimum Inhibitory Concentration (MIC) breakpoints established by the European Committee on
Antimicrobial Susceptibility Testing (EUCAST) for ceftazidime/avibactam are as follows:
Organisms Susceptible Resistant
Enterobacterales ≤8 mg/L >8 mg/L
Pseudomonas aeruginosa ≤8 mg/L >8 mg/L
Pharmacokinetic/pharmacodynamic relationshipThe antimicrobial activity of ceftazidime against specific pathogens has been shown to best correlatewith the percent time of free-drug concentration above the ceftazidime/avibactam minimum inhibitoryconcentration over the dose interval (% fT >MIC of ceftazidime/avibactam). For avibactam the PK-PDindex is the percent time of the free drug concentration above a threshold concentration over the doseinterval (% fT >CT).
Clinical efficacy against specific pathogens
Efficacy has been demonstrated in clinical studies against the following pathogens that weresusceptible to ceftazidime/avibactam in vitro.
Complicated intra-abdominal infections
Gram-negative micro-organisms
- Citrobacter freundii
- Enterobacter cloacae
- Escherichia coli
- Klebsiella oxytoca
- Klebsiella pneumoniae
- Pseudomonas aeruginosa
Complicated urinary-tract infections
Gram-negative micro-organisms
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- Enterobacter cloacae
- Pseudomonas aeruginosa
Hospital-acquired pneumonia including ventilator-associated pneumonia
Gram-negative micro-organisms
- Enterobacter cloacae
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- Serratia marcescens
- Pseudomonas aeruginosa
Clinical efficacy has not been established against the following pathogens that are relevant to theapproved indications although in vitro studies suggest that they would be susceptible toceftazidime/avibactam in the absence of acquired mechanisms of resistance.
Gram-negative micro-organisms
- Citrobacter koseri
- Enterobacter aerogenes
- Morganella morganii
- Proteus vulgaris
- Providencia rettgeri
In-vitro data indicate that the following species are not susceptible to ceftazidime/avibactam.
- Staphylococcus aureus (methicillin-susceptible and methicillin-resistant)
- Anaerobes
- Enterococcus spp.
- Stenotrophomonas maltophilia
- Acinetobacter spp.
Paediatric populationZavicefta has been evaluated in paediatric patients aged 3 months to < 18 years in two Phase 2single-blind, randomised, comparative clinical studies, one in patients with cIAI and one in patientswith cUTI. The primary objective in each study was to assess safety and tolerability ofceftazidime-avibactam (+/- metronidazole). Secondary objectives included assessment ofpharmacokinetics and efficacy; efficacy was a descriptive endpoint in both studies. Clinical cure rate at
TOC (ITT) was 91.8% (56/61) for Zavicefta compared to 95.5% (21/22) for meropenem in paediatricpatients with cIAI. Microbiological eradication rate at TOC (micro-ITT) was 79.6% (43/54) for
Zavicefta compared to 60.9% (14/23) for cefepime in paediatric patients with cUTI.
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 in the treatment of cIAI, cUTI,pneumonia and Gram-negative bacterial infections (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The human protein binding of both ceftazidime and avibactam is approximately 10% and 8%,respectively. The steady-state volumes of distribution of ceftazidime and avibactam were about 17 Land 22 L, respectively in healthy adults following multiple doses of 2 g/0.5 g ceftazidime/avibactaminfused over 2 hours every 8 hours. Both ceftazidime and avibactam penetrate into human bronchialepithelial lining fluid (ELF) to the same extent with concentrations around 30% of those in plasma.
The concentration time profiles are similar for ELF and plasma.
Penetration of ceftazidime into the intact blood-brain barrier is poor. Ceftazidime concentrations of4 to 20 mg/L or more are achieved in the CSF when the meninges are inflamed. Avibactam penetrationof the blood brain barrier has not been studied clinically; however, in rabbits with inflamed meninges,
CSF exposures of ceftazidime and avibactam were 43% and 38% of plasma AUC, respectively.
Ceftazidime crosses the placenta readily, and is excreted in the breast milk.
BiotransformationCeftazidime is not metabolised. No metabolism of avibactam was observed in human liverpreparations (microsomes and hepatocytes). Unchanged avibactam was the major drug-relatedcomponent in human plasma and urine following dosing with [14C]-avibactam.
EliminationThe terminal half-life (t½) of both ceftazidime and avibactam is about 2 h after intravenousadministration. Ceftazidime is excreted unchanged into the urine by glomerular filtration;approximately 80-90% of the dose is recovered in the urine within 24 h. Avibactam is excretedunchanged into the urine with a renal clearance of approximately 158 mL/min, suggesting activetubular secretion in addition to glomerular filtration. Approximately 97% of the avibactam dose isrecovered in the urine, 95% within 12 h. Less than 1% of ceftazidime is excreted via the bile and lessthan 0.25% of avibactam is excreted into faeces.
Linearity/non-linearityThe pharmacokinetics of both ceftazidime and avibactam are approximately linear across the doserange studied (0.05 g to 2 g) for a single intravenous administration. No appreciable accumulation ofceftazidime or avibactam was observed following multiple intravenous infusions of 2 g/0.5 g ofceftazidime/avibactam administered every 8 hours for up to 11 days in healthy adults with normalrenal function.
Special populationsRenal impairment
Elimination of ceftazidime and avibactam is decreased in patients with moderate or severe renalimpairment. The average increases in avibactam AUC are 3.8-fold and 7-fold in subjects withmoderate and severe renal impairment, see section 4.2.
Hepatic impairmentMild to moderate hepatic impairment had no effect on the pharmacokinetics of ceftazidime inindividuals administered 2 g intravenously every 8 hours for 5 days, provided renal function was notimpaired. The pharmacokinetics of ceftazidime in patients with severe hepatic impairment has notbeen established. The pharmacokinetics of avibactam in patients with any degree of hepaticimpairment has not been studied.
As ceftazidime and avibactam do not appear to undergo significant hepatic metabolism, the systemicclearance of either active substance is not expected to be significantly altered by hepatic impairment.
Elderly patients (≥65 years)Reduced clearance of ceftazidime was observed in elderly patients, which was primarily due toage-related decrease in renal clearance of ceftazidime. The mean elimination half-life of ceftazidimeranged from 3.5 to 4 hours following intravenous bolus dosing with 2 g every 12 hours in elderlypatients aged 80 years or older.
Following a single intravenous administration of 500 mg avibactam as a 30-minute IV infusion, theelderly had a slower terminal half-life of avibactam, which may be attributed to age related decrease inrenal clearance.
Paediatric populationThe pharmacokinetics of ceftazidime and avibactam were evaluated in paediatric patients from3 months to < 18 years of age with suspected or confirmed infections following a single dose ofceftazidime 50 mg/kg and avibactam 12.5 mg/kg for patients weighing < 40 kg or Zavicefta 2 g/0.5 g(ceftazidime 2 grams and avibactam 0.5 grams) for patients weighing ≥ 40 kg. Plasma concentrationsof ceftazidime and avibactam were similar across all four age cohorts in the study (3 months to< 2 years, 2 to < 6 years, 6 to < 12 years, and 12 to < 18 years). Ceftazidime and avibactam AUC0-t and
Cmax values in the two older cohorts (paediatric patients from 6 to < 18 years), which had moreextensive pharmacokinetic sampling, were similar to those observed in healthy adult subjects withnormal renal function that received Zavicefta 2 g/0.5 g. Data from this study and the two Phase 2paediatric studies in patients with cIAI and cUTI were pooled with PK data from adults (Phase 1 to
Phase 3) to update the population PK model, which was used to conduct simulations to assess PK/PDtarget attainment. Results from these simulations demonstrated that the recommended dose regimensfor paediatric patients with cIAI, cUTI and HAP/VAP, including dose adjustments for patients withrenal impairment, result in systemic exposure and PK/PD target attainment values that are similar tothose in adults at the approved Zavicefta dose of 2 g/0.5 g administered over 2 hours, every 8 hours.
There is limited experience with the use of ceftazidime plus avibactam in the paediatric groups of3 months to < 6 months. The recommended dosing regimens are based on simulations conducted usingthe final population PK models. Simulations demonstrated that the recommended dose regimens resultin comparable exposures to other age groups with PK/PD target attainment > 90%. Based on data fromthe completed paediatric clinical trials, at the recommended dose regimens, there was no evidence ofover or under exposure in the subjects aged 3 months to < 6 months.
In addition, there is very limited data in paediatric patients aged 3 months to < 2 years with impairedrenal function (CrCL ≤ 50 mL/min/1.73 m2), with no data in severe renal impairment from thecompleted paediatric clinical trials. Population PK models for ceftazidime and avibactam were used toconduct simulations for patients with impaired renal function.
Gender and raceThe pharmacokinetics of ceftazidime/avibactam is not significantly affected by gender or race.
5.3 Preclinical safety data
Ceftazidime
Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, reproduction toxicity or genotoxicity. Carcinogenicity studieshave not been conducted with ceftazidime.
Avibactam
Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity or genotoxicity. Carcinogenicity studies have not beenconducted with avibactam.
Reproduction toxicity
In pregnant rabbits administered avibactam at 300 and 1000 mg/kg/day, there was a dose-related lowermean foetal weight and delayed ossification, potentially related to maternal toxicity. Plasma exposurelevels at maternal and foetal NOAEL (100 mg/kg/day) indicate moderate to low margins of safety.
In the rat, no adverse effects were observed on embryofetal development or fertility. Followingadministration of avibactam throughout pregnancy and lactation in the rat, there was no effect on pupsurvival, growth or development, however there was an increase in incidence of dilation of the renalpelvis and ureters in less than 10% of the rat pups at maternal exposures greater than or equal toapproximately 1.5 times human therapeutic exposures.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium carbonate (anhydrous)
6.2 Incompatibilities
The compatibility of Zavicefta with other medicines has not been established. Zavicefta should not bemixed with or physically added to solutions containing other medicinal products.
This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.
6.3 Shelf life
Dry powder3 years.
After reconstitutionThe reconstituted vial should be used immediately.
After dilutionInfusion bags
If the intravenous solution is prepared with diluents listed in section 6.6 (ceftazidime concentration8 mg/mL), the chemical and physical in-use stability has been demonstrated (from initial vialpuncture) for up to 12 hours at 2 - 8°C, followed by up to 4 hours at not more than 25°C.
If the intravenous solution is prepared with diluents listed in section 6.6 (ceftazidime concentration> 8 mg/mL to 40 mg/mL), the chemical and physical in-use stability has been demonstrated (frominitial vial puncture) for up to 4 hours at not more than 25°C.
From a microbiological point of view, the medicinal product should be used immediately, unlessreconstitution and dilution have taken place in controlled and validated aseptic conditions. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andmust not exceed those stated above.
Infusion syringes
The chemical and physical in-use stability has been demonstrated (from initial vial puncture) for up to6 hours at not more than 25°C.
From a microbiological point of view, the medicinal product should be used immediately unlessreconstitution and dilution have taken place in controlled and validated aseptic conditions. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andmust not exceed 6 hours at not more than 25°C.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
Store in the original package in order to protect from light.
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
20 mL glass vial (Type 1) closed with a rubber (halobutyl) stopper and aluminium seal with flip-offcap.
The medicinal product is supplied in packs of 10 vials.
6.6 Special precautions for disposal and other handling
The powder must be reconstituted with water for injections and the resulting concentrate must then beimmediately diluted prior to use. The reconstituted solution is a pale yellow solution and is free ofparticles.
Zavicefta (ceftazidime/avibactam) is a combination product; each vial contains 2 g of ceftazidime and0.5 g of avibactam in a fixed 4:1 ratio. Dosage recommendations are based on the ceftazidimecomponent only.
Standard aseptic techniques should be used for solution preparation and administration. Doses may beprepared in an appropriately sized infusion bag or infusion syringe.
Parenteral medicinal products should be inspected visually for particulate matter prior toadministration.
Each vial is for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
The total time interval between starting reconstitution and completing preparation of the intravenousinfusion should not exceed 30 minutes.
Instructions for preparing adult and paediatric doses in INFUSION BAG or in INFUSION SYRINGE:
NOTE: The following procedure describes the steps to prepare an infusion solution with a finalconcentration of 8-40 mg/mL of ceftazidime. All calculations should be completed prior to initiatingthese steps. For paediatric patients aged 3 to 12 months, detailed steps to prepare a 20 mg/mLconcentration (sufficient for most scenarios) are also provided.
1. Prepare the reconstituted solution (167.3 mg/mL of ceftazidime):
a) Insert the syringe needle through the vial closure and inject 10 mL of sterile water forinjections.
b) Withdraw the needle and shake the vial to give a clear solution.c) Insert a gas relief needle through the vial closure after the product has dissolved to relieve theinternal pressure (this is important to preserve product sterility).2. Prepare the final solution for infusion (final concentration must be 8-40 mg/mL of ceftazidime):
a) Infusion bag: Further dilute the reconstituted solution by transferring an appropriatelycalculated volume of the reconstituted solution to an infusion bag containing any of thefollowing: sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%)solution for injection, or Lactated Ringer’s solution.
b) Infusion syringe: Further dilute the reconstituted solution by transferring an appropriatelycalculated volume of the reconstituted solution combined with a sufficient volume of diluent(sodium chloride 9 mg/mL (0.9%) solution for injection or dextrose 50 mg/mL (5%) solutionfor injection) to an infusion syringe.
Refer to Table 7 below.
Table 7: Preparation of Zavicefta for adult and paediatric doses in INFUSION BAG or in INFUSION
SYRINGE.
Zavicefta Volume to withdraw from Final volume after Final volume in
Dose reconstituted vial dilution in infusion infusion syringe(ceftazidime)1 bag22 g Entire contents50 mL to 250 mL 50 mL(approximately 12 mL)1g 6 mL 25 mL to 125 mL 25 mL to 50 mL0.75 g 4.5 mL 19 mL to 93 mL 19 mL to 50 mL
All other doses Volume (mL) will vary Volume (mL) will vary
Volume (mL) calculatedbased on infusion bag based on infusionbased on dose required:size availability and syringe size availabilitypreferred final and preferred final
Dose (mg ceftazidime) ÷concentration concentration167.3 mg/mL ceftazidime(must be 8-40 mg/mL of (must be 8-40 mg/mL ofceftazidime) ceftazidime)1 Based on ceftazidime component only.2 Dilute to final ceftazidime concentration of 8 mg/mL for in-use stability up to 12 hours at 2 - 8°C,followed by up to 4 hours at not more than 25°C (i.e. dilute 2 g dose of ceftazidime in 250 mL, 1 gdose of ceftazidime in 125 mL, 0.75 g dose of ceftazidime in 93 mL, etc.). All other ceftazidimeconcentrations (> 8 mg/mL to 40 mg/mL) have in-use stability up to 4 hours at not more than 25°C.
Preparation of Zavicefta for use in paediatric patients aged 3 to 12 months of age in INFUSION
SYRINGE:
NOTE: The following procedure describes the steps to prepare an infusion solution with a finalconcentration of 20 mg/mL of ceftazidime (sufficient for most scenarios). Alternative concentrationsmay be prepared, but must have a final concentration range of 8-40 mg/mL of ceftazidime.
1. Prepare the reconstituted solution (167.3 mg/mL of ceftazidime):
a) Insert the syringe needle through the vial closure and inject 10 mL of sterile water forinjections.
b) Withdraw the needle and shake the vial to give a clear solution.c) Insert a gas relief needle through the vial closure after the product has dissolved to relieve theinternal pressure (this is important to preserve product sterility).2. Prepare the final solution for infusion to a final concentration of 20 mg/mL of ceftazidime:
a) Further dilute the reconstituted solution by transferring an appropriately calculated volume ofthe reconstituted solution combined with a sufficient volume of diluent (sodium chloride9 mg/mL (0.9%) solution for injection or dextrose 50 mg/mL (5%) solution for injection) to aninfusion syringe.
b) Refer to Table 8, 9, or 10 below to confirm the calculations. Values shown are approximate asit may be necessary to round to the nearest graduation mark of an appropriately sized syringe.
Note that the tables are NOT inclusive of all possible calculated doses but may be utilized toestimate the approximate volume to verify the calculation.
Table 8: Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in paediatricpatients 3 to 12 months of age with creatinine clearance (CrCL) > 50 mL/min/1.73 m2
Volume of
Volume ofreconstituted
Age and Zavicefta Dose diluent to add1 Weight (kg) solution to be
Dose (mg/kg) (mg ceftazidime) for mixingwithdrawn from vial(mL)(mL)5 250 1.5 116 300 1.8 136 months to 7 350 2.1 1512 months 8 400 2.4 1850 mg/kg 9 450 2.7 20of ceftazidime 10 500 3 2211 550 3.3 2412 600 3.6 274 160 1 7.43 months to 5 200 1.2 8.8< 6 months 6 240 1.4 107 280 1.7 1340 mg/kg 8 320 1.9 14of ceftazidime 9 360 2.2 1610 400 2.4 181 Based on ceftazidime component only.
Table 9: Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in paediatricpatients 3 to 12 months of age with CrCL 31 to 50 mL/min/1.73 m2
Volume of
Volume ofreconstituted solution
Age and Zavicefta Dose diluent to add1 Weight (kg) to be withdrawn from
Dose (mg/kg) (mg ceftazidime) for mixingvial(mL)(mL)5 125 0.75 5.56 150 0.9 6.66 months to 7 175 1 7.412 months 8 200 1.2 8.825 mg/kg 9 225 1.3 9.6of ceftazidime 10 250 1.5 1111 275 1.6 1212 300 1.8 134 80 0.48 3.53 months to 5 100 0.6 4.4< 6 months 6 120 0.72 5.37 140 0.84 6.220 mg/kg 8 160 1 7.4of ceftazidime 9 180 1.1 8.110 200 1.2 8.81 Based on ceftazidime component only.
Table 10: Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in paediatricpatients 3 to 12 months of age with CrCL 16 to 30 mL/min/1.73 m2
Volume of
Dose reconstituted solution Volume of
Age and Zavicefta1 Weight (kg) (mg to be withdrawn from diluent to add
Dose (mg/kg)ceftazidime) vial for mixing (mL)(mL)5 93.75 0.56 4.16 112.5 0.67 4.96 months to 7 131.25 0.78 5.712 months 8 150 0.9 6.618.75 mg/kg 9 168.75 1 7.4of ceftazidime 10 187.5 1.1 8.111 206.25 1.2 8.812 225 1.3 9.64 60 0.36 2.73 months to 5 75 0.45 3.3< 6 months 6 90 0.54 47 105 0.63 4.615 mg/kg 8 120 0.72 5.3of ceftazidime 9 135 0.81 610 150 0.9 6.61 Based on ceftazidime component only.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.