Zavicefta

Ceftazidime pentahydrate, avibactam sodium.

Zavicefta is a white to yellow sterile powder.
Each vial contains ceftazidime (as pentahydrate) equivalent to 2000 mg ceftazidime and avibactam (as sodium salt) equivalent to 500 mg avibactam.
After reconstitution, 1 mL of solution contains 167.3 mg of ceftazidime (CAZ) and 41.8 mg of avibactam (AVI).
Ceftazidime (as pentahydrate) is a white to almost white crystalline powder. It is soluble in acid, alkali and dimethyl sulphoxide and slightly soluble in water, methanol and dimethylformamide.
Avibactam (as sodium) is a crystalline powder. It is freely soluble in water, relatively soluble in methanol and insoluble in ethanol.
The reconstituted solution is a clear and colourless to yellow solution free from visible particulate matter.
Excipients with known effect: Each vial contains approximately 6.44 mmol of sodium (approximately 148 mg).
Excipient/Inactive Ingredient: Anhydrous sodium carbonate.

Pharmacotherapeutic group: Antibacterials for systemic use, ceftazidime, combinations. ATC code: J01DD52.
Pharmacology: Pharmacodynamics: Mechanism of action: Ceftazidime inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin binding proteins (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 to hydrolysis. 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 AmpC enzymes. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many class D enzymes.
Resistance: Bacterial resistance mechanisms that could potentially affect ceftazidime/avibactam include mutant or acquired PBPs, decreased outer membrane permeability to either compound, active efflux of either compound, and β-lactamase enzymes refractory to inhibition by avibactam and able to hydrolyze ceftazidime.
Antibacterial activity in combination with other antibacterial agents: No synergy or antagonism was demonstrated in in vitro drug combination studies with ceftazidime/avibactam and metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistin and tigecycline.
Cross-resistance: An absence of cross-resistance between ceftazidime-avibactam and fluoroquinolones or aminoglycosides has been demonstrated in vitro using molecularly-characterized clinical isolates. Some isolates resistant to ceftazidime (and other cephalosporins) or to carbapenems are susceptible to ceftazidime-avibactam. There is cross-resistance with β-lactam antibacterial agents, including carbapenems, when the mechanism is production of metallo-β-lactamases, such as VIM-2.
Susceptibility testing breakpoints: Minimum Inhibitory Concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for ceftazidime/avibactam are as follows: (see Table 1.)

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Clinical efficacy against specific pathogens: As detailed in the clinical studies discussed as follows, efficacy has been demonstrated against the following pathogens that were susceptible to ceftazidime/avibactam in vitro.
Complicated intra-abdominal infections: Gram-negative micro-organisms: Citrobacter freundii (C. freundii), Enterobacter cloacae (E. cloacae), Escherichia coli (E. coli), Klebsiella oxytoca (K. oxytoca), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa).
Complicated urinary tract infections: Gram-negative micro-organisms: E. coli, K. pneumoniae, Proteus mirabilis (P. mirabilis), E. cloacae, P. aeruginosa.
Hospital-acquired pneumonia including ventilator-associated pneumonia: Gram-negative micro-organisms: E. cloacae, E. coli, K. pneumoniae, P. mirabilis, Serratia marcescens (S. marcescens), P. aeruginosa.
Clinical efficacy has not been established against the following pathogens that are relevant to the approved indications although in vitro studies suggest that they would be susceptible to ceftazidime/avibactam in the absence of acquired mechanisms of resistance.
Gram-negative micro-organisms: Citrobacter koseri (C. koseri), Enterobacter aerogenes (E. aerogenes), Morganella morganii (M. morganii), Proteus vulgaris (P. vulgaris), Providencia rettgeri (P. 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.
Clinical trials: Complicated intra-abdominal infections (cIAI): In two identical randomised, multi-centre, multinational, double-blind studies (RECLAIM 1 and RECLAIM 2), a total of 1058 adults with cIAI were randomised to receive treatment comparing Zavicefta (2000 mg of CAZ and 500 mg of AVI) administered intravenously over 120 minutes every 8 hours plus metronidazole (500 mg) to meropenem (1000 mg) administered intravenously over 30 minutes. Treatment duration was 5 to 14 days. cIAI (defined as infections that require surgical intervention and extend beyond the hollow viscus into the intraperitoneal space) included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intra-abdominal abscesses and peritonitis.
The modified intent-to-treat (MITT) population included all patients who met the disease definition of cIAI and received at least 1 dose of the study drug. The clinically evaluable (CE) population included patients who had an appropriate diagnosis of cIAI and excluded patients with a bacterial species typically not expected to respond to both study drugs (i.e. Acinetobacter baumannii or Stenotrophomonas spp.) and/or who had an important protocol deviation impacting the assessment of efficacy.
The primary efficacy endpoint was the clinical response at the Test of Cure (TOC) visit in the co-primary populations of the CE and MITT patients in the table 2 as follows. (See Table 2.)

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Clinical cure rates at TOC by pathogen in the microbiologically Modified Intent to Treat (mMITT) population for Gram-negative aerobes are shown in Table 3 as follows. (See Table 3.)

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A further 432 adults with complicated intra-abdominal infections were randomised and received treatment in a multi-centre, double-blind study (RECLAIM 3) conducted in 3 Asian countries (China, Republic of Korea and Vietnam). The patient population and key aspects of the study design were identical to RECLAIM apart from the primary efficacy endpoint of clinical response at the TOC visit being solely in the CE population (see Table 4 as follows).

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Clinical cure rates at TOC by pathogen in the microbiologically modified Intent to Treat (mMITT) population for Gram-negative aerobes are shown in the Table 5 as follows. (See Table 5.)

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Among patients with baseline bacteraemia who were enrolled in any of the phase 3 cIAI studies (RECLAIM, RECLAIM3 or REPRISE), clinical response at TOC in the subset of patients with bacteraemia due to aerobic Gram negative pathogens was observed in 9/11 (81.8%) patients treated with CAZ-AVI + MTZ and 9/10 (90.0%) patients treated with comparators (meropenem or best available therapy). The most common Gram-negative baseline pathogens isolated from the blood were E. coli and P. aeruginosa. A favourable per-pathogen microbiological response at TOC was reported in 9/11 (81.8%) CAZ-AVI- and 6/6 (100.0%) comparator-treated patients with E. coli bacteraemia; and 3/4 (75.0%) CAZ-AVI- and 2/2 (100.0%) comparator-treated patients with P.aeruginosa bacteraemia.
Complicated urinary tract infections (cUTI): A total of 1020 adults with documented cUTI (737 with acute pyelonephritis and 283 with cUTI without acute pyelonephritis) were randomized and received treatment in a phase III multicenter, double-blind, comparative study. cUTI included acute pyelonephritis and complicated lower urinary tract infections. Treatment was with either ceftazidime/avibactam (2000 mg/500 mg) IV over 120 mins every 8 hours or doripenem 500 mg IV over 60 mins every 8 hours. There was an optional switch to oral therapy for patients who had clinical improvement as defined in the study protocol after a minimum of 5 days IV treatment. Total duration of antibiotic therapy (IV plus oral) was 10 days (optionally up to 14 if bacteraemic). The mMITT population included all patients with a confirmed cUTI diagnosis, received at least 1 dose of study treatment and had a study-qualifying pre-treatment urine culture containing 10⁵ CFU/mL of a Gram-negative pathogen and no more than 2 species of microorganisms. Any patient with a Gram-positive pathogen, or a bacterial species not expected to respond to both study drugs was excluded. Patients with CrCL <30 mL/min were excluded.
The primary efficacy endpoint was per-patient microbiological response at the TOC visit in the mMITT analysis set. (See Table 6.)

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Favourable microbiological response rates at TOC by pathogen in the mMITT population are shown in the table 7 as follows. (See Table 7.)

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Among patients with baseline bacteraemia who were enrolled in any of the phase 3 cUTI studies (RECAPTURE or REPRISE), clinical cure at TOC in the subset of patients with bacteraemia due to aerobic Gram-negative pathogens was observed in 28/28 (100.0%) patients treated with CAZAVI and 25/29 (86.2%) patients treated with comparators (doripenem or best-available therapy). For the endpoint of per-patient microbiological response at TOC, a favourable response at TOC was reported in 26/28 (92.9%) patients treated with CAZ-AVI and 20/29 (69.0%) patients treated with comparator. The most commonly isolated pathogen was E. coli. A total of 21/23 (91.3%) patients in the CAZ-AVI group and 19/23 (82.6%) in the comparator group had a favourable per pathogen microbiological response for E. coli, which was the most common pathogen.
Hospital-acquired pneumonia (HAP): In a phase III double-blind, comparative study, a total of 808 adults with nosocomial pneumonia (280/808, 34.7% with VAP and 40/808 (5.0%) were bacteraemic at baseline) were randomised to receive treatment of ceftazidime/avibactam (2000 mg/500 mg) IV over 120 mins every 8 hours or meropenem 1 g IV over 30 mins every 8 hours. Treatment duration was 7 to 14 days. Nosocomial pneumonia was defined as an onset of relevant signs and symptoms ≥48 hours after admission or <7 days after discharge from an inpatient acute or chronic care facility, and a new or worsening infiltrate on chest X-ray obtained within 48 hours prior to randomisation. Patients with infections only due to Gram-positive organisms were excluded from the trial, when this could be determined before enrollment. Following randomisation, patients in both treatment groups could receive empiric open-label linezolid or vancomycin to cover for Gram-positive pathogens while awaiting culture results. Treatment with Gram-positive coverage continued in patients with Gram-positive pathogens.
The clinically modified intent to treat (cMITT) population included patients who met the minimum disease criteria, received at least 1 dose of study treatment and who had properly obtained baseline respiratory or blood cultures demonstrating Gram-negative pathogens excluding patients with monomicrobial Gram-negative infections with species not expected to respond to both study drugs (e.g. Acinetobacter species or Stenotrophomonas species). The cMITT also included patients in whom no etiologic pathogens were identified from respiratory or blood cultures at baseline. The CE at TOC analyses set was the clinically evaluable subset of the cMITT.
The primary efficacy endpoint was the clinical response at the TOC visit in the co-primary populations of the cMITT and CE at TOC. See the table as follows. (See Table 8.)

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All-cause mortality rates at Day 28 (cMITT) was 8.4% (30/356) and 7.3% (27/370) ceftazidime-avibactam and meropenem treated patients, respectively.
Clinical cure rate and favourable microbiological response rate at TOC by pathogen in mMITT for Gram-negative aerobes are shown in Tables 9 and 10. (See Tables 9 and 10.)

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For HAP/VAP patients enrolled with baseline bacteraemia, clinical cure at TOC in the subset of patients with bacteraemia due to aerobic Gram-negative pathogens was observed in 10/15 (66.7%) patients treated with CAZ-AVI and 5/8 (62.5%) patients treated with meropenem. Although patient numbers were small for any given pathogen, favourable per-pathogen microbiological response rates in this sub-group were broadly similar to those of the overall population.
Among patients enrolled with baseline bacteraemia in the Phase 3 program across all indications combined (cIAI, cUTI or HAP/VAP), clinical cure at TOC in the subset of patients with bacteraemia due to aerobic Gram-negative pathogens was observed in 47/54 (87.0%) patients treated with CAZ-AVI ± MTZ and 39/47 (83.0%) patients treated with comparators. For the two most commonly occurring pathogens in this sub-group, a favourable per-pathogen microbiological response at TOC was reported in 32/37 (86.5%) CAZ-AVI ± MTZ- and 29/33 (87.9%) comparator‑treated patients with E. coli bacteraemia; and 6/11 (54.5%) CAZ-AVI ± MTZ- and 3/6 (50.0%) comparator‑treated patients with P. aeruginosa bacteraemia.
Paediatric population: Zavicefta has been evaluated in paediatric patients aged 3 months to <18 years in two Phase 2 single blind, randomised, comparative clinical studies, one in patients with cIAI and one in patients with cUTI. The primary objective in each study was to assess safety and tolerability of ceftazidime-avibactam (+/- metronidazole). Secondary objectives included assessment of pharmacokinetics 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 paediatric patients 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.
Limitations of clinical trial data: Patients with evidence of significant immunocompromise were excluded from the Phase 2 and 3 clinical trials.
Pharmacokinetics: Distribution: 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 L and 22 L, respectively in healthy adults following multiple doses of 2000 mg/500 mg ceftazidime-avibactam infused over 2 hours every 8 hours. Both ceftazidime and avibactam penetrate into human bronchial epithelial 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 of 4 to 20 mg/L or more are achieved in the CSF when the meninges are inflamed. Avibactam penetration of 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.
Metabolism: Ceftazidime is not metabolized. No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged avibactam was the major drug-related component in human plasma and urine following dosing with [¹⁴C]-avibactam.
Excretion: The terminal half-life (t½) of both ceftazidime and avibactam is about 2 h after intravenous administration. 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 excreted unchanged into the urine with a renal clearance of approximately 158 mL/min, suggesting active tubular secretion in addition to glomerular filtration, Approximately 97% of the avibactam dose is recovered in the urine, 95% within 12 h. Less than 1% of ceftazidime is excreted via the bile and less than 0.25% of avibactam is excreted into faeces.
Linearity/non-linearity: The pharmacokinetics of both ceftazidime and avibactam are approximately linear across the dose range studied (50 mg to 2000 mg) for a single intravenous administration. No appreciable accumulation of ceftazidime or avibactam was observed following multiple intravenous infusions of 2000 mg/500 mg of ceftazidime/avibactam administered every 8 hours for up to 11 days in healthy adults with normal renal function.
Pharmacokinetic/pharmacodynamic relationship(s): The antimicrobial activity of ceftazidime against specific pathogens has been shown to best correlate with the percent time of free-drug concentration above the ceftazidime/avibactam minimum inhibitory concentration over the dose interval (%fT >MIC of ceftazidime/avibactam). For avibactam the PK-PD index is the percent time of the free drug concentration above a threshold concentration over the dose interval (% fT >C_T).
Renal impairment: Adults: Ceftazidime is eliminated almost solely by the kidneys; its serum half-life is significantly prolonged in patients with impaired renal function. The clearance of avibactam was significantly decreased in subjects with mild (CrCL >50 to 80 mL/min, n=6), moderate (CrCL 30 to 50 mL/min, n=6), and severe (≤CrCL 30 mL/min, not requiring haemodialysis; n=6) renal impairment compared to healthy subjects with normal renal function (CrCL ≥80 mL/min, n=6) following administration of a single 100 mg intravenous dose of avibactam. The slower clearance resulted in increases in systemic exposure (AUC) of avibactam of 2.6-fold, 3.8-fold and 7-fold in subjects with mild, moderate and severe renal impairment, respectively.
A single 100 mg dose of avibactam was administered to subjects with ESRD (n=6) either 1 hour before or after haemodialysis. The avibactam AUC following the post-haemodialysis infusion was 19.5-fold the AUC of healthy subjects with normal renal function. Avibactam was extensively removed by haemodialysis, with an extraction coefficient of 0.77 and a mean haemodialysis clearance of 9.0 L/h. Approximately 55% of the avibactam dose was removed during a 4-hour haemodialysis session.
Dosage adjustment of Zavicefta is recommended in patients with moderate and severe renal impairment and end-stage renal disease. Population PK models for ceftazidime and avibactam were used to conduct simulations for patients with impaired renal function. Simulations demonstrated that the recommended dose adjustments provide comparable exposures of ceftazidime and avibactam in patients with moderate and severe renal impairment and end-stage renal disease to those in patients with normal renal function or mild renal impairment. For patients with changing renal function, CrCL should be monitored at least daily and the dose of Zavicefta adjusted accordingly (see Dosage & Administration and Use in renal impairment under Precautions).
Hepatic impairment: Mild to moderate hepatic impairment had no effect on the pharmacokinetics of ceftazidime in individuals administered 200 mg intravenously every 8 hours for 5 days, provided renal function was not impaired. The pharmacokinetics of ceftazidime in patients with severe hepatic impairment has not been established. The pharmacokinetics of avibactam in patients with any degree of hepatic impairment has not been studied.
As ceftazidime and avibactam do not appear to undergo significant hepatic metabolism, the systemic clearance of either active substance is not expected to be significantly altered by hepatic impairment.
Use in the elderly: Reduced clearance of ceftazidime was observed in elderly patients which was primarily due to age-related decrease in renal clearance of ceftazidime. The mean elimination half-life of ceftazidime ranged from 3.5 to 4 hours following intravenous bolus dosing with 2000 mg every 12 hours in elderly patients aged 80 years or older.
Following single intravenous administration of 500 mg avibactam as a 30-minute IV infusion, the elderly had a slower terminal half-life of avibactam, which may be attributed to age-related decrease in renal clearance.
Paediatric population: The pharmacokinetics of ceftazidime and avibactam were evaluated in paediatric patients from 3 months to <18 years of age with suspected or confirmed infections following a single dose of ceftazidime 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 concentrations of 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 andavibactam AUC_0-t and C_max values in the two older cohorts (paediatric patients from 6 to <18 years), which had more extensive pharmacokinetic sampling, were similar to those observed in healthy adult subjects with normal renal function that received Zavicefta 2 g/0.5 g. Data from this study and the two Phase 2 paediatric 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/PD target attainment. Results from these simulations demonstrated that the recommended dose regimens for paediatric patients with cIAI and cUTI, including dose adjustments for patients with renal impairment, result in systemic exposure and PK/PD target attainment values that are similar to those 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 of 3 months to <6 months. The recommended dosing regimens are based on simulations conducted using the final population PK models. Simulations demonstrated that the recommended dose regimens result incomparable exposures to other age groups with PK/PD target attainment >90%. Based on data from the completed paediatric clinical trials, at the recommended dose regimens, there was no evidence of over 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 impaired renal function (CrCL ≤50 mL/min/1.73 m²), with no data in severe renal impairment from the completed paediatric clinical trials. Population PK models for ceftazidime and avibactam were used to conduct simulations for patients with impaired renal function.
Gender and race: The pharmacokinetics of ceftazidime/avibactam is not significantly affected by gender or race.
Toxicology: Preclinical safety data: Genotoxicity: For ceftazidime a mouse Micronucleus test and an Ames test were both negative for mutagenic effects. In genotoxicity assays with avibactam, there was no induction of gene mutation in the in vitro bacterial reverse mutation tests, nor were there any indications of genotoxicity in an in vitro micronucleus test in mouse lymphoma cells. In cultured human lymphocytes, statistically significant increases in chromosomal aberrations were observed under a single treatment condition (44 h harvest time, -S9). As these findings were not replicated in an independent study, the results are considered to be of limited biological relevance. When administered up to the limit dose of 2 g/kg IV, avibactam was negative in a rat in vivo micronucleus assay. No genetic toxicology studies have been conducted on ceftazidime-avibactam.
Carcinogenicity: Carcinogenicity studies have not been conducted with ceftazidime-avibactam.

Zavicefta is indicated in adults and paediatric patients aged 3 months and older for the treatment of the following infections (see Precautions and Pharmacology: Pharmacodynamics under Actions): Complicated intra-abdominal infection (cIAI), in combination with metronidazole; Complicated urinary tract infection (cUTI), including pyelonephritis.
Zavicefta is indicated for the treatment of the following infections in adults (see Precautions and Pharmacology: Pharmacodynamics under Actions): Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP).
Treatment of adult patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed as previously mentioned.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zavicefta and other antibiotics, Zavicefta should be used in combination with an antibacterial agent(s) active against Gram-positive and/or anaerobic pathogens when these are known or suspected to be contributing to the infectious process.

Posology: Dosage in Adults with Creatinine Clearance (CrCL >50 mL/min): Table 11 shows the recommended intravenous dose for adults with estimated creatinine clearance (CrCL) >50 mL/min (see Precautions and Pharmacology: Pharmacodynamics under Actions). (See Table 11.)

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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 creatinine clearance (CrCL) >50 mL/min/1.73 m² (see Precautions and Pharmacology: Pharmacodynamics under Actions). (See Table 12.)

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Special populations: Elderly: No dosage adjustment is required in elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dosage adjustment is required in patients with mild renal impairment (estimated CrCL >50 - ≤80 mL/min) (see Pharmacology: Pharmacokinetics under Actions).
Table 13 shows the recommended dose adjustments for adults with estimated CrCL ≤50 mL/min (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Dosage in adults with creatinine clearance (CrCL) ≤50 mL/min: (See Table 13.)

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Table 14 and Table 15 shows the recommended dose adjustments for paediatric patients with estimated CrCL ≤50 mL/min/1.73 m² according to different age groups (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Dosage in paediatric patients 2 years of age with CrCl50 mL/min/1.73 m²: (See Table 14.)

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Dosage in paediatric patients <2 years of age with CrCl 50 mL/min/1.73 m²: (See Table 15.)

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There is insufficient information to recommend a dosage regimen for paediatric patients <2 years of age that have a CrCL <16 mL/min/1.73 m².
Hepatic impairment: No dosage adjustment is required in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric patients: The safety and efficacy in paediatric patients <3 months old have not been established. No data are available.
Method of administration: Intravenous use.
Zavicefta is administered by intravenous infusion over 120 minutes in an appropriate infusion volume (see Instructions for use, handling and disposal under Cautions for Usage).
For instructions on reconstitution and dilution of the medicinal product before administration, (see Instructions for use, handling and disposal under Cautions for Usage).

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-hour haemodialysis period, 55% of the avibactam dose was removed.

Hypersensitivity to the active substances or to any of the excipients listed in Description.
Hypersensitivity to any cephalosporin antibacterial agent.
Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).

Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity reactions are possible (see Contraindications and Adverse Reactions). In case of hypersensitivity reactions, treatment with Zavicefta must be discontinued immediately and adequate emergency measures must be initiated.
Before beginning treatment, it should be established whether the patient has a history of hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactam antibacterial agent. Caution should be used if ceftazidime/avibactam is given to patients with a history of non-severe hypersensitivity to penicillins, monobactams or carbapenems.
Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients receiving therapy with beta-lactams. Before initiating therapy with Zavicefta, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, carbapenems or other beta-lactam agents. If an allergic reaction occurs, Zavicefta must be discontinued immediately and appropriate alternative therapy instituted.
Clostridium difficile-associated diarrhoea: Clostridium difficile-associated diarrhoea has been reported with ceftazidime/avibactam, and can range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhoea during or subsequent to the administration of Zavicefta (see Adverse Reactions). Discontinuation of therapy with Zavicefta and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Nephrotoxicity: Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.
Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of haemolytic anaemia: 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 induced immune haemolytic anaemia (see Adverse Reactions). While DAGT seroconversion in patients receiving Zavicefta was very common in clinical studies (the estimated range of seroconversion across Phase 3 studies was 3.2% to 20.8% in patients with a negative Coombs test at baseline and at least one follow-up test), there was no evidence of haemolysis in patients who developed a positive DAGT on treatment. However, the possibility that haemolytic anaemia could occur in association with Zavicefta treatment cannot be ruled out. Patients experiencing anaemia during or after treatment with Zavicefta should be investigated for this possibility.
Dermatological adverse events: Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected, Zavicefta should be discontinued immediately and an alternative treatment should be considered. See Adverse Reactions.
Spectrum of activity of ceftazidime/avibactam: Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions). Additional antibacterial agents should be used when these pathogens are known 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 B enzymes (metallo-β-lactamases) and is not able to inhibit many of the class D enzymes (see Pharmacology: Pharmacodynamics under Actions).
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.
Development of drug-resistant bacteria: Prescribing Zavicefta in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria (see Indications/Uses).
Controlled sodium diet: Each vial contains a total of approximately 6.44 mmol of sodium (approximately 148 mg). This should be considered when administering Zavicefta to patients who are on a controlled sodium diet.
Effects on laboratory tests: Ceftazidime may interfere with copper reduction methods (Benedict's, Fehling's, Clinitest) for detection of glycosuria leading to false positive results. Ceftazidime does not interfere with enzyme-based tests for glycosuria.
Effects on ability to drive and use machines: Undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines following administration of Zavicefta (see Adverse Reactions).
Use in renal impairment: Ceftazidime and avibactam are eliminated via the kidneys, therefore the dose should be reduced according to the degree of renal impairment (see Dosage & Administration). Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment.
In patients with renal impairment, close monitoring of estimated creatinine clearance is advised.
In some patients, the creatinine clearance estimated from serum creatinine can change quickly, especially early in the course of treatment for the infection (see Pharmacology: Pharmacodynamics: Clinical trials and Pharmacokinetics: Renal impairment under Actions).
Use in Children: The safety and efficacy of Zavicefta in paediatric patients (<18 years of age) have not been established.
Use in the Elderly: No dosage adjustment is required in elderly patients (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).

Effects on fertility: The effects of ceftazidime/avibactam on fertility in humans have not been studied. No data are available on animal studies with ceftazidime. Animal studies with avibactam do not indicate harmful effects with respect to male fertility. Studies in female rats showed a dose-related increase in pre- and post-implantation losses and smaller live litter size at ≥500 mg/kg/day (≥3 times the human therapeutic exposure at 500 mg three times a day, based on AUC).
Use in pregnancy - Pregnancy Category B3.
Ceftazidime: The safety of ceftazidime in pregnancy has not been established, although animal studies have not produced evidence of embryopathic or teratogenic effects attributable to ceftazidime.
Avibactam: Animal studies with avibactam have shown reproductive toxicity without evidence of teratogenic effects.
In pregnant rabbits administered avibactam at 300 and 1000 mg/kg/day (5-21 times the human therapeutic exposure based on AUC), there was a dose-related lower mean fetal weight and delayed ossification, associated with maternal toxicity (decreased food consumption and body weight gain). Plasma exposure levels at maternal and fetal NOAEL (100 mg/kg/day) indicate low margins of safety (1.5 times the human therapeutic exposure based on AUC).
In the rat, no adverse effects were observed on embryofetal development at up to 1000 mg/kg/day (6 times the human therapeutic exposure based on AUC). Following administration of avibactam throughout pregnancy and lactation in the rat, there was no effect on pup survival, growth or development, however there was an increase in incidence of dilation of the renal pelvis and ureters in less than 10% of the rat pups at maternal exposures ≥450 mg/kg/day (greater than or equal to approximately 3 times the human therapeutic exposures based on AUC). Ceftazidime/avibactam should only be used during pregnancy if the potential benefit outweighs the possible risk.
Use in lactation: Ceftazidime is excreted in human milk in small quantities.
It is unknown whether avibactam is excreted in human milk. Avibactam was excreted in rat milk (~20% of plasma C_max), and very low levels were detected in pup plasma (<0.03% of nonclinical maternal plasma C_max) as a result of exposure from milk.
A risk to newborns/infants 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.

In seven Phase 2 and Phase 3 clinical trials, 2024 adult patients were treated with Zavicefta. The table as follows lists the adverse events (regardless of causality) occurring in ≥1% of patients treated with Zavicefta with or without metronidazole or comparator from Phase 2 and Phase 3 clinical trials. (See Table 16.)

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The most common adverse reactions occurring in ≥5% of patients treated with Zavicefta were Coombs direct test positive, nausea, and diarrhoea. Nausea and diarrhoea were usually mild or moderate in intensity. No clinically significant differences were observed in the safety profile across indications.
The following adverse reactions have been reported with ceftazidime alone and/or identified during the Phase 2 and Phase 3 clinical trials with Zavicefta. Adverse reactions are classified according to frequency and System Organ Class. Frequency categories are derived from adverse reactions and/or potentially clinically significant laboratory abnormalities. (See Table 17.)

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Paediatric population: The safety assessment in paediatric patients is based on the safety data from two trials in which61 patients with cIAI (aged from 3 years to less than 18 years) and 67 patients with cUTI (aged from 3 months to less than 18 years) received ceftazidime/avibactam. Overall, the safety profile in these 128 paediatric patients was similar to that observed in the adult population with cIAI and cUTI.

In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake of avibactam from the blood compartment and therefore affect its excretion. Probenecid (a potent OAT inhibitor) inhibits this uptake by 56% to 70% in vitro and therefore, has the potential to alter the elimination of avibactam. Since a clinical interaction study of avibactam and probenecid has not been conducted, co-administration of avibactam with probenecid is not recommended.
Avibactam showed no significant inhibition of cytochrome P450 enzymes in vitro. Avibactam and ceftazidime 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 clinically relevant exposure range, therefore the interaction potential via these mechanisms is considered to be low.
Clinical data have demonstrated that there is no interaction between ceftazidime and avibactam, and between ceftazidime/avibactam and metronidazole.
Other types of interaction: Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function (see Precautions).
Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but due to the possibility of antagonism in vivo this drug combination should be avoided.

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Dosage & Administration.
Instructions for use, handling and disposal: The powder must be reconstituted with water for injections and the resulting concentrate must then be immediately diluted prior to use. The reconstituted solution is a pale yellow solution and is free of particles.
Zavicefta (ceftazidime/avibactam) is a combination product; each vial contains 2 g of ceftazidime and 0.5 g of avibactam in a fixed 4:1 ratio. Dosage recommendations are based on the ceftazidime component only.
Standard aseptic techniques should be used for solution preparation and administration. Doses may be prepared in an appropriately sized infusion bag.
Parenteral medicinal products should be inspected visually for particulate matter prior to administration.
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 intravenous infusion should not exceed 30 minutes.
Instructions for preparing adult and paediatric doses in Infusion Bag: NOTE: The following procedure describes the steps to prepare an infusion solution with a final concentration of 8-40 mg/mL of ceftazidime. All calculations should be completed prior to initiating these steps.
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 for injections.
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 the internal 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): Infusion bag: Further dilute the reconstituted solution by transferring an appropriately calculated volume of the reconstituted solution to an infusion bag containing any of the following: sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution for injection, or Lactated Ringer's solution.
Infusion syringe: Further dilute the reconstituted solution by transferring an appropriately calculated 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%) solution for injection) to an infusion syringe.
Refer to Table 18 as follows. (See Table 18.)

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Store below 30°C.
Store in the original package in order to protect from light.
For storage conditions of the reconstituted and diluted medicinal product, see Shelf-life as follows.
Shelf-life: Dry powder: 3 years when stored below 30°C.
After reconstitution: The reconstituted vial should be used immediately.
After dilution: Infusion bags: The chemical and physical in-use stability of the reconstituted product has been demonstrated for up to 24 hours at 2-8°C followed by up to 12 hours at not more than 25°C.
From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 12 hours at not more than 25°C or 24 hours at 2-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
Infusion syringes: The chemical and physical in-use stability has been demonstrated for up to 6 hours at not more than 25°C.
From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not exceed 6 hours at not more than 25°C.

Cephalosporins

J01DD52 - ceftazidime and beta-lactamase inhibitor ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

B