Zavicefta

Ceftazidime pentahydrate, avibactam sodium.

Ceftazidime pentahydrate is a white to almost white, crystalline powder chemically described as (Z)-7-[2-(2-Amino-1, 3-thiazol-4-yl)-2-(1-carboxy-1-methylethyloxyimino) acetylamino]-3-(1-pyridiniumylmethyl)-3-cephem-4-carboxylate pentahydrate with a molecular formula of C₂₂H₃₂N₆O₁₂S₂ (as pentahydrate).
Avibactam sodium is a white to pale yellow crystalline powder chemically described as Sodium; [(2S, 5R)-2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1]octan-6-yl] sulfate with a molecular formula of C₇H₁₀N₃O₆SNa.
Each vial contains ceftazidime (as pentahydrate) equivalent to 2 g and avibactam (as sodium) equivalent to 0.5 g.
After reconstitution, 1 ml of solution contains 167.3 mg of ceftazidime and 41.8 mg of avibactam.
Excipients/Inactive Ingredients: Sodium carbonate.

Pharmacology: Pharmacodynamics: Mechanism of action: Ceftazidime inhibits bacterial peptidoglycan cell wall synthesis following attachment to penicillin binding proteins (PBPs), which leads to bacterial cell lysis and death. This broad spectrum cephalosporin is active against many important Gram-negative and Gram-positive bacterial pathogens in vitro. 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, including extended-spectrum β-lactamases (ESBLs), KPC carbapenemases, and AmpC enzymes. Avibactam also inhibits the class D carbapenemase OXA-48, which does not significantly hydrolyze ceftazidime. Avibactam has no clinically relevant in vitro antibacterial activity. Avibactam did not induce transcription of bla_AmpC in Enterobacter cloacae, Citrobacter freundii or Pseudomonas aeruginosa in vitro at concentrations used to treat patients.
Mechanism of resistance: Ceftazidime-avibactam is not active against metallo-β-lactamase-producing bacteria. 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, mutated or acquired β-lactamase enzymes insensitive to avibactam and able to hydrolyze ceftazidime.
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.
Interaction with other antimicrobial agents: In vitro interaction tests with ceftazidime-avibactam show ceftazidime-avibactam has little potential to antagonize or be antagonized by other antibiotics of various classes (e.g. metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistin, tigecycline).
Susceptibility testing: The prevalence of acquired resistance may vary geographically and with time for selected species. Local information on resistance is desirable, particularly when treating severe infections.
The susceptibility to ceftazidime-avibactam of a given clinical isolate should be determined by standard methods. Interpretations of test results should be made in accordance with local infectious diseases and clinical microbiology guidelines.
Pharmacokinetic/pharmacodynamic relationship: The antimicrobial activity of ceftazidime-avibactam 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 ceftazidime, and the percent time of the free drug concentration above a threshold concentration over the dose interval (% fT>CT) for avibactam.
Clinical efficacy against specific pathogens: Efficacy has been demonstrated in clinical studies against the pathogens, listed under each indication, that were susceptible 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 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; Enterobacter aerogenes; Morganella morganii; Proteus vulgaris; Providencia rettgeri.
Ceftazidime-avibactam is active in vitro against Streptococcus pyogenes and Streptococcus agalactiae, but not generally active against other clinically-important Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA).
Clinical efficacy and safety: Complicated intra-abdominal infections: A total of 1058 adults with complicated intra-abdominal infections (defined as infections that require surgical intervention and extend beyond the hollow viscus into the intraperitoneal space) were randomized and received treatment in two identical randomized, multi-centre, multinational, double-blind studies (RECLAIM 1 and RECLAIM 2) comparing Ceftazidime-avibactam (2 g of ceftazidime and 500 mg of avibactam) 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. 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 Table 1 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 Table 2 as follows.

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A further 432 adults with complicated intra-abdominal infections were randomized 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 3 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 Table 4 as follows.

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Complicated urinary tract infections: A total of 1020 adults with documented complicated urinary tract infection (cUTI) (737 with acute pyelonephritis and 283 with cUTI without acute pyelonephritis) were randomized and received treatment in a phase III multicentre, double-blind, comparative study. Treatment was with either Ceftazidime-avibactam (2 g/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 bacteremic). 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.
The primary efficacy endpoint was per-patient microbiological response at the TOC visit in the mMITT analysis set. (See Table 5.)

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Favourable microbiological response rates at TOC by pathogen in the mMITT population are shown in Table 6 as follows.

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Hospital-acquired pneumonia: A total of 808 adults with nosocomial pneumonia (35% with VAP) were randomized and received treatment in a phase III double-blind, comparative study of Ceftazidime-avibactam (2 g/500 mg) IV over 120 mins every 8 hours or meropenem 1g IV over 30 mins every 8 hours. Treatment duration was 7 to 14 days. 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 Table 7 as follows.

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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 8 and 9.

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Pharmacokinetics: Distribution: The human protein binding of both ceftazidime and avibactam is low, approximately 10% and 8%, respectively. The steady-state volumes of distribution of ceftazidime and avibactam were comparable, about 22 L and 18 L, respectively in healthy adults following multiple doses of 2 g/500 mg ceftazidime-avibactam infused over 2 hours every 8 hours. Pharmacokinetic parameters of ceftazidime and avibactam following single and multiple dose administration of Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) were similar to those determined when ceftazidime or avibactam were administered alone. Both ceftazidime and avibactam penetrate into human bronchial epithelial lining fluid (ELF) to the same extent with concentrations around 30% that of plasma, and a similar concentration time profile between ELF and plasma.
Ceftazidime and avibactam plasma exposure were comparable across patients with different indications, cIAI, cUTI and NP.
Penetration of ceftazidime into the intact blood-brain barrier is poor, resulting in low levels of ceftazidime in the CSF in the absence of inflammation. However, 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. For ceftazidime, concentrations in excess of the MIC of ceftazidime-avibactam for common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, pleural and peritoneal fluids. Ceftazidime crosses the placenta readily, and is excreted in the breast milk. Avibactam penetrates into the subcutaneous tissue at the site of skin infections, with tissue concentrations approximately equal to free drug concentrations in plasma.
Biotransformation: 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.
Elimination: The terminal half-life (t½) of both ceftazidime and avibactam is about 2 h after IV 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 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 feces.
Linearity/non-linearity: The pharmacokinetics of both ceftazidime and avibactam are approximately linear across the dose range studied (50 mg to 2 g) for a single IV administration. No appreciable accumulation of ceftazidime or avibactam was observed following multiple IV infusions of 2 g/500 mg of ceftazidime-avibactam administered every 8 hours for up to 11 days in healthy adults with normal renal function.
Special populations: Patients with renal impairment: Elimination of ceftazidime and avibactam is decreased in patients with moderate or severe renal impairment, and end stage renal disease including patients undergoing hemodialysis; the dose should be reduced in patients with CrCl ≤50 ml/min) (see Dosage & Administration).
Patients with hepatic impairment: Mild to moderate hepatic impairment had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 g IV 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 drug is not expected to be significantly altered by hepatic impairment. Therefore, no dosage adjustment of ceftazidime-avibactam is recommended for patients with hepatic impairment (see Dosage & Administration).
Elderly patients: The reduced clearance observed in elderly patients was primarily due to age-related decrease in renal clearance of ceftazidime. The mean elimination half-life ranged from 3.5 to 4 hours following single or 7 days repeated every 12 hours dosing of 2 g IV bolus injections in elderly patients 80 years or older.
Following single dose IV 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. Dosage adjustment for ceftazidime-avibactam is not required in elderly subjects (≥ 65 years of age) with CrCl > 50 ml/min.
Pediatric patients: The safety and efficacy of Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) in pediatric patients (< 18 years of age) have not been established.
Gender: The pharmacokinetics of ceftazidime-avibactam was similar between males and females. No dose adjustment is required based on sex.
Race: Based on a population pharmacokinetic analysis, no dose adjustment of ceftazidime-avibactam is required based on race.
Toxicology: Preclinical Safety Data: Genetic toxicology: For ceftazidime a mouse Micronucleus test and an Ames test were both negative for mutagenic effects. Carcinogenicity studies have not been conducted. 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 unscheduled DNA synthesis test in rat liver cells or 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. Carcinogenicity studies have not been conducted. No genetic toxicology studies have been conducted on ceftazidime-avibactam.
Reproductive toxicology: Reproduction studies have been performed with ceftazidime in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus. In pregnant rabbits at exposures of avibactam approximately 8 fold higher than those observed in humans at 0.5 g three times daily there was a significant effect on maternal food consumption and a slight effect on fetal weight and slight retardation of ossification of a few bones in the fetus. In the rat, no adverse effects were observed on embryofetal development or fertility. 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 greater than or equal to approximately 1.5 times human therapeutic exposures. No reproductive toxicology studies have been conducted on ceftazidime-avibactam.

Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) is indicated in adults for the treatment of the following infections (see Precautions and Pharmacology: Pharmacodynamics under Actions): Complicated Intra-Abdominal Infection (cIAI); Complicated Urinary Tract Infection, including Pyelonephritis (cUTI); Hospital-acquired Pneumonia (HAP), including ventilator associated pneumonia (VAP); Infections due to aerobic Gram-negative organisms in patients with limited treatment options.
Consideration should be given to official guidance on the appropriate use of antibacterial agents. For treatment of cIAI use in combination with metronidazole.

The recommended dosage of Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) is 1 vial where each vial contains 2 g ceftazidime and 0.5 g avibactam administered by intravenous (IV) infusion in a volume of 100 ml at a constant rate over 120 minutes in patients aged 18 years or older. Treatment is repeated every 8 hours. For patients with renal impairment where CrCl ≤ 50 ml/min, see dose recommendations in Table 11.
Treatment duration: see Table 10.

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For Complicated Urinary Tract Infection (cUTI) including Pyelonephritis, the total duration of treatment could be increased to 14 days for patients with bacteremia.
The duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress.
Special populations: Elderly patients: No dosage adjustment is considered necessary in elderly patients (≥65 years). The dose regimen should be adjusted if renal impairment is present (see Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: The following dose adjustment is recommended in patients with renal impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Dose adjustments for Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) for patients with an estimated creatinine clearance (CrCl) ≤50 ml/min are outlined in Table 10 as follows. The only information on dosing of Ceftazidime pentahydrate/Avibactam sodium (Zavicefta) for patients requiring dialysis is in the setting of intermittent hemodialysis. For other types of dialysis, it is suggested that the dose/frequency of ceftazidime-avibactam should follow local label/local guidelines for dosing of ceftazidime. For example, for a dose of 500 mg ceftazidime the dose of ceftazidime-avibactam would be 500 mg ceftazidime/125 mg avibactam. (See Table 11.)

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In patients with impaired renal function, regular monitoring of estimated creatinine clearance is advised as in some patients, especially early in the course of their infection, the creatinine clearance estimated from serum creatinine can change quickly.
Hemodialysis: Both ceftazidime and avibactam are hemodialyzable; thus, Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) should be administered after hemodialysis on hemodialysis day.
Hemofiltration: There is insufficient data to make specific dosage adjustment recommendations for patients undergoing continuous venovenous hemofiltration.
Peritoneal dialysis: There is insufficient data to make specific dosage adjustment recommendations for patients undergoing peritoneal dialysis.
Patients with hepatic impairment: No dosage adjustment is considered necessary in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions). Close clinical monitoring for safety and efficacy is advised.
Pediatric patients: Safety and efficacy in children and adolescents below 18 years of age have not yet been established.
Currently available data are described in Adverse Reactions but no recommendation on a posology can be made.
Method of administration: Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) is administered by intravenous infusion over 120 minutes in an infusion volume of 100 ml.
Constitution and compatibility: For instructions on reconstitution and dilution of the medicinal product before administration.

Overdosage of ceftazidime-avibactam is unlikely, although overdosing could potentially occur in patients with moderate to severe renal impairment, and in end stage renal disease including patients undergoing hemodialysis (see Precautions and Pharmacology: Pharmacokinetics under Actions). Overdosing with ceftazidime-avibactam can lead to neurological sequelae including encephalopathy, convulsions and coma, due to the ceftazidime component.
Treatment for overdose should follow local standard medical practice. Both ceftazidime and avibactam can be partially removed by hemodialysis.

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

Hypersensitivity reactions: As with all β-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with Ceftazidime (as pentahydrate)/Avibactam (as sodium) (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 severe hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactam agent. Caution should be used if ceftazidime-avibactam is given to patients with a history of non-severe hypersensitivity to other β-lactam agents.
Limitation of the clinical data: Use of ceftazidime-avibactam to treat patients with Gram negative aerobic infections (see Pharmacology: Pharmacodynamics under Actions for species against which evidence of clinical efficacy has been observed) where therapeutic options are limited should be only after consultation with a physician with appropriate experience in the management of infectious diseases. Use of ceftazidime-avibactam in these infections is based on PK/PD extrapolations: no clinical studies have been conducted.
Hospital-Acquired Pneumonia (HAP), including Ventilator-Associated Pneumonia (VAP): In a single study in patients with nosocomial pneumonia 280/808 (34.7%) had VAP and 40/808 (5.0%) were bacteraemic at baseline.
Clostridium difficile-associated diarrhea: Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all anti-bacterial agents, including ceftazidime-avibactam, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or subsequent to the administration of Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) (see Adverse Reactions). Discontinuation of therapy with Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Patients with renal impairment: Ceftazidime and avibactam are eliminated via the kidneys, therefore the dose should be reduced according to the degree of renal impairment. Patients with renal impairment should be closely monitored for both safety and efficacy. Neurological sequelae, including tremor, myoclonus, nonconvulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment (see Dosage & Administration).
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.
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.
Non-drug interference: Ceftazidime does not interfere with enzyme-based tests for glycosuria, but slight interference (false-positive) may occur with copper reduction methods (Benedict's, Fehling's, Clinitest).
Ceftazidime does not interfere in the alkaline picrate assay for creatinine.
Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of hemolytic anemia: Cephalosporin 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 hemolytic anemia. While DAGT seroconversion in patients receiving Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) was frequent in clinical studies, there was no evidence of hemolysis in patients who developed a positive DAGT on treatment (see Adverse Reactions). However, the possibility that hemolytic anemia could occur in association with Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) treatment cannot be ruled out. Patients experiencing anemia during or after treatment with Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) should be investigated for this possibility.
Controlled sodium diet: Each vial contains a total of 6.44 mmol of sodium (approximately 148 mg), equivalent to 7.4% of the WHO recommended maximum daily intake for sodium. The maximum daily dose of this product is equivalent to 22.2% of the WHO recommended maximum daily intake for sodium.
This should be considered when administering Zavicefta to patients who are on a controlled sodium diet.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g., dizziness), which may influence the ability to drive and use machines (see Adverse Reactions).

Pregnancy: There is limited clinical data from the use of ceftazidime-avibactam in pregnant women. Animal embryofetal development studies conducted with ceftazidime or avibactam do not indicate harmful effects at exposures equivalent to therapeutic concentrations. Following administration of avibactam throughout pregnancy and lactation in the rat at maternal exposures greater than or equal to approximately 1.5 times human therapeutic exposures, there were minor changes in the morphology of the kidney and ureters in the rat pups (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Ceftazidime-avibactam should not be used during pregnancy unless clearly necessary and only if the potential benefit outweighs the possible risk.
Lactation: There are no data on human milk excretion of ceftazidime-avibactam. Ceftazidime is excreted in human milk in small quantities. It is unknown whether avibactam is excreted in human milk. Women who are breast-feeding should be treated with ceftazidime-avibactam only if clearly indicated. Interruption of breast-feeding is recommended.
Fertility: The effects of ceftazidime-avibactam on fertility in humans have not been studied. Animal studies with ceftazidime or avibactam do not indicate harmful effects with respect to fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).

In seven Phase 2 and Phase 3 clinical trials, 2024 adult patients were treated with Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta). The most common adverse reactions occurring in ≥5% of patients treated with Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) were Coombs direct test positive, nausea, and diarrhea. These 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 all Phase 2 and Phase 3 clinical trials with Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) (N = 2024). 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, 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).
If an event was not seen in the overall Phase 2 and Phase 3 pool but was a known ADR for ceftazidime alone, the frequency category for ceftazidime alone was used (including the category Unknown). (See Table 12.)

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Pediatric population: The safety assessment in children is based on the safety data from 1 trial in which 61 pediatric patients aged from 3 years to less than 18 years with cIAI received Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta). Overall, the safety profile in these 61 children was similar to that observed in the adult population with cIAI.

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 if concurrent administration of ceftazidime-avibactam with chloramphenicol is proposed, the possibility of antagonism should be considered.
Avibactam showed no significant inhibition of cytochrome P450 enzymes. Avibactam and ceftazidime showed no in vitro cytochrome P450 induction in the clinically relevant exposure range. Avibactam and ceftazidime do not inhibit the major renal or hepatic transporters in the clinically relevant exposure range, therefore the drug-drug interaction potential via these mechanisms is considered low.
In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment and, thereby 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 when co-dosed. Since a clinical interaction study of avibactam and probenecid has not been conducted, co-dosing of avibactam with probenecid is not recommended.

Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Special Precautions for Disposal and Other Handling: The powder must be reconstituted with sterile water for injection and the resulting concentrate must then be immediately diluted prior to use. The reconstituted solution is a pale yellow solution that is free of any particles.
Standard aseptic techniques should be used for solution preparation and administration.
1. Introduce the syringe needle through the vial closure and inject 10 mL of sterile water for injection.
2. Withdraw the needle and shake the vial to give a clear solution.
3. Do not insert a gas relief needle until the product has dissolved. Insert a gas relief needle through the vial closure to relieve the internal pressure.
4. Transfer the entire contents (approximately 12.0 mL) of the resultant solution to an infusion bag immediately. Reduced doses may be achieved by transfer of an appropriate volume of the resultant solution to an infusion bag, based upon ceftazidime and avibactam content of 167.3 mg/mL and 41.8 mg/mL, respectively. A dose of 1000 mg/250 mg or 750 mg/187.5 mg is achieved with 6.0 mL or 4.5 mL aliquots, respectively.
Note: To preserve product sterility, it is important that the gas relief needle is not inserted through the vial closure before the product is dissolved.
Vials of ceftazidime-avibactam powder should be reconstituted with 10 ml of sterile water for injections, followed by shaking until the content dissolves. An infusion bag may contain any of the following: sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution for injection, sodium chloride 4.5 mg/mL and dextrose 25 mg/mL solution for injection (0.45% sodium chloride and 2.5% dextrose) or Lactated Ringer's solution. A 100 mL infusion bag can be used to prepare the infusion, based on the patient's volume requirements. The total time interval between starting reconstitution and completing preparation of the intravenous infusion should not exceed 30 minutes.
Each vial is for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.

Special Precautions for Storage: Store at temperatures not exceeding 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 at temperatures not exceeding 30°C.
After reconstitution: The reconstituted vial should be used immediately.
After dilution: Once the intravenous solution is prepared with diluents it should be administered within 12 hours of preparation. The chemical and physical in-use stability has been demonstrated for up to 24 hours at 2-8°C. Once removed from refrigeration the diluted product must be stored at room temperature and used within 12 hours.
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 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Cephalosporins

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

Rx

Powd for conc for soln for infusion (vial) 10's.