ZAVICEFTA Ceftazidime / Avibactam 2g / 500mg Powder for IV Infusion 10's

Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) is indicated in adults, infants (aged 3 months and older), children and adolescents 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, 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.
Treatment of adult patients with bacteremia that occurs in association with, or is suspected to be associated with cIAI, cUTI, or HAP/VAP.
Consideration should be given to official guidance on the appropriate use of antibacterial agents. For treatment of cIAI use in combination with metronidazole.

 

It is recommended that Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) should be used to treat infections due to aerobic Gram-negative organisms in adults and pediatric patients aged 3 months and older with limited treatment options only after consultation with a physician with appropriate experience in the management of infectious diseases (see Precautions).
Dosage in Adults with Creatinine Clearance (CrCL >50 mL/min): 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) over 2 hours. Treatment is repeated every 8 hours. The duration of treatment is provided in Table 14.
Treatment Duration for Adult Patients: see Table 14.

The duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress.
Dosage in pediatric patients with creatinine clearance (CrCL) >50 mL/min/1.73 m²: The recommended dosage of Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) in pediatric patients (3 months to <18 years) is based on the age and weight of the patient. Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) is administered every 8 hours by intravenous infusion over 2 hours, see Table 15. The duration of therapy should be guided by the severity, site of infection and the patient's clinical and bacteriological progress. (See Table 15.)

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 16 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.
Dosage in adults and pediatric patients with creatinine clearance (CrCL) ≤50 mL/min: See Table 16.

Dosage in pediatric patients <2 years of age with creatinine clearance (CrCl) ≤ 50 mL/min/1.73 m²: There is insufficient information to recommend a dosage regimen for pediatric patients < 2 years of age that have a CrCL ≤ 50 mL/min/1.73 m².
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 <18 years of age have not yet been established for HAP/HAV and is based on extrapolation (see Precautions).
Safety and efficacy in pediatric patients <3 months old have not been established.
Method of administration: Intravenous use.
Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) is administered to adults by intravenous infusion over 2 hours in an appropriate infusion volume (see Special Precautions for Disposal and Other Handling under Cautions for Usage).
Constitution and compatibility: For instructions on reconstitution and dilution of the medicinal product before administration (see Special Precautions for Disposal and Other Handling under Cautions for Usage).

 

Overdosage

Hypersensitivity to the active substances or to any of the excipients listed in Inactive Ingredients/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.
No clinical studies have been conducted in pediatric patients with nosocomial pneumonia. The efficacy of Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) for the treatment of pediatric patients ≥3 months of age with HAP/VAP is extrapolated from adults and is based on analyses of the pharmacokinetic-pharmacodynamic relationship for Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) and on pediatric experience with ceftazidime alone (see Pharmacology: Pharmacokinetics under Actions).
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).
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.
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.
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: 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 22.2% of the WHO recommended maximum daily intake for sodium. Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) is considered high in sodium.
This should be considered when administering Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) to patients who are on a controlled sodium diet.
Ceftazidime (as pentahydrate)/Avibactam (as sodium) Zavicefta may be diluted with sodium-containing solutions (see Special Precautions for Disposal and Other Handling under Cautions for Usage) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.
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).
Use in Children: There is a potential risk of overdosing, particularly for pediatric patients aged from 3 to less than 12 months of age. Care should be taken when calculating the volume of administration of the dose (see Overdosage and Special Precautions for Disposal and Other Handling under Cautions for Usage).

 

Use In Pregnancy & Lactation

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). (See Table 17.)

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) and 67 patients with cUTI (aged from 3 months to less than 18 years) received Ceftazidime (as pentahydrate)/Avibactam (as sodium). Overall, the safety profile in these 128 pediatric patients was similar to that observed in the adult population with cIAI and cUTI.

 

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.

 

Caution For Usage

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Special Precautions for Disposal and Other Handling as follows.
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.
Instructions for preparing Pediatric Doses: Infusion Bags: 1. Introduce the syringe needle through the vial closure and inject 10 mL of sterile water for injections.
2. Withdraw the needle and shake the vial to give a clear solution.
3. After the product has dissolved, insert a gas relief needle through the vial closure to relieve the internal pressure.
4. The reconstituted solution must be further diluted to a ceftazidime concentration of 8-40 mg/mL to produce Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) solution for infusion. For a ceftazidime dose of 2g, transfer the entire contents (approximately 12.0 mL) of the reconstituted solution to an infusion bag immediately. A ceftazidime dose of 1g or 0.75 g is achieved with 6.0 mL or 4.5 mL aliquots, respectively. For all other doses, transfer an appropriately calculated volume of the reconstituted solution to an infusion bag, based upon ceftazidime content of 167.3 mg/mL. Table 18 shows the recommended instructions on reconstitution of Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) before administration.
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.
Infusion Syringes: 1. Introduce the syringe needle through the vial closure and inject 10 mL of sterile water for injections.
2. Withdraw the needle and shake the vial to give a clear solution.
3. After the product has dissolved, insert a gas relief needle through the vial closure to relieve the internal pressure.
4. The reconstituted solution must be further diluted to a ceftazidime concentration of 8-40 mg/mL to produce Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) solution for infusion. Doses may be achieved by transfer of an appropriately calculated volume of the reconstituted solution combined with additional diluent necessary to achieve a ceftazidime concentration of 8-40 mg/mL to an infusion syringe, based upon ceftazidime content of 167.3 mg/mL. Table 18 shows the recommended instructions on reconstitution of Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) before administration. (See Table 18.)

An infusion syringe may contain either of the following: sodium chloride 9 mg/mL (0.9%) solution for injection or dextrose 50 mg/mL (5%) solution for injection.
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.

 

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.

 

Action

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).
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.

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.

A further 432 adults with cIAI 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).

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.

Among patients with baseline bacteremia 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 bacteremia 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 favorable 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 bacteremia; and 3/4 (75.0%) CAZ-AVI- and 2/2 (100.0%) comparator-treated patients with P. aeruginosa bacteremia.
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 2 hours 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.)

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

Among patients with baseline bacteremia who were enrolled in any of the phase 3 cUTI studies (RECAPTURE or REPRISE), clinical cure at TOC in the subset of patients with bacteremia due to aerobic Gram-negative pathogens was observed in 28/28 (100.0%) patients treated with CAZ-AVI 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 favorable 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 CAZAVI group and 19/23 (82.6%) in the comparator group had a favorable per-pathogen microbiological response for E. coli, which was the most common pathogen.
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.

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.

For HAP/VAP patients enrolled with baseline bacteremia, clinical cure at TOC in the subset of patients with bacteremia 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, favorable per-pathogen microbiological response rates in this sub-group were broadly similar to those of the overall population.
Among patients enrolled with baseline bacteremia in the Phase 3 program across all indications combined (cIAI, cUTI or HAP/VAP), clinical cure at TOC in the subset of patients with bacteremia 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 subgroup, a favorable 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 bacteremia; and 6/11 (54.5%) CAZ-AVI ± MTZ- and 3/6 (50.0%) comparator-treated patients with P. aeruginosa bacteremia.
Pediatric population: Ceftazidime-avibactam has been evaluated in pediatric patients aged 3 months to <18 years in two Phase 2 single-blind, randomized, comparative clinical studies, one in patients with cIAI and one in patients with cUTI (Doses provided in Table 15). Patients aged ≥3 months to <1 year must have been born at term (defined as gestational age ≥37 weeks). Patients treated with ceftazidime-avibactam in the cIAI trial also received metronidazole (administered per local label; suggested dose: 10 mg/kg every 8 hours, administered IV over 20 to 30 minutes). The primary objective in each study was to assess safety and tolerability of ceftazidime-avibactam (+/- metronidazole). Secondary objectives included assessment of PK and efficacy; efficacy was a descriptive endpoint in both studies.
cIAI: A total of 83 pediatric patients with cIAI were randomized (3:1) and received treatment with either ceftazidime-avibactam plus metronidazole (n=61) (doses provided in Table 15), or meropenem (n=22), 20 mg/kg IV every 8 hours. After a minimum of 72 hours of IV treatment, there was an optional switch to oral therapy for patients who had clinical improvement, as defined in the study protocol. The total duration of antibiotic therapy (IV plus oral) was between 7 and 15 days. TOC assessments were performed 8 to 15 days after the last dose of study drug (IV or oral).
The majority of patients (87%) had appendiceal perforation or peri-appendiceal abscess (52/61, 85.2% ceftazidime-avibactam plus metronidazole; 20/22, 90.9% meropenem). The CE population included patients who had a confirmed diagnosis of cIAI and received a minimum duration of IV study drug, and excluded patients who had a clinical response of indeterminate and/or an important protocol deviation impacting the assessment of efficacy. The microbiological intent-to treat (micro-ITT) population included 69 patients (50 ceftazidime-avibactam plus metronidazole, 19 meropenem) who had at least one baseline intra-abdominal pathogen. Favourable clinical response rates at TOC are presented in Table 10. (See Table 10.)

The predominant pathogens isolated at baseline were E. coli (55/69, 79.7%) and P. aeruginosa 23/69 (33.3%). Favourable clinical response rates at TOC by baseline pathogen in the micro-ITT population are presented in Table 11. (See Table 11.)

cUTI: A total of 95 pediatric patients with cUTI were randomized (3:1) and received treatment with either ceftazidime-avibactam (n=67) (doses provided in Table 2), or cefepime (n=28), dosed per local prescribing information (maximum dose 2 g). After a minimum of 72 hours of IV treatment, there was an optional switch to oral therapy for patients who had clinical improvement, as defined in the study protocol. The total duration of antibiotic therapy (IV plus oral) was between 7 and 14 days. TOC assessments were performed 8 to 15 days after the last dose of study drug (IV or oral).
The majority of patients (83.2%) had acute pyelonephritis (55/67, 82.1% ceftazidime-avibactam; 24/28, 85.7% cefepime). The micro-ITT population included 77 randomized patients (54 ceftazidime-avibactam, 23 cefepime) who had at least 1 Gram-negative typical pathogen known to cause cUTI and no Gram-positive pathogen in the urine at baseline. Favorable clinical, microbiological and combined clinical and microbiological response rates at TOC in the micro-ITT population are presented in Table 12. (See Table 12.)

The predominant baseline pathogen was E. coli (71/77, 92.2%). Favourable microbiological response rates by baseline pathogen at TOC in the micro-ITT population are presented in Table 13. (See Table 13.)

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 17 L and 22 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 pharmacokinetics of ceftazidime and avibactam were evaluated in pediatric 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 Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) 2.5 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 and avibactam AUC_0-t and C_max values in the two older cohorts (children 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 Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) 2 g/0.5 g. Data from this study and the two Phase 2 pediatric 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 pediatric patients with cIAI, cUTI and HAP/VAP, 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 Ceftazidime (as pentahydrate)/Avibactam (as sodium) (Zavicefta) dose of 2 g/0.5 g administered over 2 hours, every 8 hours.
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.

 

Cephalosporins