Approval Date.
Ceftazidime Avibactam Sodium for Injection Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Ceftazidime Avibactam Sodium for Injection
Trade name: Ceftazidime®/ZaviceftaÒ
English name: Ceftazidime and Avibactam Sodium for Injection
Hanyu Pinyin: Zhusheyong Toubaotading Aweibatanna
Ingredients
This product is a compound preparation, its components are Ceftazidime Pentahydrate (equivalent to Ceftazidime C22H22N6O7S2 2.0g) and Avibactam Sodium (equivalent to Avibactam C7H11N3O6S 0.5g).
Ceftazidime pentahydrate
Chemical name: (6R,7R)-7-[[(2-amino-4-thiazolyl)-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-methylpyridinium inner salt pentahydrate
Chemical structure formula.
Molecular formula: C22H32N6O12S2
Molecular weight: 636.7
Avibactam sodium
Chemical name: Sodium [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl]sulfate
Chemical structure formula.
Molecular formula: C7H10N3O6SNa
Molecular weight: 287.23
Excipient: anhydrous sodium carbonate.
【Properties】.
This product is white to light yellow powder.
Indications】
1.Complex intra-abdominal infection (cIAI)
This product is indicated for the treatment of complicated intra-abdominal infections caused by the following Gram-negative bacteria sensitive to this product in patients aged 18 years and above in combination with metronidazole: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella acidophilus, Citrobacter fowleri complex and Pseudomonas aeruginosa.
2. Hospital-acquired pneumonia and ventilator-associated pneumonia (HAP/VAP)
This product is indicated for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia caused by the following Gram-negative bacteria that are sensitive to this product in patients 18 years of age and older: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Acinetobacter chimaera, Pseudomonas aeruginosa and Haemophilus influenzae.
3. Treatment of infections caused by the following Gram-negative bacteria sensitive to this product in adult patients with limited treatment options: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Acinetobacter chimaera and Pseudomonas aeruginosa.
This indication is based on experience with ceftazidime alone and an analysis of the pharmacokinetic-pharmacodynamic relationship of ceftazidime/avibactam. It should only be used for this indication by physicians with extensive experience in the treatment of infectious diseases.
To reduce the emergence of drug-resistant bacteria and to maintain the effectiveness of this and other antibacterial drugs, this product is indicated only for the treatment of infections diagnosed or highly suspected to be caused by susceptible bacteria. Drug selection or adjustment should be based on new culture and drug sensitivity results. In the absence of such data, local epidemiology and resistance analysis may be useful for empirical treatment selection.
Specification
2.5g (C22H22N6O7S2 2.0g with C7H11N3O6S 0.5g).
Dosage]
Dosage
The recommended intravenous doses1 for patients with an estimated creatinine clearance (eCrCL) ≥51 mL/min are shown in Table 1 (see [Precautions] and [Pharmacokinetics]).
Table 1 Doses of this product administered summarized by indication
Infection Dose Administration Frequency Infusion Time (hours) Regimen Complex Intra-abdominal Infections2,3 [in combination with metronidazole] 2.5 g (2 g/0.5 g) once every 8 hours 25 to 14 days Hospital-acquired pneumonia and ventilator-associated pneumonia 32.5 g (2 g/0.5 g) once every 8 hours 27 to 14 days Treatment regimen Options for aerobic Gram-negative bacteria caused by aerobic Gram-negative bacteria in adult patients with limited Infections 2,32.5 g (2 g/0.5 g) every 8 hours2 depending on the severity of the infection, the causative organism, the patient’s clinical condition, and bacteriologic progress.41 CrCL was estimated using the Cockcroft-Gault formula.
2 If anaerobic bacteria are also known or suspected to be associated with the infectious process, they should be combined with metronidazole.
3 If gram-positive bacteria are also known or suspected to be associated with the infectious process, it should be used in combination with an antimicrobial agent that is active against gram-positive bacteria.
4 There is limited experience with the use of this product for more than 14 days.
Special Populations
Elderly
No dose adjustment is required in the elderly (see [Pharmacokinetics]).
Patients with renal impairment
No dose adjustment is required in patients with mild renal impairment (51 mL/min ≤ eCrCL ≤ 80 mL/min) (see [Pharmacokinetics]).
Recommended dose adjustments for patients with eCrCL ≤ 50 mL/min are shown in Table 2. For patients with changing renal function, monitor CrCL at least daily and adjust the dose accordingly (see [Precautions] and [Pharmacokinetics]).
(see [Precautions] and [Pharmacokinetics]).
Table 2 Recommended doses for intravenous infusion in patients with eCrCL ≤ 50 mL/min1
eCrCL (mL/min) dose2 dosing frequency infusion time (hours) 31~501.25 g (1g/0.25 g)
1 every 8 hours2 16~300.94 g (0.75g/0.19 g) 1 every 12 hours2 6~150.94 g (0.75g/0.19 g) 1 every 24 hours2 ≤530.94 g (0.75g/0.19 g) 1 every 48 hours21 CrCL was estimated using the Cockcroft-Gault formula.
2 Dosing recommendations were based on pharmacokinetic models.
3 Ceftazidime and avibactam are cleared by hemodialysis (see [Drug Overdose] and [Pharmacokinetics]). The product should be administered after hemodialysis is completed on the day of hemodialysis.
Patients with Hepatic Impairment
No dose adjustment is required in patients with hepatic impairment (see [Pharmacokinetics]).
Pediatric Population
Efficacy and safety in children and adolescents under 18 years of age have not been established.
Mode of administration
Intravenous infusion over 120 minutes in a volume of 100 ml.
Instructions for re-dissolution and dilution prior to administration are as follows.
Special handling and other operational considerations
The product must be reconstituted with water for injection and the reconstituted concentrate should be diluted immediately for use. The re-dissolved solution is light yellow and free of particles.
The solution should be prepared and administered using standard aseptic technique.
1.Insert the syringe needle into the vial and inject 10 ml of sterile water for injection.
2.Pull out the needle and shake the vial until the solution is clarified.
3.Do not insert the needle to deflate the drug before it dissolves. Dissolve and then insert the needle into the vial to release the internal pressure.
4. Immediately transfer all of the prepared solution (approximately 12.0 ml) to the infusion bag. Depending on the content of ceftazidime and avibactam of 167.3 mg/ml and 41.8 mg/ml, respectively, a reduced dose can be obtained by transferring the appropriate volume of solution to the infusion bag. 6.0 ml or 4.5 ml of solution can be used to obtain a dose of 1.25 g (1 g/0.25 g) or 0.94 g (0.75 g/0.19 g), respectively.
Note: To maintain the sterility of the drug, do not insert the deflation needle into the bottle before dissolving the drug.
Vials containing ceftazidime/avibactam powder should be re-dissolved with 10 ml sterile water for injection and then shaken until the contents are dissolved. Infusion bags may contain the following components: sodium chloride solution for injection (9 mg/ml, 0.9%), glucose solution for injection (50 mg/ml, 5%), sodium chloride solution for glucose for injection (glucose 25 mg/ml, 2.5% and sodium chloride 4.5 mg/ml, 0.45%), or lactated Ringer’s solution. Depending on the volume requirements of the patient, a 100 ml infusion bag may be used to prepare the infusion. The total time interval between the start of the re-dissolution and the completion of the preparation of the intravenous infusion should not exceed 30 minutes.
This product should not be mixed with drugs other than those described above.
Each vial is for a single use only.
Any unused medication or waste material should be disposed of according to local requirements.
After reconstitution
It should be used immediately after re-dissolution.
After dilution
In-use stability data have confirmed chemical and physical stability for 24 hours in 2 to 8°C and subsequently for 12 hours below 25°C.
From a microbiological point of view, this product should be used immediately. If not used immediately, the user needs to ensure the storage time and conditions prior to use; it should not normally be stored longer than 24 hours at 2~8°C unless it is re-dissolved/diluted in a controlled and verified sterile environment.
[Adverse Reactions].
The following adverse reactions are discussed in detail in the Precautions section.
Hypersensitivity reactions (see [Precautions]).
Clostridium difficile-associated diarrhea (CDAD) (see [Precautions]).
Central nervous system reactions (see [Precautions]).
Clinical Study Experience
In seven Phase II and Phase III clinical trials, 2024 adult patients were treated with this product. The most common adverse reactions that occurred at an incidence of ≥5% after treatment with this product were a positive direct Coombs test, nausea, and diarrhea. The degree of nausea and diarrhea was usually mild to moderate.
List of adverse reactions
Table 3 reports the adverse reactions identified with ceftazidime alone and/or with this product in Phase II and Phase III clinical trials. Adverse reactions are categorized by incidence and systemic organ classification. The incidence classification was derived from adverse reactions and/or potentially clinically significant laboratory abnormal values and was defined according to the following convention.
Very common (≥ 1/10)
Common (≥ 1/100 and < 1/10)
Uncommon (≥ 1/1,000 and < 1/100)
Rare (≥ 1/10,000 and < 1/1,000)
Very rare (< 1/10,000)
Unknown (cannot be estimated from available data)
Table 3 Incidence of adverse reactions by system organ classification
Systemic organ classification Very common Common Uncommon Very rare Unknown Infections and infestations Candidiasis (including vulvovaginal candidiasis and oral candidiasis) Clostridium difficile colitis, pseudomembranous colitis Hematologic and lymphatic system abnormalities Direct positive Coombs test Eosinophilia, thrombocytosis, thrombocytopenia Neutropenia, leukocytopenia, leukocytosis
Lymphocytosis Granulocyte deficiency, hemolytic anemia Immune system abnormalities Rapid onset allergic reactions Neurologic and psychiatric abnormalities Headache, dizziness Sensory abnormalities Gastrointestinal abnormalities Diarrhea, abdominal pain, nausea, vomiting Taste disturbances Hepatobiliary system abnormalities Elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated blood alkaline phosphatase, elevated gamma-glutamyl transferase, elevated blood lactate dehydrogenase Jaundice Skin and subcutaneous tissue abnormalities maculopapular rash, urticaria, pruritus toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, drug reactions with eosinophilia and systemic symptoms renal and urinary system abnormalities elevated blood creatinine levels, elevated blood urea, acute renal injury tubulointerstitial nephritis systemic disease and site of administration abnormalities infusion Site thrombosis, injection site phlebitis, fever
In phase III clinical trials of this product, the incidence <1% of anxiety, hypokalemia, and renal stone adverse events were observed in the treatment group, but there was no evidence of a significant causal relationship with the application of this product.
[Contraindications].
Hypersensitivity to the active substance or any of the excipients listed under [Ingredients].
Hypersensitivity to cephalosporin-based antibacterial drugs.
Severe hypersensitivity (e.g. rapid onset allergic reaction, severe skin reaction) to other types of β-lactam antibacterial drugs (e.g. penicillin, monoamide bacteriocins or carbapenems).
[Precautions].
Hypersensitivity reactions
Severe or occasionally fatal hypersensitivity reactions (rapid-onset allergic reactions) or severe skin reactions have been reported in patients treated with β-lactam antibacterial drugs. Carefully ask for a history of prior hypersensitivity reactions to cephalosporins, penicillins, or carbapenems before starting treatment with this product. Cross-sensitivity between β-lactam antibacterial drugs is well established, so caution should be used in patients with hypersensitivity to penicillin or other β-lactam antibiotics. If hypersensitivity occurs while using this product, the drug should be discontinued.
Clostridium difficile-associated diarrhea (CDAD)
CDAD has been reported with almost all systemic antimicrobials (including this product) and can range in severity from mild diarrhea to fatal enterocolitis. Antimicrobial drug therapy can cause alterations in the normal colonic flora, leading to overgrowth of C. difficile.
Toxins A and B produced by C. difficile contribute to the progression of CDAD. Virulent producing strains of C. difficile cause increased morbidity and mortality because antimicrobial therapy for these infections may be ineffective and may require colonic resection. This diagnosis should be considered in patients who develop diarrhea during or after administration of this product (see [Adverse Reactions]). Careful history taking is required as CDAD has been reported more than 2 months after administration of antimicrobial therapy. Discontinuation of treatment with this product and specific C. difficile treatment should be considered. Drugs that inhibit GI motility should not be used. Control fluid and electrolyte levels as appropriate, supplement protein intake, monitor antimicrobial therapy for C. difficile, and perform surgical evaluation when clinically indicated.
Central nervous system reactions
Seizures, non-convulsive continuous status epilepticus (NCSE), encephalopathy, coma, fluttering tremor, neuromuscular excitability, and myoclonus have been reported in patients receiving ceftazidime therapy, particularly in patients with renal impairment. Adjust the dose according to creatinine clearance (see [DOSAGE AND ADMINISTRATION]).
Antibacterial spectrum of ceftazidime/avibactam
Ceftazidime has low or no activity against most Gram-positive and anaerobic bacteria. If these pathogenic bacteria are also known or suspected to be involved in the infection process, they should be used in combination with other antibacterial drugs.
The antibacterial spectrum of avibactam contains inhibition of many enzymes that inactivate ceftazidime, including Ambler class A beta-lactamases and class C beta-lactamases. Avibactam does not inhibit class B enzymes (metallo-beta-lactamases) and does not inhibit many class D enzymes.
Non-susceptible bacteria
Prolonged dosing may result in overgrowth of non-susceptible bacteria (e.g., enterococci, fungi) and may require interruption of therapy or other appropriate measures.
Development of drug-resistant bacteria
Use of this product in cases of undiagnosed or not highly suspected bacterial infections may not be beneficial to the patient and may increase the risk of development of drug-resistant bacteria (see [Indications]).
Impairment of renal function
Ceftazidime and avibactam are cleared by the kidneys; therefore, the dose needs to be reduced according to the degree of renal impairment (see [DOSAGE AND ADMINISTRATION]). Neurological sequelae, including tremor, myoclonus, nonconvulsive seizure disorder, convulsions, encephalopathy, and coma, have occasionally been reported in patients with renal impairment who have not had their dose of ceftazidime reduced.
In patients with renal impairment, close monitoring of eCrCL is recommended. in some patients, creatinine clearance estimated from serum creatinine changes rapidly, especially early in the treatment of infection.
There has been a reduction in clinical efficacy in cIAI patients with baseline 30 mL/min< CrCL ≤50 mL/min at inadequate therapeutic doses
In a phase III cIAI clinical trial, patients with a baseline 30 mL/min< CrCL ≤50 mL/min had a lower clinical cure rate compared to patients with a CrCL> 50 mL/min (Table 4). Patients treated with this product in combination with metronidazole had a more significant reduction in clinical cure rates compared with patients treated with meropenem. In this subgroup, the daily dose for patients treated with this product was 33% lower than the current recommended dose for patients with 30 mL/min<CrCL ≤50 mL/min.
No reduction in clinical efficacy was observed in patients with moderate renal impairment at baseline (30 mL/min<CrCL ≤50 mL/min) in the Phase III cUTI clinical trial or the Phase III HAP/VAP clinical trial.
In patients with changing renal function, CrCL should be monitored at least daily and the dose of this product adjusted accordingly (see [Dosage] and [Adverse Reactions]).
Table 4 Clinical cure rate at cure test summarized by baseline renal function in phase III cIAI clinical trials – mMITT population1
This product + metronidazole
% (n/N) Meropenem
% (n/N) Normal renal function/mild impairment (CrCL> 50 mL/min) 85% (322/379) 86% (321/373) Moderate impairment (30 mL/min< CrCL ≤50 mL/min) 45% (14/31) 74% (26/35) 1 Microbiology modified intention-to-treat (mMITT) population Includes patients with at least one bacterial pathogen at baseline and who have received at least one dose of study drug.
Nephrotoxicity
Combination of high doses of cephalosporins and nephrotoxic agents, such as aminoglycosides or potent diuretics (e.g., furosemide), may adversely affect renal function.
Interference with laboratory tests
Ceftazidime may interfere with copper reduction methods (Benedict’s, Fehling’s, Clinitest) used to detect urine glucose, leading to false positive results. Ceftazidime does not interfere with enzymatic assays for urine glucose.
Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of hemolytic anemia. Use of ceftazidime/avibactam may result in a positive direct antiglobulin test (DAGT or Coombs test) result, which may interfere with crossmatching and/or may cause pharmacogenic immune hemolytic anemia (see [ADVERSE REACTIONS]). Although DAGT seroconversion was common in patients receiving this product in clinical trials (in Phase III studies, the estimated range of seroconversion in patients with a negative Coombs test at baseline and at least one negative follow-up test result was 3.2% to 20.8%), there was no evidence of hemolysis in patients whose DAGT results turned positive during treatment. However, the possibility that the presence of hemolytic anemia is associated with treatment with this product cannot be excluded. This possibility should be investigated in patients who develop anemia during or after treatment with this product.
Sodium controlled diet
Each dose contains a total of 6.44 mmol of sodium (approximately 148 mg), which corresponds to 7.4% of the maximum daily intake of sodium recommended by the WHO. The maximum daily dose of this product is equivalent to 22.2% of the maximum daily intake of sodium recommended by the WHO. This should be considered when using this product in patients on a controlled sodium diet.
Effects on the ability to drive and operate machinery
Adverse reactions (e.g., dizziness) may occur with the administration of this product, which may affect the ability to drive and operate machinery (see [Adverse Reactions]).
Pregnant women and nursing mothers
Pregnant women
Summary of risks
Studies with adequate and well-controlled studies of this product, ceftazidime or avibactam have not been conducted in pregnant women. Ceftazidime and avibactam did not cause teratogenicity in rats when administered at doses 40 and 9 times the clinically recommended dose for humans. Exposure in rabbits did not affect embryo-fetal development at doses 2 times the human clinical dose.
The background risk of significant birth defects and miscarriage in the target population is not known. The background risk of major birth defects in the general population is 2-4%, and the background risk of clinically recognized pregnancy miscarriage is 15-20%. Because the results of animal reproduction studies do not always accurately predict human response, this product should be used in pregnancy only when clearly needed.
Data
Animal data
See [Pharmacology and Toxicology].
Lactating women
Risk Summary
Ceftazidime can enter human milk in small amounts. Although studies have shown that avibactam can be secreted into rat milk, it is not known if it also enters human milk. There is no information to suggest that ceftazidime and avibactam affect breastfed infants or breast milk production.
The developmental and health benefits of breastfeeding must be considered in the context of the maternal clinical need for the product and any potential side effects of the product or maternal underlying disease on the breastfed infant.
Data
In a prenatal and postnatal study in rats receiving up to 825 mg/kg/day of avibactam (11 times the human exposure [AUC]) IV administration, it was observed that the exposure to avibactam in the litter was minor compared to the dam. At postnatal day 7 (PND7), avibactam was detected in both litters and milk.
Fertility
The effect of ceftazidime/avibactam on human fertility has not been studied. No data are available from animal tests with ceftazidime. Animal tests have shown that avibactam has no harmful effects on fertility.
Pediatric Use
Efficacy and safety have not been established in children and adolescents under 18 years of age.
Geriatric Use
In phase II and III clinical trials (2024 cases), 32.7% (661/2024 cases) of patients ≥65 years old were in the treatment group, including 15.5% (314/2024 cases) ≥75 years old.
In a pooled analysis of phase II and III cIAI trials, 19.6% (168/857) of patients ≥65 years of age were in the treatment group, of whom 7.1% (61/857) were ≥75 years of age. adverse event rates were similar in the two treatment groups and higher in older patients (≥65 years). In a global cIAI trial called RECLAIM, the clinical cure rates were 74.8% (89/119 patients) and 76.4% (94/123 patients) in the modified intention-to-treat (MITT) and meropenem groups, respectively, for patients ≥65 years of age, and 74.8% (89/119 patients) and 76.4% (94/123 patients) in the clinically evaluable (CE) groups for patients ≥65 years of age, respectively. The clinical cure rates were 89.9% (80/89 cases) and 87.2% (75/86 cases) for patients aged 65 years in the clinically evaluable (CE) population. In an Asia-Pacific cIAI trial called RECLAIM 3, the clinical cure rates for the CE population were 93.8% (30/32 cases) and 92.9% (39/42 cases) for patients ≥65 years of age in the treatment with metronidazole and meropenem groups, respectively, at the time of the visit of cure (TOC).
In the phase III cUTI trial, 30.7% (157/511 patients) of patients ≥65 years of age were in the treatment group, including 15.3% (78/511 patients) ≥75 years of age. the incidence of adverse events was similar in the two treatment groups and lower in older patients (≥65 years). In the phase III cUTI trial in patients ≥65 years of age, the rate of resolution of symptoms at day 5 was 66.1% (82/124 patients) and 56.6% (77/136 patients) in the treatment group and the doripenem group, respectively. At the test of cure (TOC) visit, the combined efficiency rate (microbiological cure rate and symptom remission rate) was 58.1% (72/124 patients) and 58.8% (80/136 patients) for patients ≥65 years old in the 2 groups, respectively.
In the phase III HAP/VAP clinical trial, 54.1% (236/436 cases) of patients ≥65 years old were in the treatment group, of which 29.6% (129/436 cases) were ≥75 years old. The incidence of adverse reactions in patients ≥65 years of age was similar to that in patients <65 years of age. 28-day all-cause mortality was similar in patients ≥65 years of age in the 2 treatment groups (12.7% [29/229 cases] and 11.3% [26/230 cases] in the Benzedrine and meropenem groups, respectively).
Ceftazidime and avibactam are mainly excreted through the kidneys, so the risk of adverse reactions may be higher in patients with decompensated renal function. Because elderly patients are more likely to have reduced renal function, dose selection should be cautious and renal function should be closely monitored. The 17% higher exposure in older healthy subjects given the same dose of avibactam in a single dose compared to younger healthy subjects may be related to the reduced renal function in older subjects. Dosing in elderly patients should be adjusted according to renal function (see [Dosage] and [Pharmacokinetics]).
Drug Interactions]
In vitro, avibactam has no significant inhibitory effect on cytochrome P450 enzymes. Clinically relevant concentrations of avibactam and ceftazidime have no induction of cytochrome P450 in vitro. In the clinically relevant exposure range, avibactam and ceftazidime do not inhibit major renal or hepatic transport proteins, so it is thought that interactions that may be induced by these mechanisms are minimal.
In vitro, clinically relevant concentrations of avibactam in human liver microsomes do not inhibit the cytochrome P450 isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. In vitro in human hepatocytes avibactam has no ability to induce CYP1A2/2B6/ 2C9 and 3A4 in human hepatocytes in vitro. Very high concentrations of avibactam above clinically relevant exposures had a slight ability to induce CYP2E1. Ceftazidime was evaluated in human hepatocytes alone and showed no induction of CYP1A1/2, CYP2B6 and CYP3A4/5 activity or mRNA expression by ceftazidime.
Neither ceftazidime nor avibactam at clinically relevant concentrations are inhibitors of the following liver or kidney transport proteins: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, MRP4, OCT1 and OCT2. Based on results in human embryonic kidney cells expressing these transport proteins, avibactam is not an inhibitor of MDR1, BCRP, MRP4 or OCT2 substrates, but rather substrates of human OAT1 and OAT3 renal transporter proteins. In vitro, propofol inhibits 56-70% of avibactam uptake by inhibiting OAT1 and OAT3. Ceftazidime does not inhibit OAT1- and OAT3-mediated avibactam transport. The clinical impact of potent OAT inhibitors on avibactam pharmacokinetics is not known. Concomitant use of this product and probenecid is not recommended.
Human clinical trials have demonstrated no interaction between ceftazidime and avibactam and no interaction between ceftazidime/avibactam and metronidazole.
Ceftazidime administration may result in a false positive reaction for glucose in urine for some tests. A glucose oxidase-mediated enzymatic reaction is recommended for the detection of glucose.
Other forms of interactions
The combination of high doses of cephalosporins and nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g., furosemide) may have adverse effects on renal function (see [Precautions]).
In vitro, chloramphenicol is antagonistic to ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but combination use should be avoided due to the possible antagonistic effect in vivo.
Drug overdose]
Because this product contains ceftazidime, ceftazidime/avibactam overdose can lead to neurological sequelae including encephalopathy, convulsions and coma.
In case of overdose, discontinue the product and administer general supportive therapy.
Ceftazidime and avibactam can be cleared by hemodialysis. In patients with end-stage renal disease (ESRD) who received 1 g ceftazidime administration, the mean overall recovery in the dialysate after 4 hours of hemodialysis was 55% of the administered dose. In ESRD patients receiving 100 mg avibactam administration, the mean overall recovery in dialysate after 4 hours of hemodialysis was 55% of the administered dose.
There is no clinical information regarding the use of hemodialysis to manage overdose of this product.
[Clinical Trial].
Complex intra-abdominal infection
Global RECLAIM study:
In 2 identical randomized, multicenter, multinational, double-blind studies (RECLAIM 1 and RECLAIM 2, collectively RECLAIM), a total of 1058 adult patients with complicated intra-abdominal infections (defined as infections requiring surgical intervention and extending from the cavernous organs into the peritoneal space) were randomized and treated to compare ceftazidime/avibactam (2000 mg ceftazidime and 500 mg avibactam) given by intravenous infusion of metronidazole (500 mg) every 8 hours over 120 minutes versus meropenem (1000 mg) given by intravenous infusion every 8 hours over 30 minutes. The duration of treatment was 5 to 14 days. the MITT population included all patients who met the definition of cIAI disease and received at least 1 dose of study drug. the CE population included patients with an appropriate cIAI diagnosis, excluding patients whose strains were expected to be generally unresponsive to both study drugs (e.g., Acinetobacter baumannii or narrow-feeding Aeromonas spp.) and/or patients who experienced a significant regimen violation that affected the assessment of efficacy.
The primary efficacy endpoint was clinical efficacy at the test of cure (TOC) visit, with CE and MITT patients as a synergistic primary analysis population, as shown in Table 5 below.
Table 5 Clinical cure rates at TOC (RECLAIM study, MITT and CE analysis sets)
Analysis set Number of patients (%) Efficacy CAZ-AVI + MTZ Meropenem Differencea (95% CI )b MITT (N=520) (N=523) Clinical cure429 (82.5)444 (84.9)-2.4 (-6.90, 2.10) Clinical treatment failure47 (9.0)39 (7.5) Uncertain44 (8.5)40 (7.6 ) CE (N=410) (N=416) Clinical cure376 (91.7)385 (92.5)-0.8 (-4.61, 2.89)Clinical treatment failure34 (8.3)31 (7.5) aDifference = difference in clinical cure rate (CAZ-AVI treatment group minus meropenem treatment group).
bConfidence intervals (CI) for differences between groups were calculated using the non-stratified Miettinen and Nurminen method.
Table 6 below summarizes the clinical cure rates at TOC for the microbiologically modified intention-to-treat (mMITT) population by pathogen for aerobic Gram-negative bacteria.
Table 6 Analysis of clinical cure rates at TOC by common (total frequency ≥10 in both groups) baseline gram-negative organisms (RECLAIM study, mMITT analysis set)
Number of patients CAZ-AVI + MTZ (N=413) Meropenem (N=410) Pathogenic bacteria cure rate
(%) Number of patients clinically cured n Cure rate
(%) Number of patients clinically cured n Enterobacteriaceae bacteria 81.427233486.4305353 Fusobacterium citricum complex 77.8141875.0912 Enterobacter aerogenes 80.04510055 Enterobacter cloacae 84.6111384.21619 Escherichia coli 80.421827187.0248285 Acid-producing Klebsiella 77.8141880.01215 Klebsiella pneumoniae 78.4405175.53749 Aspergillus chimaera 62.55877.879 Pseudomonas aeruginosa 85.7303594.43436
RECLAIM3 study in Asia Pacific.
A multinational, multicenter, double-blind phase III clinical study (RECLAIM3) was conducted in 3 Asian countries (China, Korea, and Vietnam) to evaluate the efficacy, safety, and tolerability of ceftazidime-avibactam (CAZ-AVI) plus metronidazole against meropenem for the treatment of complicated internal abdominal infections (cIAI) in hospitalized adult patients. A total of 432 adult inpatients with cIAI were randomized and treated in the study. The patient population and key aspects of the study design were the same as RECLAIM, except that its primary efficacy endpoint, which refers only to clinical outcomes at the time of the TOC visit in the CE population
(see Table 7 below).
Table 7 Clinical efficacy at TOC in the overall population (RECLAIM3, CE analysis set at TOC)
Number of patients (%) Efficacy CAZAVI + metronidazole (N=177) Meropenem (N=184) Differencea (95% CI)b Clinical cure 166 (93.8) 173 (94.0) -0.2 (-5.53, 4.97) Clinical treatment failure 11 (6.2) 11 (6.0) a
Difference = difference in clinical cure rate (CAZ-AVI + metronidazole-treated group minus meropenem-treated group).
b
Confidence intervals (CI) for the differences were calculated using the non-stratified Miettinen and Nurminen method.
Table 8 below shows the clinical cure rates at TOC for aerobic gram-negative bacteria summarized by pathogen in the microbiologically modified intention-to-treat (mMITT) population.
Table 8 Clinical cure rates at TOC by common (total frequency ≥7 in both groups) baseline gram-negative bacteria analysis (RECLAIM3 study, mMITT analysis set)
Number of patients CAZ-AVI + MTZ (N=143) Meropenem (N=152) Pathogenic bacteria cure rate
(%) Number of clinically cured patients n cure rate
(%) Number of clinically cured patients n Enterobacteriaceae bacteria 80.99311592.7115124 Fusobacterium citricum complex 62.558 00 Enterobacter cloacae 1005566.723 Escherichia coli 83.3708494.48489 Klebsiella acidophilus 1005510055 Klebsiella pneumoniae 82.1232888. 63135 Aspergillus oddis 66.72310055 Pseudomonas aeruginosa 82.4141785.01720
RECLAIM3 study China data.
A total of 270 patients were enrolled in China. The primary efficacy outcomes in the Chinese subset were consistent with those in the main study population, with clinical cure rates of 98.0% and 96.6% (difference 1.5%; 95% CI: 3.88 to 6.84) in the Chinese subset of the CE analysis set at TOC in the CAZ-AVI combined with metronidazole group and meropenem group at TOC, respectively (see Table 9 below).
Table 9 Clinical outcome at TOC in the Chinese subset (RECLAIM3 study, CE analysis set at TOC)
Number of patients (%) Efficacy CAZAVI + metronidazole (N=101) Meropenem (N=116) Differencea (95% CI)b Clinical cure 99 (98.0) 112 (96.6) 1.5 (3.88, 6.84) Clinical treatment failure2 (2.0) 4 (3.4) a
Difference = difference in clinical cure rate (CAZ-AVI + metronidazole-treated group minus meropenem-treated group).
b Confidence intervals (CIs) for differences were calculated using the unstratified Miettinen and Nurminen method.
Hospital-acquired pneumonia and ventilator-associated pneumonia
Global REPROVE study.
A total of 808 adult patients (35% VAP) with hospital-acquired pneumonia were randomized and treated in a phase III double-blind controlled study (REPROVE) comparing ceftazidime-avibactam (2000 mg/500 mg) administered intravenously every 8 hours for 120 minutes with meropenem 1 g administered intravenously every 8 hours for 30 minutes. Treatment duration ranged from 7 to 14 days. The clinical modified intention-to-treat (cMITT) population included patients who met minimum disease criteria, received at least one dose of study treatment, and correctly obtained baseline respiratory or blood cultures confirming Gram-negative pathogens, excluding patients with Gram-negative monomicrobial infections of strains not expected to respond to both study drugs (e.g., Bacteroides immobilis or Narrow-feeding Aeromonas spp.). cMITT also included patients who at baseline The CE analysis set at TOC is a clinically evaluable subset of the cMITT analysis set.
The primary efficacy endpoint was the clinical cure rate at the TOC visit in the two synergistic primary analysis populations, cMITT and CE at TOC, as shown in Table 10.
Table 10 Clinical cure rates at TOC (REPROVE study, cMITT and CE at TOC analysis sets)
Number of patients (%) Analysis set Efficacy CAZ-AVI Meropenem Differencea (%) 95% CI bcMITT
Clinical cure (N=356)
245 (68.8) (N=370)
270 (73.0)
-4.2 (-10.76, 2.46)
Clinical treatment failure 79 (22.2) 70 (18.9)
Uncertain 32 (9.0) 30 (8.1) CE at TOC
Clinically cured (N=257)
199 (77.4) (N=270)
211 (78.1)
-0.7 (-7.86, 6.39)
Clinical treatment failure 58 (22.6) 59 (21.9) aDifference = difference in clinical cure rate (CAZ-AVI treatment group minus meropenem treatment group).
bConfidence intervals (CI) for differences between groups were calculated using the unstratified Miettinen and Nurminen method.
In addition, all-cause mortality at day 28 (cMITT population) was 8.4% (30/356) and 7.3% (27/370) in the ceftazidime/avibactam and meropenem-treated groups, respectively.
Tables 11 and 12 summarize the clinical cure rate and microbiological efficiency of the mMITT population at TOC by pathogenic organism for aerobic Gram-negative bacteria.
Table 11 Analysis of clinical cure rates at TOC by common (total frequency ≥10 in both groups) baseline gram-negative organisms (REPROVE study, mMITT analysis set)
Number of patients CAZ-AVI (N=171) Meropenem (N=184) Pathogenic organisms cure rate (%) Clinical
Number cured n Cure rate (%) Number clinically cured n Enterobacteriaceae bacteria 73.68912175.4104138 Enterobacter aerogenes 62.55850.048 Enterobacter cloacae 92.3242654.51222 Escherichia coli 64.7111775.01520 Klebsiella pneumoniae 72.9435977.55571 Aspergillus chimaerae 85.7121475.0912Salmonella mucilaginosa73.3111592.31213Pseudomonas aeruginosa60.3355874.53547Hemophilus influenzae81.3131680.02025
Table 12 Microbiological efficiency by common (total frequency ≥10 in both groups) baseline gram-negative bacteria when analyzing TOC by pathogen (REPROVE study, mMITT analysis set)
Number of patients CAZ-AVI (N=171) Meropenem (N=184) Pathogenic bacteria Effective rate (%) Effective number n Effective rate (%) Effective number n Enterobacteriaceae Bacteriaceae Enterobacter aerogenes 62.55862.558 Enterobacter pubescens 80.8212659.11322 Escherichia coli 76.5131780.01620 Klebsiella pneumoniae 62.7375974.65371 Aspergillus chimaera 78.6111466.7812 Serratia marcescens 66.7101561.5813 Pseudomonas aeruginosa 37.9225838.31847 Haemophilus influenzae 87.5141692.02325
REPROVE study China data
Tables 13 and 14 summarize the clinical cure rates for the CE and cMITT populations at the TOC visit in the Chinese subset, respectively. No formal statistical significance comparisons were designed for the Chinese subset of this study, and for the cMITT and CE analysis sets, the results are consistent with the global results, although the differences observed in the Chinese subset are slightly larger, with confidence intervals (CIs) mostly overlapping.
Table 13 Clinical outcomes at TOC (REPROVE study, CE analysis set) – China
Number of patients (%) Between-group comparison response CAZAVI Meropenem differencea % (% 95% CI of difference b) China, N103107 Clinical cure 68 (66.0)80 (74.8)-8.7 (-20.98, 3.63) Clinical treatment failure 35 (34.0)27 (25.2) a Difference = difference in clinical cure rate (CAZAVI treatment group) minus meropenem-treated group).
b Confidence intervals (CI) for differences between groups were calculated using the unstratified Miettinen and Nurminen method.
Table 14 Clinical outcomes at TOC (REPROVE study, cMITT analysis set) – China
Number of patients (%) Between-group comparison response CAZ-AVI Meropenem Differencea
(95% CI)b China, N124130 Clinical cure73 (58.9)91 (70.0)-11.1 (-22.68, 0.66) Clinical treatment failure41 (33.1)31 (23.8) Uncertain10 (8.1)8 (6.2) a Difference = difference in clinical cure rate (CAZ-AVI treatment group minus meropenem treatment group).
b Confidence intervals (CI) for differences between groups were calculated using the unstratified Miettinen and Nurminen method.
Pharmacology and toxicology]
Pharmacological effects
1) Mechanism of action
Ceftazidime binds to penicillin binding proteins (PBPs) and inhibits bacterial cell wall peptidoglycan synthesis, leading to bacterial cell lysis and death. Avibactam is a non-β-lactam β-lactamase inhibitor that acts after forming covalent adducts with the enzyme that are not easily hydrolyzed. Avibactam inhibits Ambler class A and C β-lactamases and certain class D β-lactamases, including ultra broad-spectrum β-lactamases (ESBLs), KPC and OXA-48 carbapenemases, and AmpC enzymes. Avibactam does not inhibit class B enzymes (metallo-beta-lactamases) and does not inhibit many class D enzymes.
2) Drug resistance
Bacterial resistance mechanisms that may affect ceftazidime/avibactam include mutant or acquired penicillin binding proteins, reduced outer membrane permeability, active efflux mechanisms, and ceftazidime hydrolysis due to β-lactamase tolerance to the inhibitory effects of avibactam.
Cross-resistance
Cross-resistance with other classes of antimicrobial drugs has not been observed. Some isolates that are resistant to other cephalosporins (including ceftazidime) and carbapenems may be sensitive to this product.
(3) Antibacterial activity in combination with other antibacterial drugs
In vitro combination studies have shown no synergistic or antagonistic effects of ceftazidime/avibactam with metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, polymyxin and tigecycline.
4) Antibacterial spectrum
In vitro and in clinical infections, it has been shown to have antibacterial activity against most isolates of the following bacteria.
Complex intra-abdominal infections
Aerobic bacteria
Gram-negative bacteria
Fusobacterium citri complex
Enterobacter cloacae
Escherichia coli
Acid-producing Klebsiella
Klebsiella pneumoniae
Aspergillus chimaera
Pseudomonas aeruginosa
Complex urinary tract infections, including pyelonephritis
Aerobic bacteria
Gram-negative bacteria
Fusobacterium citri complex
Enterobacter cloacae
Escherichia coli
Klebsiella pneumoniae
Aspergillus chimaera
Pseudomonas aeruginosa
Hospital-acquired pneumonia, including ventilator-associated pneumonia
Aerobic bacteria
Gram-negative bacteria
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Aspergillus chimaerae
Pseudomonas aeruginosa
Serratia marcescens
Data from in vitro trials have shown a minimum inhibitory concentration (MIC) of ≤8 μg/mL for more than 90% of similar genera or microbiome isolates of the following bacteria, but the clinical significance of this product is unknown and its efficacy in treating clinical infections caused by these bacteria has not been demonstrated in adequately and well-controlled clinical trials.
Gram-negative bacteria
Citrobacter graminearum
Enterobacter aerogenes
Morganella morganii
Proteus mirabilis
Proteus spp.
Aspergillus oryzae
5) Pharmacokinetics/pharmacodynamic relationship
Studies have shown that the antibacterial activity of ceftazidime against specific pathogenic bacteria correlates most strongly with the PK-PD parameter %fT > MIC (i.e., the time that the free drug concentration remains above the minimum inhibitory concentration as a percentage of the interdose period) for ceftazidime/avibactam. For avibactam, the relevant PK-PD index was %fT >CT (i.e., the time the free drug concentration remained above the threshold concentration as a percentage of the dosing interval).
6) Drug sensitivity test methods
When applicable, clinical microbiology laboratories should provide periodic cumulative reports of in vitro drug sensitivity test results for antimicrobials used in local hospitals and clinics, which should describe the drug sensitivity profile for hospital and community-acquired pathogens. These reports should assist physicians in the selection of antimicrobial drugs for therapeutic use.
Dilution method
Quantitative methods are usually used to determine the MIC value of an antimicrobial drug.MIC values can be used to estimate the susceptibility of bacteria to an antimicrobial drug. MIC values should be determined using standardized test methods (broth or agar). The MIC value for ceftazidime administered in combination with a fixed concentration of 4 μg/mL avibactam should be determined by serial dilution. the MIC value should be interpreted according to the criteria in Table 15.
Diffusion method
Bacterial susceptibility to antimicrobial drugs can also be estimated repeatedly using a quantitative method that measures the diameter of the inhibition circle. Bacterial susceptibility to antimicrobial drugs can be estimated from the diameter of the inhibition circle. A standardized method was used to determine the diameter of the inhibition circle. This procedure uses paper slices containing 30 μg ceftazidime and 20 μg avibactam to determine the susceptibility of bacteria to the product. The criteria for the interpretation of the paper sheet method are shown in Table 15.
Table 15 Ceftazidime/avibactam susceptibility reading criteria
Pathogen MIC (mg / L) paper diffusion inhibition circle diameter (mm) SRSR Enterobacteriaceae ≤ 8/4 ≥ 16/4 ≥ 21 ≤ 20 Pseudomonas aeruginosa ≤ 8/4 ≥ 16/4 ≥ 21 ≤ 20
When the reported result is “sensitive (S)”, it means that if the antimicrobial drug reaches the usual concentration at the infection site, it may inhibit the growth of the pathogen. When the reported result is “resistant (R)”, it means that even if the antimicrobial drug reaches the usual concentration at the infection site, it may not be able to inhibit the growth of the pathogen and other therapies should be chosen.
Quality Control
Standardized drug sensitivity testing procedures require the use of laboratory quality control measures to monitor and ensure the accuracy and precision of the materials and reagents used in this test and the proper handling of the test performers. A standard powder of this product should yield the range of MIC values listed in Table 16. The criteria listed in Table 16 should be achieved using the 30 μg ceftazidime/20 μg avibactam paper diffusion method.
Table 16 Acceptable quality control ranges for drug sensitivity testing
Quality control microorganism MIC (mg/L)a Paper disc diffusion inhibition circle diameter (mm) Staphylococcus aureus ATCC 292134~16- Staphylococcus aureus ATCC 25923-16~22 Escherichia coli ATCC 259220.06~0.527~35 Escherichia coli ATCC 352180.03~0.1228~35 Pseudomonas aeruginosa Pseudomonas aeruginosa ATCC 278530.5~425~31 Klebsiella pneumoniae ATCC 700603b0.25~2-Haemophilus influenzae ATCC 492470.06~0.528~34 Haemophilus influenzae ATCC 497660.015~0.06-Streptococcus pneumoniae ATCC 496190.25~2-Combined fixed concentration 4 mg /L avibactam administration of ceftazidime MIC.
b Klebsiella pneumoniae ATCC 700603 should be tested for susceptibility to ceftazidime/avibactam and ceftazidime alone to determine the activity of avibactam in co-administration, ensuring that the plasmid encoding the β-lactamase is not lost in this strain. The acceptable ceftazidime monotherapy range >16 mg/L.
Toxicological studies
Genotoxicity.
Mutagenicity of ceftazidime and avibactam was evaluated in multiple in vitro and in vivo assays, respectively. Ceftazidime showed negative results in the Ames test and the mouse micronucleus test. Avibactam was negative in the Ames test, the in-process DNA synthesis test, the chromosomal aberration test, and the rat micronucleus test.
Reproductive toxicity.
Ceftazidime
No toxicity of ceftazidime to fetuses was observed in reproduction studies in mice and rats administered at doses up to 40 times the human dose.
Avibactam
Avibactam 1000 mg/kg/day (approximately 20 times the clinically recommended human dose based on body surface area) was not shown to affect fertility in rats. Dose-dependent early pregnancy effects, such as a mild increase in pre- and post-arrival loss and a decrease in litter size, were seen in female rats given intravenous avibactam at 500 mg/kg and higher two weeks prior to mating.
No teratogenic effects of avibactam were observed in rats or rabbits. Intravenous administration of avibactam at 0, 250, 500 and 1000 mg/kg/day to rats on days 6 to 17 of conception showed no embryo-fetal toxicity at doses up to 1000 mg/kg/day (approximately 9 times the human dose in terms of AUC). In a perinatal toxicity study in rats, intravenous infusion of avibactam up to 825 mg/kg/day (11 times the human exposure in terms of AUC) had no effect on the growth and survival of the litter. A dose-related increase in the incidence of renal pelvis and ureteral dilatation was observed in female littermates, but was not associated with pathological changes in renal parenchyma or renal function, and renal pelvis dilatation persisted in female littermates until they became adult rats.
Avibactam 0, 100, 300 and 1000 mg/kg/day given intravenously to rabbits on days 6-19 of gestation showed no effect on embryo-fetal development at a dose of 100 mg/kg/day (twice the human exposure in terms of AUC). Higher doses may result in increased post-arrival loss, decreased mean fetal weight, delayed ossification, and other abnormalities.
Pharmacokinetics]
The mean pharmacokinetic parameters of ceftazidime and avibactam after single or multiple intravenous infusions over 2 hours (once every 8 hours) in healthy adult male subjects with normal renal function are summarized in Table 17.
The values of ceftazidime and avibactam pharmacokinetic parameters were similar after single and multiple doses of ceftazidime and avibactam and were also similar to the results of ceftazidime or avibactam alone.
Table 17 Pharmacokinetic parameters of ceftazidime and avibactam after administration in healthy male subjects (geometric mean [% coefficient of variation])
Ceftazidime Avibactam parameters Single infusion of this producta 2 h
(n=16) Multiple infusions of this producta (1 every 8 hours for 2 hours) for 11 consecutive days
(n=16) Single infusion of this producta 2 hours
(n=16) Multiple infusions of this producta (1 every 8 hours for 2 hours) for 11 consecutive days
(n=16) Cmax (mg/L) 88.1 (14) 90.4 (16) 15.2 (14) 14.6 (17) AUC (mg h/L) b289 (15) c291 (15) 42.1 (16) d38.2 (19) T1/2 (h) 3.27 (33) c2.76 (7) 2.22 (31) d2.71 (25 ) CL (L/h) 6.93 (15) c6.86 (15) 11.9 (16) d13.1 (19) Vss (L) 18.1 (20) c17 (16) 23.2 (23) d22.2 (18) CL = plasma clearance; Cmax = peak concentration; T1/2 = terminal elimination half-life; Vss (L) = steady-state volume of distribution
a 2 g ceftazidime + 0.5 g avibactam.
b AUC0-inf (area under the drug-time curve from time 0 to the moment of infinity) for a single dose; AUC0-tau (area under the drug-time curve during the dosing interval) for multiple doses.
c n=15
d n=13
The Cmax and AUC of ceftazidime were dose proportional. The pharmacokinetic profile of avibactam after a single IV dose was approximately linear over the dose range studied (50 to 2000 mg). In healthy adults with normal renal function, no significant accumulation of ceftazidime or avibactam was observed after multiple IV infusions (1 every 8 hours) over 11 consecutive days.
Distribution
Ceftazidime is bound to plasma proteins<10%. The degree of protein binding was not concentration dependent. Human plasma protein binding of avibactam was low (5.7 to 8.2%) and similar to that measured in vitro in the concentration range 0.5 to 50 mg/L.
In healthy adults, the steady-state volume of distribution of ceftazidime and avibactam was 17 and 22.2 L, respectively, after multiple intravenous infusions of the product (1 every 8 hours) for 11 consecutive days.
The mean ratio of bronchial epithelial lining fluid to plasma avibactam Cmax and AUC0-tau was 35% in healthy male subjects after multiple infusions (1 every 8 hours for 2 hours) for 3 consecutive days. The mean ratios of ceftazidime Cmax and AUC0-tau in bronchial epithelial lining fluid to plasma were 26% and 31%, respectively.
Ceftazidime rarely crosses the intact blood-brain barrier. In the presence of meningeal inflammation, ceftazidime concentrations in the cerebrospinal fluid (CSF) can range from 4 to 20 mg/L or higher. The blood-brain barrier permeation of avibactam has not been studied clinically. However, in rabbits with meningeal inflammation, CSF exposure to ceftazidime and avibactam was 43% and 38% of the plasma AUC, respectively. Ceftazidime readily enters the placenta and can pass into breast milk.
Metabolism
The majority of ceftazidime (80-90% of the dose) is cleared in the prototype form. No metabolism of avibactam has been observed in human liver preparations (microsomes and hepatocytes). Following a single intravenous infusion of 0.5 g of 14C-labeled avibactam, avibactam in its prodrug form is the major drug-related component in human plasma and urine.
Excretion
Both ceftazidime and avibactam are excreted primarily through the kidneys.
Following intravenous infusion of ceftazidime, approximately 80-90% of the dose is excreted renally in the prototype form within 24 hours. After a single intravenous infusion of 0.5 or 1 g, approximately 50% of the dose is recovered in the urine within the first 2 hours. In addition, 20% of the dose is excreted within 2 to 4 hours after administration, and about 12% of the dose is excreted in the urine after 4 to 8 hours. The renal clearance of ceftazidime results in high concentrations in the urine. The mean renal clearance of ceftazidime is approximately 100 mL/min. The calculated plasma clearance is approximately 115 mL/min, which indicates that ceftazidime is almost completely cleared by the kidneys.
A single intravenous infusion of 0.5 g of radiolabeled avibactam recovered an average of 97% of the radioactivity in the urine and more than 95% of the radioactivity within 12 hours of administration. An average of 0.20% of the total radioactivity was recovered in the feces 96 hours after administration. An average of 85% of the prodrug of avibactam was recovered in the urine 96 hours after administration and 50% was recovered within 2 hours of starting the infusion. Renal clearance was 158 mL/min, which is higher than the glomerular filtration rate, suggesting that active tubular secretion in addition to glomerular filtration also facilitates avibactam excretion.
Special Populations
Patients with renal impairment
Ceftazidime is almost exclusively cleared by the kidneys, and thus the half-life of ceftazidime in plasma is significantly prolonged in patients with renal impairment.
Compared to healthy subjects with normal renal function (CrCL>80 mL/min, n=6), mild (50<CrCL ≤80 mL/min, n=6), moderate (30<CrCL ≤50 mL/min, n=6) and severe (CrCL ≤30 mL/min but no hemodialysis, n=6) clearance of avibactam was significantly lower in subjects with renal impairment. Compared with subjects with normal renal function, the slowed clearance of avibactam resulted in a 2.6-, 3.8-, and 7-fold increase in systemic exposure (AUC) in subjects with mild, moderate, and severe renal impairment, respectively.
A single infusion of 100 mg of avibactam was given to ESRD subjects (n=6) 1 hour before and after hemodialysis. The AUC of post-dialysis infusion of avibactam was 19.5 times higher than the AUC in healthy subjects with normal renal function. Hemodialysis resulted in extensive clearance of avibactam with an extraction factor of 0.77 and a mean hemodialysis clearance of 9.0 L/h. Approximately 55% of the avibactam dose was cleared during a 4-hour hemodialysis session.
Dose adjustment of this product is recommended for patients with moderate or severe renal impairment and ESRD. A population PK model of ceftazidime and avibactam was used to simulate patients with renal impairment. The results showed that ceftazidime and avibactam in patients with moderate or severe renal impairment and ESRD using the adjusted recommended dose produced comparable exposures to patients with normal renal function or mild renal impairment. Because exposure to both ceftazidime and avibactam is highly dependent on renal function, patients with changing renal function should be monitored for CrCL at least daily and the dose adjusted accordingly (see [DOSAGE AND ADMINISTRATION]).
Patients with hepatic impairment
Abnormal hepatic function had no effect on the pharmacokinetics of ceftazidime in patients receiving an intravenous infusion of 2 g every 8 hours for 5 consecutive days.
The pharmacokinetics of avibactam have not been established in patients with hepatic impairment. Since avibactam has no significant hepatic metabolism, the systemic clearance of avibactam is not expected to be affected by hepatic impairment.
No dose adjustment of this product is currently considered necessary in patients with hepatic impairment.
Geriatric patients
The mean AUC of avibactam was 17% higher in healthy elderly subjects (≥65 years, n=16) than in healthy younger subjects (18-45 years, n=17) following a single intravenous infusion of 0.5 g avibactam over 30 minutes. There was no significant age effect on the Cmax of avibactam.
No dose adjustment based on age is required. The dose of this product should be adjusted for renal function in elderly patients (see [Dosage]).
Gender
After a single 30-minute infusion of 0.5 g of avibactam, avibactam Cmax values were 18% lower in healthy male subjects (n=17) than in healthy female subjects (n=16). There was no gender effect for the AUC parameter of avibactam.
No dose adjustment according to gender was required.
Pharmacokinetic Data in Chinese Subjects
The pharmacokinetic (PK) profile of single and multiple doses of CAZ-AVI administered intravenously was evaluated in healthy Chinese male subjects. A total of 12 subjects received a single dose of 2 g ceftazidime + 0.5 g avibactam intravenously for 2 hours on study day 1, followed by 2 hours of intravenous infusion at the same dose every 8 hours (q8h) for 7 days (day 2 to day 8), and a single dose of CAZ-AVI on day 9. The pharmacokinetic characteristics of ceftazidime and avibactam were determined. The mean values of pharmacokinetic parameters are summarized in Table 18.
The pharmacokinetics of ceftazidime and avibactam were non-time-dependent: exposure was similar after single or multiple dose (q8h) administration, and no accumulation was observed.
Table 18. Pharmacokinetic parameters of ceftazidime and avibactam after administration in healthy Chinese male subjects (geometric mean [% coefficient of variation])
Ceftazidime Avibactam Parameters
Single infusion of this producta 2 h
(n = 12) Multiple infusions of this producta (1 every 8 hours for 2 hours) for 7 consecutive days
(n = 12) Single infusion of this producta
for 2 hours
(n = 12) Multiple infusions of this producta for 7 consecutive days (1 every 8 hours for 2 hours)
(n = 12) Cmax (mg/L) 101 (15)111 (15)18.2 (16)17.6 (18)AUC (mg-h/L)b306 (14)322 (15)47.6 (18)43.6 (19)T1/2 (h) 2.14 (13)2.51 (13)2.09 (17)2.80 (31)CL ( L/h) 6.53 (14) 6.22 (15) 10.5 (18) 11.5 (19) Vss (L) 15.8 (13) 14.0 (16) 20.4 (20) 19.1 (20) CL = plasma clearance; Cmax = peak concentration; T1/2 = terminal elimination half-life; Vss (L) = steady-state volume of distribution
a 2 g ceftazidime + 0.5 g avibactam.
b
AUC0-inf (area under the drug-time curve from time 0 to infinity) for single dosing; AUC0-tau (area under the drug-time curve during the dosing interval) for multiple dosing.
PK results for ceftazidime and avibactam after single- and multiple-dose intravenous administration of CAZ-AVI were similar in healthy male subjects in China and in male subjects with normal renal function in other regions (Table 17).
In addition, the potential impact of “race” on ceftazidime and avibactam PK was evaluated in a population PK analysis in CAZ-AVI. Chinese/non-Japanese patients. The effect of ethnicity as a covariate on clearance was not found to be clinically significant in the final population PK model. Overall, the estimated exposures were generally similar across ethnic groups.
Dose adjustment based on ethnicity was not required.
Storage
Keep away from light, tightly closed, and not more than 30°C.
Package】
This product is packed in 20mL I-type glass bottle, halobutyl rubber stopper and aluminum cap.
1 bottle/box, 10 bottles/box.
【Expiration date】.
24 months.
【Execution standard
Imported drug registration standard JX20180249
【Imported drug registration certificate number
【Manufacturer
Licensee: Pfizer Ireland Pharmaceuticals
Licensee’s address: Operations Support Group, Ringaskiddy, County Cork, Ireland
Manufacturer: GlaxoSmithKline Manufacturing S.p.A
Production Address: Via A. Fleming, 2, 37135 Verona, Italy
Domestic Contact.
Pfizer Investment Co.
Address: 8-13F, Block B, Minmetals Plaza, 3-7 Chaoyangmen North Street, Dongcheng District, Beijing
Postal Code: 100010
Telephone number: 010-85167000
Product Hotline：400 910 0055