Avycaz

1.1        Complicated Intra-abdominal Infections (cIAI)

AVYCAZ (ceftazidime and avibactam) in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa.

1.2        Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa.

1.3        Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae.

1.4        Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2.1        Recommended Dosage in Adult Patients

The recommended dosage of AVYCAZ is 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours by intravenous (IV) infusion over 2 hours in patients 18 years of age and older with CrCl greater than 50 mL/min. For treatment of cIAI, metronidazole should be given concurrently. The guidelines for dosage of AVYCAZ in patients with creatinine clearance (CrCl) greater than 50 mL/min are listed in  Table 1.

2.2        Recommended Dosage in Pediatric Patients

The recommended dosage of AVYCAZ in pediatric patients aged 2 years to less than 18 years and an estimated glomerular filtration rate (eGFR) greater than 50 mL/min/1.73 m2 and in pediatric patients less than 2 years of age without renal impairment is described in Table 2. AVYCAZ is administered every 8 hours by intravenous infusion over 2 hours. For treatment of cIAI, metronidazole should be given concurrently.

2.3        Dosage Adjustments in Adult and Pediatric Patients (Aged 2 Years and Older) with Renal Impairment

The recommended AVYCAZ dosage in adult and pediatric patients aged 2 years and older with varying degrees of renal function is presented in Table 3 and Table 4, respectively. For patients with changing renal function, monitor CrCl in adults or eGFR in pediatric patients at least daily and adjust the dosage of AVYCAZ accordingly [see Warnings and Precautions ( 5.1), Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)]. There is insufficient information to recommend a dosing regimen for pediatric patients less than 2 years of age with renal impairment.

Adult Patients

Pediatric Patients

2.4        Preparation of the AVYCAZ Solution for Administration

AVYCAZ is supplied as a dry powder, which must be constituted and subsequently diluted, using aseptic technique prior to intravenous infusion.  

a) Constitute the powder in the AVYCAZ vial with 10 mL of one of the following solutions: 

• sterile water for injection, USP
  
• 0.9% of sodium chloride injection, USP (normal saline)
  
• 5% of dextrose injection, USP
  
• all combinations of dextrose injection and sodium chloride injection, USP, containing up to 2.5% dextrose, USP, and 0.45% sodium chloride, USP, or
  
• lactated Ringer’s injection, USP

b) Mix gently and ensure that the contents are dissolved completely. The constituted AVYCAZ solution will have an approximate ceftazidime concentration of 167 mg/mL and an approximate avibactam concentration of 42 mg/mL. The final volume is approximately 12 mL. The constituted solution is not for direct injection. The constituted solution must be diluted before intravenous infusion.

c) Prepare the required dose for intravenous infusion by withdrawing the appropriate volume determined from Table 5 from the constituted vial. To prepare doses for pediatric patients weighing less than 40 kg, follow the constitution instruction above to yield a solution with a final AVYCAZ concentration of approximately 209 mg/mL (ceftazidime concentration of 167 mg/mL and an avibactam concentration of 42 mg/mL). Use these concentrations to calculate the volume of AVYCAZ required to prepare the prescribed dose.

d) Before infusion, dilute the withdrawn volume of the constituted AVYCAZ solution further with the same diluent used for constitution of the powder (except sterile water for injection), to achieve a ceftazidime concentration of 8 to 40 mg/mL and an avibactam concentration of 2 to 10 mg/mL in an infusion bag. If sterile water for injection was used for constitution, use any of the other appropriate constitution diluents for dilution.

e) Mix gently and ensure that the contents are dissolved completely. Visually inspect the diluted AVYCAZ solution (for administration) for particulate matter and discoloration prior to administration (the color of the AVYCAZ infusion solution for administration ranges from clear to light yellow).

f) Use the diluted AVYCAZ solution in the infusion bags within 12 hours when stored at room temperature.

g) The diluted AVYCAZ solution in the infusion bags may be stored under refrigeration at 2 to 8°C (36 to 46°F) up to 24 hours following dilution and used within 12 hours of subsequent storage at room temperature.

2.5        Drug Compatibility

The AVYCAZ solution for administration at the range of diluted concentrations of ceftazidime 8 mg/mL and avibactam 2 mg/mL to ceftazidime 40 mg/mL and avibactam 10 mg/mL is compatible with the more commonly used intravenous infusion fluids in infusion bags (including Baxter® Mini-Bag Plus™) such as:

• 0.9% sodium chloride injection, USP
  
• 5% dextrose injection, USP
  
• all combinations of dextrose injection and sodium chloride injection, USP, containing up to 2.5% dextrose, USP, and 0.45% sodium chloride, USP
  
• lactated ringer's injection, USP, and
  
• Baxter® Mini-Bag Plus™ containing 0.9% sodium chloride injection or 5% dextrose injection 

Intravenous Line Compatibility

Simulated Y-site compatibility of AVYCAZ admixed with other drug products in a 1:1 volume ratio at room temperature was evaluated by visual inspection, and measurement of turbidity and particulate matter at 0, 1 and 4 hours after mixing. Ceftazidime and avibactam were tested at concentrations of 20 mg/mL and 5 mg/mL, respectively, which can be obtained by dilution of constituted AVYCAZ solution in a 100 mL intravenous infusion bag. The highest recommended concentration (40 mg/mL of ceftazidime and 10 mg/mL of avibactam) was not tested in this study and should not be used during co-administration of AVYCAZ with other drugs through the same intravenous line. Compatible drugs with the corresponding compatible diluent (i.e., 0.9% Sodium Chloride Injection, 5 % Dextrose Injection or Lactated Ringer’s Injection) are listed in Tables 6, 7, 8 and 9 below. Any drug products not listed in the tables below should not be co-administered with AVYCAZ through the same intravenous line (or cannula).

2.6        Storage of Constituted Solutions

Upon constitution with appropriate diluent, the constituted AVYCAZ solution may be held for no longer than 30 minutes prior to transfer and dilution in a suitable infusion bag.

Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags are stable for 12 hours when stored at room temperature.

Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags may also be refrigerated at 2 to 8°C (36 to 46°F) for up to 24 hours; and then should be used within 12 hours of subsequent storage at room temperature.

8.1        Pregnancy

Risk Summary

There are no adequate and well-controlled studies of AVYCAZ, ceftazidime, or avibactam in pregnant women. Neither ceftazidime nor avibactam were teratogenic in rats at doses 40 and 9 times the recommended human clinical dose. In the rabbit, at twice the exposure as seen at the human clinical dose, there were no effects on embryofetal development with avibactam.

The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Data

Animal Data

Ceftazidime

Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime.

Avibactam

Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies with 0, 250, 500 and 1000 mg/kg/day avibactam during gestation days 6-17 showed no embryofetal toxicity at doses up to 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC). In a rat pre- and post-natal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weaning pups became adults.

Rabbits administered intravenous avibactam on gestation days 6-19 at 0, 100, 300 and 1000 mg/kg/day showed no effects on embryofetal development at a dose of 100 mg/kg, twice the human exposure (AUC). At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed.

8.2        Lactation

Risk Summary

Ceftazidime is excreted in human milk in low concentrations. It is not known whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats. No information is available on the effects of ceftazidime and avibactam on the breast-fed child or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AVYCAZ and any potential adverse effects on the breastfed child from AVYCAZ or from the underlying maternal conditions.

Data

In a rat pre- and post-natal study at doses up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), the exposure to avibactam was minimal in the pups in comparison to the dams. Exposure to avibactam was observed in both pups and milk on PND 7.

8.4        Pediatric Use

The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have been established in pediatric patients at least 31 weeks gestational age and older. Use of AVYCAZ is supported by evidence from adequate and well-controlled studies of AVYCAZ in adults with cUTI, cIAI, and HABP/VABP and additional pharmacokinetic and safety data from pediatric trials [see Clinical Pharmacology ( 12.3), Clinical Studies ( 14.1 and  14.2)].

The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ [see Adverse Reactions ( 6.1)].

The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have not been established in pediatric patients less than 31 weeks gestational age.

8.5        Geriatric Use

Of the 1809 patients treated with AVYCAZ in the Phase 2 and Phase 3 clinical trials 621 (34.5%) were 65 years of age and older, including 302 (16.7 %) patients 75 years of age and older.

In the pooled Phase 2 and Phase 3 cIAI AVYCAZ clinical trials, 20% (126/630) of patients treated with AVYCAZ were 65 years of age and older, including 49 (7.8%) patients 75 years of age and older. The incidence of adverse reactions in both treatment groups was higher in older patients (≥ 65 years of age) and similar in both treatment groups; clinical cure rates for patients 65 years of age or older were 73.0% (73/100) in the AVYCAZ plus metronidazole arm and 78.6% (77/98) in the meropenem arm.

In the Phase 3 cUTI trial, 30.7% (157/511) of patients treated with AVYCAZ were 65 years of age or older, including 78 (15.3%) patients 75 years of age or older. The incidence of adverse reactions in both treatment groups was lower in older patients (≥ 65 years of age) and similar between treatment groups. Among patients 65 years of age or older in the Phase 3 cUTI trial, 66.1% (82/124) of patients treated with AVYCAZ had symptomatic resolution at Day 5 compared with 56.6% (77/136) of patients treated with doripenem. The combined response (microbiological cure and symptomatic response) observed at the test-of-cure (TOC) visit for patients 65 years of age or older were 58.1% (72/124) in the AVYCAZ arm and 58.8% (80/136) in the doripenem arm.

In the Phase 3 HABP/VABP trial, 54.1% (236/436) of patients treated with AVYCAZ were 65 years of age or older, including 129 (29.6%) patients 75 years of age or older. The incidence of adverse reactions in patients ≥ 65 years of age was similar to patients < 65 years of age. The 28-day all-cause mortality was similar between treatment groups for patients 65 years of age or older (12.7% [29/229] for patients in the AVYCAZ arm and 11.3% [26/230] for patients in the meropenem arm).

Ceftazidime and avibactam are known to be substantially excreted by the kidney; therefore, the risk of adverse reactions to ceftazidime and avibactam may be greater in patients with decreased renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)].

8.6        Renal Impairment

Dosage adjustment is required in adult patients with moderately or severely impaired renal function (CrCl 50 mL/min or less). For patients with changing renal function, CrCl should be monitored at least daily, particularly early in treatment, and dosage of AVYCAZ adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)].

Dosage adjustment is also required in pediatric patients with renal impairment from 2 years to less than 18 years of age with eGFR 50 mL/min/1.73 m2 or less. There is insufficient information to recommend a dosing regimen for pediatric patients younger than 2 years of age with renal impairment [see Dosage and Administration ( 2.3) and Clinical Pharmacology ( 12.3)].

5.1        Decreased Clinical Response in Adult cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min 

In a Phase 3 cIAI trial in adult patients, clinical cure rates were lower in a subgroup of patients with baseline CrCl of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min (Table 10). The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min.

The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl of 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials or the Phase 3 HABP/VABP trial. 

Monitor CrCl at least daily in adult and pediatric patients with changing renal function and adjust the dosage of AVYCAZ accordingly [see Dosage and Administration ( 2.2, 2.3), and Adverse Reactions ( 6.1)]. 

5.2        Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs.

5.3        Clostridioides difficile-associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

5.4        Central Nervous System Reactions

Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance [see Dosage and Administration ( 2.2)].

5.5        Development of Drug-Resistant Bacteria

Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage ( 1.4)].