Avycaz

AVYCAZ is

• Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole (
  1.000000000000000e+00

  1

  Complicated Intra-

  a

  bdominal 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

  .
  )
  
  
• Complicated Urinary Tract Infections (cUTI), including Pyelonephritis (
  1.000000000000000e+00

  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

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

  .
  )

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. (

^*Used in conjunction with metronidazole 10 mg/kg intravenously every 8 hours in pediatric cIAI patients

^aIncludes full-term infants with PNA > 28 days and pre-term infants with corrected age > 28 days. Corrected age is calculated by subtracting the number of weeks born before 40 weeks of gestation from the postnatal age.

^bIncludes neonates PNA ≤ 28 days and pre-term infants with corrected age ≤ 28 days.

GA = gestational age and PNA = postnatal age.

• For treatment of cIAI, metronidazole should be given concurrently
  
  
• Recommended duration of treatment in adult and pediatric patients: (
  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

  .

  Table 1. Dosage of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) by Indication in Adult Patients (18 years of age and older)
  Infection	Dos e	Frequency	Infusion Time (hours)	Duration of Treatment
  Complicated Intra-abdominal Infections (cIAI)*	2.5 grams	Every 8 hours	2	cIAI: 5 to 14 days cUTI: 7 to 14 days HABP/VABP: 7 to 14 days
  Complicated Urinary Tract Infections including Pyelonephritis (cUTI)
  Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)
  * Used in conjunction with metronidazole 0.5 g intravenously every 8 hours in adult cIAI patients [see Clinical Studies ( 14.1 ) ].
  ,
   
  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 m²and 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.

  Table 2. Dosage of AVYCAZ (ceftazidime and avibactam) in Pediatric Patients
  Infection	Age Range	Dose	Frequency	Infusion Time (hours)	Duration of treatment
  cIAI*, cUTI including Pyelonephritis, and HABP/VABP	2 years to less than 18 yearsa	AVYCAZ 62.5 mg/kg to a maximum of 2.5 grams (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg to a maximum dose of ceftazidime 2 grams and avibactam 0.5 grams)	Every 8 hours	2	cIAI: 5 to 14 days cUTI: 7 to 14 days HABP/VABP: 7 to 14 days
  	6 months to less than 2 years	AVYCAZ 62.5 mg/kg (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg)
  	3 months to less than 6 months	AVYCAZ 50 mg/kg (ceftazidime 40 mg/kg and avibactam 10 mg/kg)
  	Greater than 28 daysbto less than 3 months	AVYCAZ 37.5 mg/kg (ceftazidime 30 mg/kg and avibactam 7.5 mg/kg)
  	Less than or equal to 28 dayscwith GA 31 weeks and older	AVYCAZ 25 mg/kg (ceftazidime 20 mg/kg and avibactam 5 mg/kg)
  *AVYCAZ was used in conjunction with metronidazole 10 mg/kg intravenously every 8 hours in pediatric cIAI patients [see Clinical Studies ( 14.1 ) ] aFor pediatric patients (aged 2 years and older) with eGFR less than or equal to 50 mL/min/1.73m2,dosage adjustments are recommended [ s ee Dosage and Administration ( 2.3 )]. bIncludes full-term infants with PNA > 28 days and pre-term infants with corrected age > 28 days. Corrected age is calculated by subtracting the number of weeks born before 40 weeks of gestation from the postnatal age. cIncludes neonates PNA ≤ 28 days and pre-term infants with corrected age ≤ 28 days. GA = gestational age and PNA = postnatal age.
  )
  • cIAI: 5 to 14 days
    
    
  • cUTI including pyelonephritis: 7 to 14 days
    
    
  • HABP/VABP: 7 to 14 days

• Dosage adjustment is required in adult patients with creatinine clearance (CrCl) less than or equal to 50 mL/min and in pediatric patients aged 2 years and older with renal impairment. There is insufficient information to recommend a dosing regimen for pediatric patients younger than 2 years of age with renal impairment. See Full Prescribing Information for additional information. 
  (
  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

  Table 3 . Dosage of AVYCAZ in Adult Patients with Renal Impairment
  Estimated Creatinine Clearance (mL/minute) a	Dose for AVYCAZ (ceftazidime and avibactam) b	Frequency
  31 to 50	AVYCAZ 1.25 grams (ceftazidime 1 gram and avibactam 0.25 grams) intravenously	Every 8 hours
  16 to 30	AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously	Every 12 hours
  6 to 15c	AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously	Every 24 hours
  Less than or equal to 5c	AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously	Every 48 hours
  aAs calculated using the Cockcroft-Gault formula bAll doses of AVYCAZ are administered over 2 hours cBoth ceftazidime and avibactam are hemodialyzable; thus, administer AVYCAZ after hemodialysis on hemodialysis days

  Pediatric Patients

  Table 4 . Dosage of AVYCAZ in Pediatric Patients Aged 2 years and older with Renal Impairment a
  Estimated eGFR b (mL/min/1.73m 2 )	Dose for AVYCAZ (ceftazidime and avibactam) c	Frequency
  31 to 50	AVYCAZ 31.25 mg/kg to a maximum of 1.25 grams (ceftazidime 25 mg/kg and avibactam 6.25 mg/kg to a maximum dose of ceftazidime 1 gram and avibactam 0.25 grams)	Every 8 hours
  16 to 30	AVYCAZ 23.75 mg/kg to a maximum of 0.94 grams (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 grams and avibactam 0.19 grams)	Every 12 hours
  6 to 15	AVYCAZ 23.75 mg/kg to a maximum of 0.94 grams (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 grams and avibactam 0.19 grams)	Every 24 hours
  Less than or equal to 5d	AVYCAZ 23.75 mg/kg to a maximum of 0.94 grams (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 grams and avibactam 0.19 grams)	Every 48 hours
  aDosing was derived based on the population PK modeling, which assumed similar proportional effects of renal impairment in adults and pediatric patients aged 2 years and older [see Clinical Pharmacology ( 12.3 )] bAs calculated using the Schwartz bedside formula cAll doses of AVYCAZ are administered over 2 hours dBoth ceftazidime and avibactam are hemodialyzable; thus, administer AVYCAZ after hemodialysis on hemodialysis days
  )
  
  
  
• See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution.
  (
  2.000000000000000e+00

  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.

  Table 5 . Preparation of AVYCAZ Doses for Adult and Pediatric Patients (Weighing 40 kg or More)
  AVYCAZ (ceftazidime and avibactam) Dose	Volume to Withdraw from Constituted Vial for Further Dilution to 50 to 250 a mL
  2.5 grams (2 grams and 0.5 grams)	12 mL (entire contents)
  1.25 grams (1 gram and 0.25 grams)	6 mL
  0.94 grams (0.75 grams and 0.19 grams)	4.5 mL
  a.Dilution to 250 mL should only be used for the 2.5 gram 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.
  )
  
  
  
• See Full Prescribing Information for drug compatibilities.
  (
  2.000000000000000e+00

  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).

  Table 6. Compatible Drugs for use with 0.9% Sodium Chloride, 5% Dextrose or Lactated Ringer’s Injection as Diluents

  Daptomycin

  Dexmedetomidine Injection

  Dopamine Hydrochloride Injection

  Furosemide Injection

  Gentamicin Injection

  Imipenem and Cilastatin for Injection

  Magnesium Sulfate Injection

  Norepinephrine Bitartrate Injection

  Phenylephrine Hydrochloride Injection

  Vasopressin Injection

  Vecuronium Bromide

  Metronidazole Injection

  Aztreonam Injection or Aztreonam for Injection

  Colistimethate for Injection

  Amikacin Sulfate Injection

  Azithromycin for Injection

  Ceftaroline fosamil for Injection

  Levofloxacin

  Table 7. Compatible Drugs for use with 0.9% Sodium Chloride or 5% Dextrose Injection as Diluents

  Ertapenem Sodium

  Potassium Phosphates Injection

  Table 8. Compatible Drugs for use with 5% Dextrose or Lactated Ringer’s Injection as Diluents

  Heparin Sodium Injection

  Linezolid Injection

  Tobramycin Injection or Tobramycin for Injection

  Table 9. Compatible Drugs for use with One Compatible Diluent only

  Meropenem for Injection (0.9% Sodium Chloride Injection diluent only)

  Sodium Bicarbonate Injection (5% Dextrose Injection diluent only)

  Tedizolid Phosphate for Injection (5% Dextrose Injection diluent only)

  Potassium Chloride in Water for Injection (40 mEq/100 mL) (Lactated Ringer’s Injection diluent only)
  )

AVYCAZ 2.5 grams (ceftazidime and avibactam) for injection is supplied as a white to yellow sterile powder for constitution in a single-dose, sterile, clear glass vial containing ceftazidime 2 grams and avibactam 0.5 grams. 

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.

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 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.

• Decreased
  Clinical Response
   
  in
   
  A
  dult
  cIAI
   
  P
  atients with
  B
  aseline CrC
  l
   
  of
   
  30 to
   
  L
  ess
  T
  han
  or
  E
  qual
  to
  50 mL/ min
  : Monitor CrCl at least daily in adult and pediatric patients with changing renal function and adjust the dosage of AVYCAZ accordingly. (
  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

  )

  ]

  .

  Table 10. Clinical Cure Rate at Test of Cure in a Phase 3 cIAI Trial, by Baseline Renal Function – mMITT Population a
  	AVYCAZ + Metronidazole % (n/N)	Meropenem % (n/N)
  Normal function / mild impairment (CrCl greater than 50 mL/min)	85% (322/379)	86% (321/373)
  Moderate impairment (CrCl 30 to less than or equal to 50 mL/min)	45% (14/31)	74% (26/35)
  aMicrobiological modified intent-to-treat (mMITT) population included patients who had at least one bacterial pathogen at baseline and received at least one dose of study drug.
  )
  
  
• Hypersensitivity
  R
  eactions
  : Includes anaphylaxis and serious skin reactions. Cross sensitivity may occur in patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue AVYCAZ. (
  5.000000000000000e+00

  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.
  )
  
  
• Clostrid
  io
  i
  des
  difficile
  -associated
   
  D
  iarrhea
   
  (CDAD)
  : CDAD has been reported with nearly all systemic antibacterial agents, including AVYCAZ. Evaluate if diarrhea occurs. (
  5.000000000000000e+00

  3

  Clostridi

  oides

  difficile-

  associated Diarrhea

  Clostridi

  oides

  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.
  )
  
  
• C
  entral Nervous System Reactions
  : Seizures and other neurologic events may occur, especially in patients with renal impairment. Adjust dose in patients with renal impairment. (
  5.000000000000000e+00

  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

  )

  ]

  .
  )