Ceftazidime and avibactam

Ceftazidime and avibactam
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: AKT

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Overview

Ceftazidime and avibactam is a combination of a cephalosporin and a beta-lactamase inhibitor that is FDA approved for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. Common adverse reactions include diarrhea and nausea.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Complicated Intra-abdominal Infections (cIAI)

AVYCAZ in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa in patients 18 years or older.

• 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 in patients with normal renal function.
• Metronidazole should be given concurrently.
• Duration of treatment should range from 5 to 14 days.
• The recommended AVYCAZ dosage in patients with varying degrees of renal function is presented in TABLE 2. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of AVYCAZ accordingly.

This image is provided by the National Library of Medicine

Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

AVYCAZ is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa in patients 18 years or older.

• 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 in patients with normal renal function.
• Duration of treatment should range from 7 to 14 days.
• The recommended AVYCAZ dosage in patients with varying degrees of renal function is presented in TABLE 2. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of AVYCAZ accordingly.
• The recommended AVYCAZ dosage in patients with varying degrees of renal function is presented in TABLE 2. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of AVYCAZ accordingly.

This image is provided by the National Library of Medicine

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ceftazidime and avibactam in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftazidime and avibactam in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Ceftazidime and avibactam FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ceftazidime and avibactam in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftazidime and avibactam in pediatric patients.

Contraindications

AVYCAZ is contraindicated in patients with known serious hypersensitivity to ceftazidime or avibactam, avibactam-containing products, or other members of the cephalosporin class.

Warnings

• Decreased Clinical Response in cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min
  • In a Phase 3 cIAI trial, 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 4). 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.
  • Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly.

This image is provided by the National Library of Medicine

• 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.
• Clostridium difficile-associated Diarrhea
  • Clostridium 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.
• 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
• Development of Drug-Resistant Bacteria
  • Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. AVYCAZ was evaluated in five active-controlled clinical trials in patients with cIAI or cUTI, including pyelonephritis. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as three Phase 3 trials, one in cIAI, one in cUTI (Trial 1), and one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2). Data from Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling, but provided supportive information. The five clinical trials included a total of 1373 adult patients treated with AVYCAZ and 1375 patients treated with comparators.

Complicated Intra-abdominal Infections

The Phase 3 cIAI trial included 529 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours plus 0.5 grams metronidazole administered intravenously over 60 minutes every 8 hours and 529 patients treated with meropenem. The median age of patients treated with AVYCAZ was 50 years (range 18 to 90 years) and 22.5% of patients were 65 years of age or older. Patients were predominantly male (62%) and Caucasian (76.6%).

Treatment discontinuation due to an adverse reaction occurred in 2.6% (14/529) of patients receiving AVYCAZ plus metronidazole and 1.3% (7/529) of patients receiving meropenem. There was no specific adverse reaction leading to discontinuation.

Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ plus metronidazole were diarrhea, nausea and vomiting.

TABLE 5 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ plus metronidazole and with incidences greater than the comparator in the Phase 3 cIAI clinical trial.

This image is provided by the National Library of Medicine

Increased Mortality:

In the Phase 3 cIAI trial, death occurred in 2.5% (13/529) of patients who received AVYCAZ plus metronidazole and in 1.5% (8/529) of patients who received meropenem. Among a subgroup of patients with baseline CrCl 30 to less than or equal to 50 mL/min, death occurred in 19.5% (8/41) of patients who received AVYCAZ plus metronidazole and in 7.0% (3/43) of patients who received meropenem. 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.\

In patients with normal renal function or mild renal impairment (baseline CrCl greater than 50 mL/min), death occurred in 1.0% (5/485) of patients who received AVYCAZ plus metronidazole and in 1.0% (5/484) of patients who received meropenem. The causes of death varied and contributing factors included progression of underlying infection, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention.

Complicated Urinary Tract Infections, Including Pyelonephritis Trial 1 included 511 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours and 509 patients treated with doripenem; in some patients parenteral therapy was followed by a switch to an oral antimicrobial agent [see Clinical Studies (14.2)]. Median age of patients treated with AVYCAZ was 54 years (range 18 to 89 years). Patients were predominantly female (68.3%) and Caucasian (82.4%). Patients with CrCl less than 30 mL/min were excluded.

There were no deaths in Trial 1. Treatment discontinuation due to adverse reactions occurred in 1.4% (7/511) of patients receiving AVYCAZ and 1.2% (6/509) of patients receiving doripenem. There was no specific adverse reaction leading to discontinuation.

The most common adverse reactions occurring in 3% of cUTI patients treated with AVYCAZ were nausea and diarrhea.

TABLE 6 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in Trial 1.

This image is provided by the National Library of Medicine

Other Adverse Reactions of AVYCAZ and Ceftazidime

The following selected adverse reactions were reported in AVYCAZ-treated patients at a rate of less than 1% in the Phase 3 trials.

• Blood and lymphatic disorders - Thrombocytopenia
• General disorders and administration site conditions - Injection site phlebitis
• Infections and infestations - Candidiasis
• Investigations - Increased aspartate aminotransferase, Increased alanine aminotransferase, Increased gamma-glutamyltransferase
• Metabolism and nutrition disorders - Hypokalemia
• Nervous system disorders - Dysgeusia
• Renal and urinary disorders - Acute renal failure, Renal impairment, Nephrolithiasis
• Skin and subcutaneous tissue disorders - Rash, Rash maculo-papular, Urticaria, Pruritus
• Psychiatric disorders - Anxiety

Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ-treated patients in the Phase 3 trials are listed below:

• Blood and lymphatic disorders - Agranulocytosis, Hemolytic anemia, Leukopenia, Lymphocytosis, Neutropenia, Thrombocytosis, Eosinophilia
• General disorders and administration site conditions - Infusion site inflammation, Injection site hematoma, Injection site thrombosis
• Hepatobiliary disorders – Jaundice
• Investigations - Increased blood lactate dehydrogenase, Prolonged prothrombin time
• Nervous system disorders - Paresthesia
• Renal and urinary disorders - Tubulointerstitial nephritis
• Reproductive and breast disorders - Vaginal inflammation
• Skin and subcutaneous tissue disorders - Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis

Laboratory Changes

Seroconversion from a negative to a positive direct Coombs' test result at any time up to the last visit occurred in 31/240 (12.9%) of patients receiving AVYCAZ plus metronidazole with initial negative Coombs' test and at least one follow up test and in 7/235 (3.0%) of patients receiving meropenem in the Phase 3 cIAI trial. Seroconversion from a negative to a positive direct Coombs' test result at any time up to the last visit occurred in 7/216 (3.2%) of patients receiving AVYCAZ with initial negative Coombs' test and at least one follow up test and 2/214 (0.9%) of patients receiving doripenem in the Phase 3 cUTI trial. No adverse reactions representing hemolytic anemia were reported in any treatment group.

Postmarketing Experience

There is limited information regarding Ceftazidime and avibactam Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Ceftazidime and avibactam Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Ceftazidime and avibactam in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftazidime and avibactam in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Ceftazidime and avibactam during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Ceftazidime and avibactam in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Ceftazidime and avibactam in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Ceftazidime and avibactam in geriatric settings.

Gender

There is no FDA guidance on the use of Ceftazidime and avibactam with respect to specific gender populations.

Race

There is no FDA guidance on the use of Ceftazidime and avibactam with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Ceftazidime and avibactam in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Ceftazidime and avibactam in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Ceftazidime and avibactam in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Ceftazidime and avibactam in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Ceftazidime and avibactam Administration in the drug label.

Monitoring

There is limited information regarding Ceftazidime and avibactam Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Ceftazidime and avibactam and IV administrations.

Overdosage

There is limited information regarding Ceftazidime and avibactam overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Ceftazidime and avibactam Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Ceftazidime and avibactam Mechanism of Action in the drug label.

Structure

There is limited information regarding Ceftazidime and avibactam Structure in the drug label.

Pharmacodynamics

There is limited information regarding Ceftazidime and avibactam Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Ceftazidime and avibactam Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Ceftazidime and avibactam Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Ceftazidime and avibactam Clinical Studies in the drug label.

How Supplied

There is limited information regarding Ceftazidime and avibactam How Supplied in the drug label.

Storage

There is limited information regarding Ceftazidime and avibactam Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Ceftazidime and avibactam Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Ceftazidime and avibactam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Ceftazidime and avibactam Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Ceftazidime and avibactam Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.