AVYCAZ*
Manufacturer DetailsCEREXA INC.
Compositions:
Ceftazidime Avibactam- mg,
Ceftazidime Avibactam- mg,
| Strength | Rate | Packing Style |
|---|---|---|
| mg | 0.00 | unit |
List of Related Indications:
- For Complicated Urinary Tract Infections(CUTI) including Pyelonephritis and Complicated Intra-Abdominal Infections(CIAI)
List Of Drugs:
- Ceftazidime Avibactam- Avycaz -@- (2015) - Anti-Bacterial
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
.1 Probenecid -
In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered.
Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended [
2 Drug/Laboratory Test Interactions-
The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
Indication:
Proprietary Name- AVYCAZ
Established Name- Ceftazidime Avibactam
Applicant- Cerexa Inc.
Indication- For Complicated urinary tract infections (CUT) including
Pyelonephritis and Complicated Intra-abdominal infections(CIA)
Approval Date- 2/25/2015
Approved by U.S.FDA on 30-06-2015 (Ref- FDA approved List- 2015)
NEW MOLECULAR ENTITY AND NEW THERAPEUTIC BIOLOGICAL
PRODUCTS APPROVED FOR 2015
Certain drugs are classified as New molecular Emtities- NME- for FDA review
Many of these products contain active moieties that have not been approved
by FDA previously, either as a single ingredient or as part of a combination
products; these products frequently provide important new therapies for the
patients.
Some drugs are characterized as NMEs for administrative purposes ,but
nonetheless contain certain active moieties in products that have been
previously approved by FDA. For example, CDER classifies biological
products submitted in an application under section 351(a) of the Public
Service Act as NME for purposes of FDA review, regardless of whether
the agency previously approved a related active moiety in a different
product.
FDAs classification of a drug as an -NME- for review purposes is distinct
from FDAs determination of whether a drug is a - New Chemical Entity or - NCE-
within the meaning of the Federal Food,Drug, and Cosmetic Act
No.7
Drug Name - Ceftazidime -avibactan
Active Ingredient- Avycaz
Date of approval - 2/25/2015
FDA-approved use - To treat adults with complicated intra-abdominal
infections(cIAI) , in combination with Metronidazole,
and complicated Urinary Tract Infections(cUTI),
including Kidney Infections( Pyelonephritis), who
have limited or no alternative treatment options
Approved by US FDA on 2/25/2015- (Ref- FDA approved List- 2015)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use AVYCAZ safely and effectively. See full prescribing information for AVYCAZ.
AVYCAZ (ceftazidime-avibactam) for injection, for intravenous use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
AVYCAZ (ceftazidime-avibactam) is a combination of a cephalosporin and a beta-lactamase inhibitor indicated for the treatment of patients 18 years or older with the following infections caused by designated susceptible microorganisms:
• Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole
• Complicated Urinary Tract Infections (cUTI), including Pyelonephritis As only limited clinical safety and efficacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options.
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 infections that are proven or strongly suspected to be caused by susceptible bacteria.
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reactions (incidence of > 10% in either indication) are vomiting, nausea, constipation, and anxiety.
Contra-Indications:
CONTRAINDICATIONS
Known serious hypersensitivity to ceftazidime, avibactam or other members of the cephalosporin class.
WARNINGS AND PRECAUTIONS
• Decreased efficacy in patients with baseline CrCL of 30 to 50 mL/ min. Monitor CrCL at least daily in patients with changing renal function and adjust the dose of AVYCAZ accordingly.
• Hypersensitivity reactions: Includes anaphylaxis and serious skin reactions. Cross-hypersensitivity may occur in patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue AVYCAZ.
• Clostridium difficile-associated diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including AVYCAZ. Evaluate if diarrhea occurs.
• Central Nervous System Reactions: Seizures and other neurologic events may occur, especially in patients with renal impairment. Adjust dose in patients with renal impairment.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
AVYCAZ (ceftazidime-avibactam) is a combination of a cephalosporin and a beta-lactamase inhibitor indicated for the treatment of patients 18 years or older with the following infections caused by designated susceptible microorganisms:
• Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole
• Complicated Urinary Tract Infections (cUTI), including Pyelonephritis As only limited clinical safety and efficacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options.
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 infections that are proven or strongly suspected to be caused by susceptible bacteria.
• See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution.
• See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution.
• See Full Prescribing Information for drug compatibilities.
DOSAGE FORMS AND STRENGTHS
AVYCAZ (ceftazidime-avibactam) for Injection in single-use vials containing 2 grams ceftazidime and 0.5 grams avibactam.
-------------------------------CONTRAINDICATIONS-----------------------------Known serious hypersensitivity to ceftazidime, avibactam or other members of the cephalosporin class. (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------• Decreased efficacy in patients with baseline CrCL of 30 to 50 mL/ min. Monitor CrCL at least daily in patients with changing renal function and adjust the dose of AVYCAZ accordingly. (5.1) • Hypersensitivity reactions: Includes anaphylaxis and serious skin reactions. Cross-hypersensitivity may occur in patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue AVYCAZ. (5.2) • Clostridium difficile-associated diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including AVYCAZ. Evaluate if diarrhea occurs. (5.3) • Central Nervous System Reactions: Seizures and other neurologic events may occur, especially in patients with renal impairment. Adjust dose in patients with renal impairment. (5.4)
------------------------------ADVERSE REACTIONS------------------------------Most common adverse reactions (incidence of > 10% in either indication) are vomiting, nausea, constipation, and anxiety. (6.1)
To report SUSPECTED ADVERSE REACTIONS,
Patient Information:
PATIENT COUNSELING INFORMATION
Serious Allergic Reactions
Advise patients, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur that require immediate treatment. Ask them about any previous hypersensitivity reactions to AVYCAZ, other beta-lactams (including cephalosporins), or other allergens
Potentially Serious Diarrhea
Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell them to contact his or her healthcare provider
Nervous System Reactions
Advise patients, their families, or caregivers that neurological adverse reactions can occur with AVYCAZ use.
Instruct patients their families, or caregivers to inform a healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures, for immediate treatment, dosage adjustment, or discontinuation of
AVYCAZ
Antibacterial Resistance
Counsel patients, their families, or caregivers that antibacterial drugs including AVYCAZ should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
When AVYCAZ is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may
(1) decrease the effectiveness of the immediate treatment and
(2) increase the likelihood that bacteria will develop resistance and will not be treatable by AVYCAZ or other antibacterial drugs in the future
Distributed by:
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, LLC
Cincinnati, Ohio 45209
Manufactured by:
GlaxoSmithKline Manufacturing S.p.A.
Verona, 37135 Italy
AVYCAZTM is a trademark of Actavis, Inc. or its affiliates.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action-
AVYCAZ is an antibacterial drug
2.Pharmacodynamics-
As with other beta-lactam antimicrobial drugs, the time that unbound plasma concentrations of ceftazidime exceeds the AVYCAZ minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model with Enterobacteriaceae and Pseudomonas aeruginosa.
Cardiac Electrophysiology
In a thorough QT study, a supratherapeutic dose of ceftazidime (3 grams) was investigated for QT effects in combination with a supratherapeutic dose of avibactam (2 grams) given as a 30-minute single infusion.
No significant effect on QTcF interval was detected at peak plasma concentration or at any other time. The largest 90% upper bound for the placebo corrected mean change from baseline was 5.9 ms. There were no QTcF intervals greater than 450 ms, nor were there any QTcF interval changes from baseline greater than 30 ms.
3.Pharmacokinetics-
The mean pharmacokinetic parameters for ceftazidime and avibactam in healthy adult male subjects with normal renal function after single and multiple 2-hour intravenous infusions of AVYCAZ 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) administered every 8 hours were evaluated
Pharmacokinetic parameters of ceftazidime and avibactam were similar for single and multiple dose administration of AVYCAZ and were similar to those determined when ceftazidime or avibactam were administered alone.
Distribution
Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. The binding of avibactam to human plasma proteins was low (5.7% to 8.2%) and was similar across the range of concentrations tested in vitro (0.5 to 50 mg/L).
Metabolism
Ceftazidime is mostly (80% to 90% of the dose) eliminated as unchanged drug. No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged avibactam was the major drug-related component in human plasma and urine after a single intravenous dose of 0.5 grams 14C-labelled
avibactam.
Excretion
Both ceftazidime and avibactam are excreted mainly by the kidneys.
Approximately 80% to 90% of an intravenous dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. .
Specific Populations
Renal Impairment
Ceftazidime is eliminated almost solely by the kidneys; its serum half-life is significantly prolonged in patients with impaired renal function.
Dosage adjustment of AVYCAZ is recommended in patients with moderate and severe renal impairment and end-stage renal disease.
Cardiac Electrophysiology
In a thorough QT study, a supratherapeutic dose of ceftazidime (3 grams) was investigated for QT effects in combination with a supratherapeutic dose of avibactam (2 grams) given as a 30-minute single infusion.
No significant effect on QTcF interval was detected at peak plasma concentration or at any other time. The largest 90% upper bound for the placebo corrected mean change from baseline was 5.9 ms. There were no QTcF intervals greater than 450 ms, nor were there any QTcF interval changes from baseline greater than 30 ms.
3.Pharmacokinetics-
The mean pharmacokinetic parameters for ceftazidime and avibactam in healthy adult male subjects with normal renal function after single and multiple 2-hour intravenous infusions of AVYCAZ 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) administered every 8 hours were evaluated
Pharmacokinetic parameters of ceftazidime and avibactam were similar for single and multiple dose administration of AVYCAZ and were similar to those determined when ceftazidime or avibactam were administered alone.
The C max and AUC of ceftazidime increase in proportion to dose. Avibactam demonstrated approximately linear pharmacokinetics across the dose range studied (50 mg to 2000 mg) for single intravenous administration.
No appreciable accumulation of ceftazidime or avibactam was observed following multiple intravenous infusions of AVYCAZ 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) administered every 8 hours for up to 11 days in healthy adults with normal renal function.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Pregnancy Category B
Animal reproductive toxicity studies have been conducted with ceftazidime and with avibactam. However, there are no adequate and well-controlled studies of AVYCAZ, ceftazidime, or avibactam in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.
2.Nursing Mothers-
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 in a dose dependent manner.
Exercise caution if AVYCAZ is to be administered to a nursing woman.
3.Pediatric Use-
Safety and effectiveness in patients less than 18 years of age have not been established.
4.Geriatric Use-
Of the 169 patients treated with AVYCAZ in the Phase 2 cIAI and cUTI trials, 18 (10.7%) were 65 years of age and older. Because of limited data, differences in outcomes or specific risks with AVYCAZ cannot be ruled out for patients 65 years of age and older.
Ceftazidime and avibactam are excreted primarily by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment.
Because elderly patients are more likely to have renal impairment, care should be taken in dose selection in this age group and it may be useful to monitor renal function.
Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
5.Renal Impairment-
Dosage adjustment is required in 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 and dosage of AVYCAZ adjusted accordingly.
Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days
OVERDOSAGE
In the event of overdose, discontinue AVYCAZ and institute general supportive treatment.
Ceftazidime and avibactam can be removed by hemodialysis. In subjects with ESRD administered 1 gram ceftazidime, the mean total recovery in dialysate following a 4-hour hemodialysis session was 55% of the administered dose.
No clinical information is available on the use of hemodialysis to treat AVYCAZ overdosage
