DRUG INTERACTIONS-(summary)

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.

BRIEF SUMMARY

CEFTFAZIDIME-(Feb 2015)

Indn-  Urinart r Most common adverse reactions (incidence of > 10% in either indication) are vomiting, nausea, constipation, and anxiety.

ADR-      Most common adverse reactions (incidence of > 10% in either indication) are vomiting, nausea, constipation, and anxiety.

CI-

Pat Infrm-

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

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Novel Drug Approvals for 2015

1.Name                        AVYCAZ

2.Active ingredient-    Caftazidime

3. Indication-  

Date of Approval  2/23/2015

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. [see Clinical Studies

 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 REACTIONS-

 Most common adverse reactions (incidence of > 10% in either indication) are vomiting, nausea, constipation, and anxiety. 

DOSAGE AND ADMINISTRATION-

 Estimated Creatinine Clearance (mL/min)a Recommended Dosage Regimen for AVYCAZ Infuse each dose intravenously over 2 hours greater than 50 2.5 grams (2 grams/0.5 grams) every 8 hours 31 to 50 1.25 grams (1 grams/0.25 grams) every 8 hours 16 to 30 0.94 grams (0.75 grams/0.19 grams every 12 hours

DOSAGE AND ADMINISTRATION-

 Estimated Creatinine Clearance (mL/min)a Recommended Dosage Regimen for AVYCAZ Infuse each dose intravenously over 2 hours greater than 50 2.5 grams (2 grams/0.5 grams) every 8 hours 31 to 50 1.25 grams (1 grams/0.25 grams) every 8 hours 16 to 30 0.94 grams (0.75 grams/0.19 grams every 12 hours 6 to 15b 0.94 grams (0.75 grams/0.19 grams) every 24 hours Less than or equal 5b 0.94 grams (0.75 grams/0.19 grams) every 48 hours a As calculated using the Cockcroft-Gault formula. b Both ceftazidime and avibactam are hemodialyzable; thus, administer AVYCAZ after hemodialysis on hemodialysis days. Recommended duration of treatment: (2.1) cIAI: 5 to 14 days cUTI including pyelonephritis: 7 to 14 days • See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution. (2.3) • See Full Prescribing Information for drug compatibilities. (2.4)

---------------------DOSAGE FORMS AND STRENGTHS--------------------- AVYCAZ (ceftazidime-avibactam) for Injection in single-use vials containing 2 grams ceftazidime and 0.5 grams avibactam. (3)

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 [see Warnings and Precautions (5.3)].

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. ATCC is a registered trademark of the American Type Culture Collection. AVYCAZ (ceftazidime-avibactam) for Injection, for intravenous use 19 Reference ID: 3707807

CLINICAL PHARMACOLOGY-

Mechanism of Action AVYCAZ is an antibacterial drug [see Clinical Pharmacology 

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.

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 

Distribution- Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration.

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.

Renal clearance was 158 mL/min, which is greater than the glomerular filtration, suggesting that active tubular secretion contributes to the excretion of avibactam in addition to glomerular filtration.

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.

Because the exposure of both ceftazidime and avibactam is highly dependent on renal function, monitor CrCL at least daily and adjust the dosage of AVYCAZ accordingly for patients with changing renal function.

Hepatic Impairment-                                                                                                      The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 grams intravenously every 8 hours for 5 days. The pharmacokinetics of avibactam in patients with hepatic impairment have not been established.

Avibactam does not appear to undergo significant hepatic metabolism, therefore the systemic clearance of avibactam is not expected to be significantly affected by hepatic impairment.

Drug Interaction Studies-                                                                                          Avibactam at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes.

Avibactam showed no potential for in vitro induction of CYP1A2, 2B6, 2C9 and 3A4 isoenzymes in human hepatocytes. Against CYP2E1, avibactam showed a slight induction potential at very high concentrations that exceed any clinically relevant exposure.

1. USE IN SPECIFIC POPULATIONS-                                                                       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.

3. 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.

4. Pediatric Use- Safety and effectiveness in patients less than 18 years of age have not been established.

5. 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 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)]

6. Renal Impairment-                                                                                                       Dosage adjustment is required in patients with moderately or severely impaired renal function (CrCL 50 mL/min or less).

10 OVERDO