Data Presented at IDWeek Reports AVYCAZ™ (ceftazidime and avibactam) Demonstrated In Vitro Antimicrobial Activity Against Common Enterobacteriaceae Pathogens, Including Certain Carbapenem-Resistant Strains

DUBLIN, Oct. 10, 2015 /PRNewswire/ -- Researchers presented data at IDWeek from the International Network for Optimal Resistance Monitoring (INFORM) program, one of the largest ongoing surveillance programs in the United States. This program is part of a research effort developed and supported by Allergan plc (NYSE: AGN) that monitors the prevalence of resistant bacteria and changing trends of resistance, as well as the in vitro activity of antibiotics against these pathogens.

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"The INFORM program represents Allergan's significant commitment to investing in research that advances our understanding of the prevalence, impact and appropriate management of infections caused by resistant Gram-negative pathogens, such as carbapenem-resistant Enterobacteriaceae (CRE)," said David Melnick, M.D., Vice President, Clinical Development, Anti-Infectives, Allergan.  

Carbapenem-resistant Enterobacteriaceae (CRE) is one of the three most urgent public health threats identified by the U.S. Centers for Disease Control and Prevention (CDC).¹ Klebsiella pneumoniae carbapenemase (KPC) producing bacteria are a common subset of CRE bacteria and account for approximately 85 percent of all CRE infections in the U.S.¹

The INFORM data presented at IDWeek reported that the antibiotic AVYCAZ^™ (ceftazidime and avibactam) demonstrated potent in vitro activity against certain common Enterobacteriaceae pathogens isolated from patients with complicated urinary tract infections (cUTI) in U.S. hospitals, including those caused by certain KPC-producing Gram-negative bacteria, meropenem non-susceptible Klebsiella pneumoniae and isolates demonstrating an extended-spectrum beta-lactamase (ESBL)-phenotype. These pathogens are often resistant to multiple antimicrobial agents, which may be important when limited alternative treatment options are available. This analysis also found AVYCAZ was highly active against certain Klebsiella species resistant to other beta-lactam antibiotics, as well as Pseudomonas aeruginosa, including the majority of isolates non-susceptible to meropenem.   

Ceftazidime and avibactam was approved by the U.S. Food and Drug Administration (FDA) as AVYCAZ in February 2015 for the treatment of cUTI including pyelonephritis and complicated intra-abdominal infections (cIAI), in combination with metronidazole, caused by designated susceptible bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa for patients 18 years of age and older. 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.

This approval was based in part on data that found AVYCAZ demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and ESBLs of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC, and certain oxacillinases (OXA). AVYCAZ also demonstrated in vitro activity against Pseudomonas aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). AVYCAZ is not active against bacteria that produce metallo-beta lactamases and may not have activity against Gram-negative bacteria that overexpress efflux pumps or have porin mutations.

"AVYCAZ represents a significant advance in addressing urgent public health threats caused by difficult-to-treat Gram-negative pathogens," Dr. Melnick said. "Allergan looks forward to building on the 10 years of research and development the company invested in bringing this product to market and will continue to bring much-needed innovations to physicians and their patients."

The INFORM data, presented in a poster titled, "Antimicrobial Activity of Ceftazidime-Avibactam and Comparator Agents Tested Against Gram-negative Organisms Isolated from Urinary Tract Infections (UTI): Results from the International Network for Optimal Resistance (INFORM) Program," evaluated 7,262 unique patient organisms from patients with UTIs treated at 71 U.S. medical centers between 2012 and 2014. Susceptibility testing was performed for ceftazidime and avibactam, ceftazidime alone, meropenem and piperacillin-tazobactam by reference broth microdilution methods. Enterobacteriaceae with an ESBL phenotype were evaluated for the presence of genes encoding ESBLs, KPC, metallo and transferable AmpC enzymes using a microarray-based assay.

Ceftazidime and avibactam is co-developed with partner AstraZeneca. AstraZeneca has filed a variation to the Marketing Application in the EU seeking approval for similar indications.

About AVYCAZ™
AVYCAZ is an antibiotic developed to treat certain serious Gram-negative bacterial infections. It consists of ceftazidime, a third-generation, cephalosporin, that is an established and respected treatment for serious Gram-negative bacterial infections, and avibactam, a non-β lactam β-lactamase inhibitor.

The addition of avibactam to ceftazidime protects ceftazidime from breakdown by certain β-lactamases. AVYCAZ offers a differentiated profile in the treatment of serious Gram-negative infections through its coverage of a range of species of Enterobacteriaceae, including those that produce certain ESBL and KPC, together with activity against difficult to treat Pseudomonas aeruginosa.

INDICATIONS AND USAGE
As only limited clinical safety and efficacy data for AVYCAZ^TM (ceftazidime and avibactam) are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options.

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 microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosa in patients 18 years or older.

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 microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus spp., and Pseudomonas aeruginosa in patients 18 years or older.

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 infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS  
AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam‑containing products, or other members of the cephalosporin class. 

WARNINGS AND PRECAUTIONS

• In a Phase 3 complicated intra-abdominal infections (cIAI) trial, clinical cure rates were lower in a subgroup of patients with baseline creatinine clearance (CrCl) of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min. The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Clinical cure rates in patients with normal renal function/mild renal impairment (CrCl greater than 50 mL/min) was 85% (322/379) with AVYCAZ plus metronidazole vs 86% (321/373) with meropenem, and clinical cure rates in patients with moderate renal impairment (CrCl 30 to less than or equal to 50 mL/min) was 45% (14/31) with AVYCAZ plus metronidazole vs 74% (26/35) with meropenem. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl of 30 to less than or equal to 50 mL/min. Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly.
• 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 (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. 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, antibacterials not directed against C. difficile should be discontinued, if possible.
• Seizures, nonconvulsive status epilepticus, 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.
• 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

• The most common adverse reactions (incidence of >10% in either indication) were vomiting (14%), nausea (10%), constipation (10%), and anxiety (10%).

Please see the full Prescribing Information for AVYCAZ at www.avycaz.com.

About Allergan
Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a unique, global pharmaceutical company and a leader in a new industry model – Growth Pharma.  Allergan is focused on developing, manufacturing and commercializing innovative branded pharmaceuticals, high-quality generic and over-the-counter medicines and biologic products for patients around the world. 

Allergan markets a portfolio of best-in-class products that provide valuable treatments for the central nervous system, eye care, medical aesthetics, gastroenterology, women's health, urology, cardiovascular and anti-infective therapeutic categories, and operates the world's third-largest global generics business, providing patients around the globe with increased access to affordable, high-quality medicines. Allergan is an industry leader in research and development, with one of the broadest development pipelines in the pharmaceutical industry and a leading position in the submission of generic product applications globally.

With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives.

For more information, visit Allergan's website at www.allergan.com.

Forward-Looking Statement
Statements contained in this press release that refer to future events or other non-historical facts are forward-looking statements that reflect Allergan's current perspective of existing trends and information as of the date of this release. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements. Actual results may differ materially from Allergan's current expectations depending upon a number of factors affecting Allergan's business. These factors include, among others, the difficulty of predicting the timing or outcome of FDA approvals or actions, if any; the impact of competitive products and pricing; market acceptance of and continued demand for Allergan's products; difficulties or delays in manufacturing; and other risks and uncertainties detailed in Allergan's periodic public filings with the Securities and Exchange Commission, including but not limited to Allergan's Quarterly Report on Form 10-Q for the quarter ended June 30, 2015 (such periodic public filings having been filed under the "Actavis plc" name). Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements.

¹ Antibiotic resistance threats in the United States, 2013. Centers for Disease Control and Prevention website. http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed October 5, 2015.

SOURCE Allergan plc

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