Actavis Receives U.S. FDA Approval for AVYCAZ™ (CEFTAZIDIME-AVIBACTAM)

DUBLIN, Feb. 25, 2015  -- Actavis plc (NYSE: ACT) today announced the U.S. Food and Drug Administration (FDA) has approved AVYCAZ™ (ceftazidime-avibactam). AVYCAZ was approved for the treatment of adult patients with complicated intra-abdominal infections (cIAI) (in combination with metronidazole) and complicated urinary tract infections (cUTI) including pyelonephritis caused by designated susceptible bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa. AVYCAZ received a priority review based on Phase II data from the company's clinical development program and supporting in vitro data, and as such should be reserved for use in patients who have limited or no alternative treatment options.

AVYCAZ combines ceftazidime, a cephalosporin with in vitro activity against certain Gram-negative and Gram-positive bacteria, and avibactam, a non-beta-lactam beta-lactamase inhibitor that inactivates certain key beta-lactamases and protects ceftazidime from degradation by these beta-lactamases. The addition of avibactam to ceftazidime protects ceftazidime from breakdown by Extended Spectrum Beta-Lactamases (ESBL), Klebsiella pneumoniae carbapenemase (KPC) and AmpC producing pathogens. AVYCAZ is part of Actavis' leading portfolio of infectious disease products that address some of the most dangerous pathogens.

"The FDA approval of AVYCAZ is an important step forward in enhancing our ability to respond to serious infections caused by difficult to treat Gram-negative pathogens," said David Nicholson, Executive Vice President, Global Brands Research and Development, Actavis. "At Actavis, we are dedicated to helping bridge the gap in existing treatment options, and the development of new agents that may help address the urgent threat of these pathogens. We were very pleased to be working with the FDA to advance the approval of AVYCAZ as quickly as possible to make this important new treatment option available to physicians and patients at the earliest possible time."

AVYCAZ was granted priority review and approval as a Qualified Infectious Disease Product (QDIP) in accordance with the Generating Antibiotics Incentives Now (GAIN) Act, which made it eligible for theFDA's fast-track program and a five-year regulatory extension of exclusivity under the Hatch-Waxman Act.

"The recent increase in the incidence of multi-drug resistant Gram-negative pathogens poses a significant threat to patients and places a tremendous strain on the U.S. healthcare system. The increasing prevalence of KPC-producing Enterobacteriaceae in particular, have become a major therapeutic challenge for physicians managing these infections. Unfortunately, there are currently a limited number of safe and effective antimicrobials to treat these serious infections," said Jose Vazquez, MD, FACP, FIDSA, Professor of Medicine, Chief, Infectious Diseases and Chair of the Antimicrobial Subcommittee at the Medical College of Georgia/Georgia Regents University.

The approval of AVYCAZ was supported in part by the FDA's previous findings of efficacy and safety for ceftazidime for the treatment of cIAI and cUTI. In addition, the contribution of avibactam to AVYCAZ was primarily established via in vitro data and animal models of infection. AVYCAZ was studied in two Phase II, randomized, blinded, active-controlled, multicenter trials, one each in cIAI and cUTI, including pyelonephritis. These Phase II studies were not designed with any formal hypotheses for inferential testing against the active comparators.

AVYCAZ will be available in the second quarter of 2015.

About AVYCAZ

AVYCAZ (ceftazidime-avibactam) consists of ceftazidime, a cephalosporin, and avibactam, a non-beta-lactam beta-lactamase inhibitor, and is approved for the treatment of cIAI (in combination with metronidazole) and cUTI infections including pyelonephritis caused by designated susceptible microorganisms in patients 18 years of age and older. AVYCAZ should be reserved for use in patients who have limited or no alternative treatment options as limited clinical safety and efficacy data for AVYCAZ are currently available.

The addition of avibactam to ceftazidime protects ceftazidime from breakdown by certain beta-lactamases. AVYCAZ addresses important needs in the treatment of cUTI and cIAI due to designated susceptible Gram-negative pathogens.

AVYCAZ, in combination with metronidazole, is indicated for the treatment of cIAI caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca and Pseudomonas aeruginosa.

AVYCAZ is indicated for the treatment of 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.

AVYCAZ demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (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 P. 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.

The recommended dosage of AVYCAZ for patients with normal renal function [creatinine clearance (CrCL) >50 mL/min] is 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) administered every 8 hours by intravenous (IV) infusion over 2 hours in patients 18 years of age and older. For patients with changing or impaired renal function (CrCL <50mL/min), CrCL should be monitored at least daily and the dosage of AVYCAZ should be adjusted accordingly. For treatment of cIAI, metronidazole should be given concurrently.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

AVYCAZ is contraindicated in patients with known serious hypersensitivity to AVYCAZ, avibactam‑containing products, ceftazidime, 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 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. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCL 30 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, nausea, constipation, and anxiety.

AVYCAZ is being jointly developed with AstraZeneca. Actavis holds the rights to commercialize AVYCAZ in North America, while AstraZeneca holds the rights to commercialize ceftazidime-avibactam in the rest of the world.

Phase III studies  including studies evaluating AVYCAZ for the treatment of cIAI and cUTI  are underway and targeted for completion in late 2015. The company intends to submit the Phase III results to theFDA as a supplemental NDA.

For more information, visit www.AVYCAZ.com.

About Gram-Negative Infections

Gram-negative bacteria are highly adaptive pathogens that can develop resistance through several mechanisms and can pass along genetic materials that allow other bacteria to become drug-resistant as well.[1],[2] Gram-negative bacteria are common causes of complicated intra-abdominal infections and urinary tract infections.[1],[2]

Complicated intra-abdominal infections are a considerable problem, affecting approximately 1.1 million patients each year.[3] The most common pathogens associated with intra-abdominal infections includeEscherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca and Pseudomonas aeruginosa.[3]

Complicated urinary tract infections are also often caused by Gram-negative pathogens.[1] Escherichia coli (E. coli) is one of the common organisms causing urinary tract infections (UTIs), affecting 2.9 million patients each year, and is becoming increasingly resistant to available antibiotics.[1],[3]

According to the Centers for Disease Control and Prevention (CDC), rates of Klebsiella pneumoniae carbapenemase (KPC) producing organisms in particular have increased across the country significantly in the past 10 years.[4] In addition, E. coli, Klebsiella (K. pneumoniae and K. oxytoca) andPseudomonas aeruginosa are on the rise.[1],[2]

About Actavis

Actavis plc (NYSE:ACT), headquartered in Dublin, Ireland, is a unique specialty pharmaceutical company focused on developing, manufacturing and commercializing high quality affordable generic and innovative branded pharmaceutical products for patients around the world. 

Actavis markets a broad portfolio of branded and generic pharmaceuticals and develops innovative medicines for patients suffering from diseases principally in the central nervous system, gastroenterology, women's health, urology, cardiovascular, respiratory and anti-infective therapeutic categories. The Company is an industry leader in product research and development, with one of the broadest brand development pipelines in the pharmaceutical industry, and a leading position in the submission of generic product applications. Actavis has commercial operations in more than 60 countries and operates more than 30 manufacturing and distribution facilities around the world.

For more information, visit Actavis' website at www.actavis.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 Actavis' current perspective of existing trends and information as of the date of this release. Except as expressly required by law, Actavis disclaims any intent or obligation to update these forward-looking statements. Actual results may differ materially fromActavis' current expectations depending upon a number of factors affecting Actavis' 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 Actavis' products; risks associated with acquisitions, mergers and joint ventures; difficulties or delays in manufacturing; and other risks and uncertainties detailed in Actavis' periodic public filings with the Securities and Exchange Commission, including but not limited to Actavis' Annual Report on Form 10-K for the year ended December 31, 2014. Except as expressly required by law, Actavisdisclaims any intent or obligation to update these forward-looking statements.

[1]National Institute of Allergy and Infectious Diseases (NIAID) website.ttp://www.niaid.nih.gov/topic.... Accessed February 16, 2015.

[2] Peleg A, Hooper D. Hospital-acquired infections due to Gram-negative bacteria. New England Journal of Medicine. 2010; 62:1804-1813.

[3] Data on file

[4] Guidance for Control of Carbapenem-resistant Enterobacteriaceae (CRE). Centers for Disease Control and Prevention website. ttp://www.cdc.gov/hai/pdfs/cr... Accessed February 16, 2015.