FDA Accepts Supplemental New Drug Application (sNDA) filing for AVYCAZ® (ceftazidime and avibactam)

DUBLIN, Oct. 2, 2017 /PRNewswire/ -- Allergan plc (NYSE: AGN), a leading global pharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has accepted a supplemental New Drug Application (sNDA) for AVYCAZ^® (ceftazidime and avibactam) for priority review. The sNDA filing seeks to expand the current indications for AVYCAZ to include hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) in adult patients based on positive results from a Phase 3 clinical trial evaluating AVYCAZ for the treatment of patients with HABP/VABP. The FDA granted priority review status to the application based on the previous Qualified Infectious Disease Product (QIDP) designation for AVYCAZ, and is expected to take action on the filing in the first quarter of 2018.

"The increasing prevalence of difficult-to-treat Gram negative pathogens causing serious bacterial infections, like HABP and VABP, has resulted in a critical need for new effective treatments to combat these threats," said David Nicholson, Ph.D., Chief Research and Development Officer, Allergan. "Allergan is committed to bringing forward new therapies to address today's healthcare needs and to providing data that demonstrate the safety and efficacy of these therapeutics. We're encouraged by the filing acceptance; if the AVYCAZ sNDA is approved, healthcare providers will have a much-needed new treatment option for the management of HABP and VABP infections."

Pending the sNDA approval, this will be the third indication for AVYCAZ. AVYCAZ was first approved in Feburary 2015 in the U.S. 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.

This application seeks to add a new indication in the label based on favorable results from a pivotal Phase 3 study evaluating the efficacy and safety of AVYCAZ for the treatment of adult patients with HABP/VABP. The multicenter, randomized double-blind REPROVE study demonstrated the non-inferiority of AVYCAZ to meropenem with regard to the U.S. FDA primary endpoint, 28-day all-cause mortality in the ITT (intent-to-treat) population, and AVYCAZ was also non-inferior to meropenem with respect to the key secondary endpoint, clinical cure at the test of cure (TOC) visit in the ITT population. In a subset of patients infected with Gram-negative pathogens producing certain ESBL group and AmpC beta-lactamases, the clinical and microbiological cure rates were similar to the overall results. In the study, the overall safety profile observed for AVYCAZ was consistent with the current product labeling.

AVYCAZ has 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 (MBLs) and may not have activity against Gram-negative bacteria that overexpress efflux pumps or have porin mutations.

Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia (HABP/VABP)

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are serious bacterial infections that occur in hospitalized patients. The Gram-negative bacteria that commonly cause HABP and VABP include the Enterobacteriaceae (including Klebsiella penumoniae, Escherichia coli, Enterobacter spp., Citrobacter freundii complex, Proteus mirabilis) and Pseudomonas aeruginosa.

The economic burden associated with HABP and VABP is significant. HABP/VABP is currently the second most common type of nosocomial infection in the U.S. and is associated with high mortality and morbidity, especially in the intensive care unit (ICU) of hospitals.[i]   

About AVYCAZ

INDICATIONS AND USAGE

Complicated Intra-Abdominal Infections (cIAI)

AVYCAZ^® (ceftazidime and avibactam), 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.

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.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat only indicated 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 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. 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. 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. 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.
• 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 (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.
• 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 in cIAI patients (?5% when used with metronidazole) were diarrhea (8%), nausea (7%), and vomiting (5%). The most common adverse reactions in cUTI patients (3%) were diarrhea and nausea.

Please also see the full Prescribing Information at www.AVYCAZ.com.

About Allergan plc

Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global pharmaceutical company and a leader in a new industry model ? Growth Pharma. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world.

Allergan markets a portfolio of leading brands and best-in-class products for the central nervous system, eye care, medical aesthetics and dermatology, gastroenterology, women's health, urology and anti-infective therapeutic categories.

Allergan is an industry leader in Open Science, a model of research and development, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry with 65+ mid-to-late stage pipeline programs currently in development.

Allergan's success is powered by our more than 18,000 global colleagues' commitment to being Bold for Life. Together, we build bridges, power ideas, act fast and drive results for our customers and patients around the world by always doing what is right.

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 every day.

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 on existing trends and information as of the date of this release. 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 Annual Report on Form 10-K for the year ended December 31, 2016 and Allergan's Quarterly Report on Form 10-Q for the period ended June 30, 2017. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements.

ⁱAnalytical Framework for Examining the Value of Antibacterial Products, U.S. Dept. of Health and Human Services https://aspe.hhs.gov/system/files/pdf/76891/rpt_antibacterials.pdf

SOURCE Allergan plc