Allergan Receives FDA Approval of TEFLARO® (ceftaroline fosamil) for Pediatric Patients

DUBLIN, May 31, 2016 /PRNewswire/ -- Allergan plc (NYSE: AGN), a leading global pharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has approved the company's supplemental New Drug Application (sNDA) for TEFLARO^® (ceftaroline fosamil), granting new indications for pediatric patients 2 months of age to less than 18 years of age with acute bacterial skin and skin structure infections (ABSSSI), including infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and community-acquired bacterial pneumonia (CABP) caused by Streptococcus pneumoniae and other designated susceptible bacteria.

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"The impact of ABSSSI and CABP among children is significant, as these infections often require hospitalization and are met with limited pediatric treatment options, particularly as resistance increases among the pathogens that cause these infections," said David Nicholson, Chief R&D Officer, Allergan. "These new indications are yet another testament to our ongoing research and development in anti-infectives to address the evolving challenges of serious infections. Importantly, it allows us to educate physicians on the data they need to prescribe TEFLARO to appropriate pediatric patients in need of an option that is safe and effective against some of the most difficult-to-treat pathogens in ABSSSI and CABP."

ABSSSI and CABP are common causes of healthcare visits and hospitalizations among children. Studies show more than 70,000 hospitalizations for ABSSSI occur among children per year – a rate that has more than doubled over the past 13 years.¹ A study conducted by the Centers for Disease Control and Prevention (CDC) also found children younger than 5 years of age accounted for 70 percent of children hospitalized for community-acquired pneumonia.²

These new indications were approved based on results from clinical studies evaluating TEFLARO in pediatric patients (2 months to less than 18 years of age), including one active-controlled study in ABSSSI and two active-controlled studies in CABP. In the ABSSSI active-controlled study, the efficacy and safety of TEFLARO was compared with vancomycin or cefazolin (each with optional aztreonam). In the CABP studies, TEFLARO was compared with ceftriaxone. Use of TEFLARO in pediatric patients 2 months to less than 18 years of age is supported by evidence from adequate and well-controlled studies of TEFLARO in adults, as well as additional pharmacokinetic and safety data from pediatric trials.

The primary objective of the pediatric ABSSSI and CABP studies was to evaluate the safety and tolerability of TEFLARO. These studies were not powered for comparative inferential efficacy analysis, and no efficacy endpoints were identified as primary.

To evaluate the treatment effect of TEFLARO in the ABSSSI pediatric trial, an analysis was conducted in 159 patients with ABSSSI in the Modified Intent-to-Treat (MITT) population. This analysis evaluated responder rates based on achieving both cessation of lesion spread and absence of fever on Study Day 3. Patients treated with TEFLARO showed a higher response at Study Day 3 versus the comparator group, with clinical response achieved in 80.4 percent (86/107) of patients treated with TEFLARO and 75 percent (39/52) of patients in the comparator group, with a treatment difference of 5.4 percent (95 percent Confidence Interval [CI] -7.8, 20.3). Clinical cure rates at the test of cure (TOC) visit (8 to 15 days after the end of therapy) for the ABSSSI pediatric trial were 94.4 percent (101/107) for patients treated with TEFLARO and 86.5 percent (45/52) for the comparator, with a treatment difference of 7.9 (95 percent CI -1.2, 20.2).

To evaluate the treatment effect of TEFLARO in the CABP trial submitted for this pediatric filing, an analysis was conducted in 143 patients with CABP in the MITT population. This analysis evaluated responder rates at Study Day 4 based on achieving improvement in at least two out of seven symptoms (cough, dyspnea, chest pain, sputum production, chills, feeling of warmth/feverish and exercise intolerance or lethargy), and worsening in none of these symptoms. The clinical response at Study Day 4 was 69.2 percent (74/107) for patients treated with TEFLARO and 66.7 percent (24/36) for the comparator, with a treatment difference of 2.5 percent (95 percent CI -13.9, 20.9). Clinical cure rates at TOC were 87.9 percent (94/107) for patients treated with TEFLARO and 88.9 percent (32/36) for the comparator, with a treatment difference of -1.0 (95 percent CI -11.5, 14.1).

Results from the clinical studies in pediatric patients showed that TEFLARO demonstrated a safety profile that was compatible with treatment of ABSSSI and CABP at the clinical dosages studied. The safety findings were similar to those seen in the adult studies, and no safety concerns were identified beyond those already known to be cephalosporin class effects.  

TEFLARO is the first and only cephalosporin indicated in adults and pediatric patients 2 months of age and older for the treatment of ABSSSI and CABP due to designated susceptible pathogens that can be administered by intravenous (IV) infusion in five minutes to one hour.

ABOUT TEFLARO^® 
TEFLARO was first approved by the U.S. FDA in October 2010 for the treatment of adults with CABP and ABSSSI due to designated susceptible pathogens. TEFLARO is a bactericidal cephalosporin with activity against both Gram-positive and Gram-negative pathogens. TEFLARO is indicated in adult and pediatric patients 2 months of age and older for the treatment of CABP, including cases caused by Streptococcus pneumoniae, and ABSSSI, including cases caused by methicillin-resistant Staphylococcus aureus (MRSA). TEFLARO is the first and only cephalosporin with activity against MRSA in ABSSSI. In clinical trials, TEFLARO was generally well-tolerated with an adverse event profile consistent with the cephalosporin class of antibiotics. TEFLARO has been administered in over 2.3 million days of therapy, treating more than 350,000 patients.

Allergan plc (formerly Forest Laboratories) obtained the worldwide rights (excluding Japan, where Takeda Pharmaceuticals holds rights) to TEFLARO in 2007 when it acquired Cerexa, Inc., a privately held biopharmaceutical company. In August 2009, Forest Laboratories and AstraZeneca (NYSE: AZN) entered into a definitive collaboration agreement to co-develop and commercialize ceftaroline fosamil in all markets outside the U.S., Canada and Japan.

INDICATIONS AND USAGE

• TEFLARO^® (ceftaroline fosamil) is indicated in adult and pediatric patients 2 months of age and older for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca.
• TEFLARO is also indicated in adult and pediatric patients 2 months of age and older for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli.
• To reduce the development of drug-resistant bacteria and maintain the effectiveness of TEFLARO and other antibacterial drugs, TEFLARO should be used to treat only ABSSSI or CABP that are proven or strongly suspected to be caused by susceptible bacteria. Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to ceftaroline. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

IMPORTANT SAFETY INFORMATION 

Contraindications

• TEFLARO is contraindicated in patients with known serious hypersensitivity to ceftaroline or other members of the cephalosporin class. Anaphylaxis has been reported with ceftaroline.

Warnings and Precautions

Hypersensitivity Reactions

• Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported with beta-lactam antibacterial drugs. Before therapy with TEFLARO is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Maintain clinical supervision if this product is to be given to a penicillin- or other beta-lactam-allergic patient, because cross sensitivity among beta-lactam antibacterial agents has been clearly established.
• If an allergic reaction to TEFLARO occurs, discontinue TEFLARO and institute appropriate treatment and supportive measures.

Clostridium difficile-Associated Diarrhea

• Clostridium difficile-Associated Diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including TEFLARO, 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 agents. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible.

Direct Coombs' Test Seroconversion

• In adults, seroconversion from a negative to a positive direct Coombs' test result occurred in 120/1114 (10.8%) of patients receiving TEFLARO and 49/1116 (4.4%) of patients receiving comparator drugs in the four pooled adult Phase 3 trials.
• In children, seroconversion from a negative to a positive direct Coombs' test result occurred in 42/234 (17.9%) of patients receiving TEFLARO and 3/93 (3.2%) of patients receiving comparator drugs in the three pooled pediatric trials.
• No adverse reactions representing hemolytic anemia were reported in any treatment group. If anemia develops during or after treatment with TEFLARO, drug-induced hemolytic anemia should be considered. If drug-induced hemolytic anemia is suspected, discontinuation of TEFLARO should be considered and supportive care should be administered to the patient if clinically indicated.

Development of Drug-Resistant Bacteria

• Prescribing TEFLARO 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 in Adults

• In the four pooled adult Phase 3 clinical trials, serious adverse reactions occurred in 98/1300 (7.5%) of patients receiving TEFLARO and 100/1297 (7.7%) of patients receiving comparator drugs. Treatment discontinuation due to adverse reactions occurred in 35/1300 (2.7%) of patients receiving TEFLARO and 48/1297 (3.7%) of patients receiving comparator drugs with the most common adverse reactions leading to discontinuation being hypersensitivity for both treatment groups at a rate of 0.3% in the TEFLARO group and 0.5% in the comparator group.
• The most common adverse reactions occurring in >2% of patients receiving TEFLARO in the adult pooled Phase 3 clinical trials were diarrhea (5%) nausea (4%), and rash (3%).

Adverse Reactions in Pediatrics

• In the three pooled pediatric clinical trials, serious adverse reactions occurred in 10/257 (4%) of patients receiving TEFLARO and 3/102 (3%) of patients receiving comparator drugs. Treatment discontinuation due to adverse reactions occurred in 10/257 (3.9%) of patients receiving TEFLARO and 2/102 (2%) of patients receiving comparator drugs with the most common adverse reaction leading to discontinuation being rash in 2/257 (0.8%) of patients treated with TEFLARO
• The most common adverse reactions occurring in ≥ 3% of patients receiving TEFLARO in the pooled pediatric clinical trials were diarrhea (8%), rash (7%), vomiting (5%), pyrexia (3%) and nausea (3%).

Drug Interactions

• No clinical drug-drug interaction studies have been conducted with TEFLARO. There is minimal potential for drug- drug interactions between TEFLARO and CYP450 substrates, inhibitors, or inducers; drugs known to undergo active renal secretion; and drugs that may alter renal blood flow.

Use in Specific Populations

• There have been no adequate and well-controlled studies with TEFLARO in pregnant or nursing women.
• Safety and effectiveness in pediatric patients below the age of 2 months have not been established as no data are available.
• Because elderly patients, those ≥65 years of age, are more likely to have decreased renal function and ceftaroline is excreted primarily by the kidney, 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 therefore be based on renal function.
• Dosage adjustment is required in adult patients with moderate (CrCl >30 to ≤50 mL/min) or severe (CrCl ≥15 to ≤30mL/min) renal impairment and in patients with end-stage renal disease (CrCl <15 mL/min).  There is insufficient information to recommend a dosage regimen for pediatric patients with CrCl < 50 ml/min/1.73m².
• The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established.

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

About ABSSSI
In 2014, there were 2.7 million hospital admissions for ABSSSI, of which 11 percent were for pediatric patients, which included patients with cellulitis, erysipelas, wound infection and major cutaneous abscess.³ The majority of all skin and soft tissue infections in hospitalized patients are caused by streptococci and Staphylococcus aureus, and approximately 59 percent of these Staphylococcus aureus infections in the U.S. are estimated to be caused by MRSA.⁴ Early and effective treatment of ABSSSI is critical to optimize patient recovery and for certain patients may also help to avoid potentially lengthy and costly hospital stays.

About CABP

In 2014, there were 1.3 million hospital admissions for CABP, of which 8 percent were for pediatric patients.³ While the overall incidence of pneumonia is declining, it is still a leading cause of mortality accounting for more than 50,000 deaths in 2013.⁵ The economic burden of community-acquired pneumonia in the U.S. is significant, due to high hospitalization and mortality rates associated with community-acquired pneumonia.⁶ More than $17 billion is spent on caring for patients with community-acquired pneumonia annually.⁶ Community-acquired pneumonia hospitalization costs for children alone amounted to $1 billion in 2009.²

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 Annual Report on Form 10-K for the year ended December 31, 2015 (certain of 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.

CONTACTS:    

Investors:
Lisa DeFrancesco 
(862) 261-7152

Media:
Mark Marmur
(862) 261-7558

¹ Lopez MA, Cruz AT, Kowalkowski MA, et al. Trends in resource utilization for hospitalized children with skin and soft tissue infections. Pediatrics. 2013;131:e718–e725.

² Jain S, Williams DJ, Arnold SR, et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med. 2015;372:835-45.

³ Decision Resources Group. PatientBase hospital-treated infections epidemiology. 2014.

⁴ Moran GJ, Abrahamian FM, LoVecchio F, et al. Acute bacterial skin infections: developments since the 2005 Infectious Disease Society of America (IDSA) guidelines. J Emerg Med. 2013;44(6):e397-e412.

⁵ FastStats pneumonia. Centers for Disease Control and Prevention website. 2015. Available at: http://www.cdc.gov/nchs/fastats/pneumonia.htm. Accessed May 17, 2016.

⁶ Sato R, Rey GG, Nelson S, et al. Community-acquired pneumonia episode costs by age and risk in commercially insured US adults aged ‡50 years. Appl Health Econ Health Policy. 2013;11:251–258.

SOURCE Allergan plc

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