Press Release: FDA Approves New Indication for INVANZ

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FDA Approves New Indication for INVANZ (ertapenem) for the Prevention of Surgical Site Infections (SSI) following Elective Colorectal Surgery in Adults

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) recently approved INVANZ® (ertapenem), a once-daily injectable antibiotic, for the prophylaxis of surgical site infection (SSI) following elective colorectal surgery in adults. This approval was based upon the results of the landmark PREVENT trial, the largest prospective, randomized double-blind, comparative clinical trial ever conducted in antibiotic prophylaxis for elective colorectal surgery (N=1002). Results from the study were presented today in the New England Journal of Medicine.

“Given the high incidence of SSI, Merck is very pleased to be able to offer a new alternative with clinically demonstrated efficacy,” said Murray A. Abramson, M.D., M.P.H., senior medical director, Merck Research Labs, Infectious Diseases, Merck & Co. Inc. In the PREVENT study, a statistically significant difference favoring INVANZ over cefotetan with respect to the primary endpoint has been observed. A second adequate and well-controlled study to confirm these findings has not been conducted; therefore, the clinical superiority of ertapenem over cefotetan has not been demonstrated. INVANZ provides proven prophylaxis for elective colorectal surgery in a single 1 g dose given within one hour prior to surgical incision.

The primary endpoint in the PREVENT study was the test of prophylaxis, which was defined as no evidence of SSI, post-operative anastomotic leak, or unexplained antibiotic use through four weeks post-surgery in the clinically evaluable and MITT populations. The rates of successful prophylaxis at 4 weeks posttreatment in the clinically evaluable patients were 70.5 percent (244/346) for ertapenem and 57.2 percent (194/339) for cefotetan. In the MITT analysis, the prophylactic success rates at 4 weeks posttreatment were 58.3 percent (263/451) for ertapenem and 48.9 percent (220/450) for cefotetan (difference 9.4 percent, [95 percent CI, 2.9, 15.9], p=0.002).

Prophylaxis failure due to SSI, including superficial incisional, deep incisional or organ space infections, occurred in 18.2 percent (63/346) of ertapenem patients and 31 percent (105/339) of cefotetan patients. Post-operative anastomotic leak occurred in 2.9 percent (10/346) of ertapenem patients and 4.1 percent (14/339) of cefotetan patients. Unexplained antibiotic use occurred in 8.4 percent (29/346) and 7.7 percent (26/339) of ertapenem and cefotetan patients, respectively.

INVANZ is now indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery. Elective colorectal (gastrointestinal) surgery is performed to repair or remove diseased portions of the lower intestinal tract (including the colon, rectum and anus) sometimes due to cancer or diverticulosis. The incidence of surgical site infection has become a focus of the National Surgical Infection Prevention Project implemented by the Centers for Medicare and Medicaid Services in collaboration with the Centers for Disease Control and Prevention to promote the proper use of prophylactic antibiotics.

INVANZ is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. Due to the use of lidocaine HCl as a diluent, INVANZ administered intramuscularly is contraindicated in patients with known hypersensitivity to local anesthetics of the amide type. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams.

New indication based on the PREVENT study, the largest prospective clinical trial to date of antibiotic prophylaxis for elective colorectal surgery.

The PREVENT study, a randomized, double-blind, multi-center comparative trial conducted in 1,002 adult patients, compared INVANZ to cefotetan in the prophylaxis of surgical site infection following elective colorectal surgery. Patients received a single dose of either INVANZ 1 g (n=346) or cefotetan 2 g (n=339) in a 30-minute intravenous infusion started within 1 hour prior to surgical incision. All patients received one of two standard bowel preparations (sodium phosphate or polyethylene glycol) prior to surgery. Patients were evaluated during hospitalization, at discharge, and four weeks after surgery for signs or symptoms of infection at the surgical site and to determine that no further anti-microbial therapy or surgery was necessary. The modified intent-to-treat (MITT) population consisted of 451 ertapenem patients and 450 cefotetan patients and included all patients who were randomized, treated, and underwent elective colorectal surgery with adequate bowel preparation. The clinically evaluable population (346 ertapenem patients and 339 cefotetan patients) was a subset of the MITT population and consisted of patients who received a complete dose of study therapy no more than two hours prior to surgical incision and no more than six hours before surgical closure, and who had sufficient information and no confounding factors that interfered with determining outcome at the 4-week follow-up assessment.

The adverse experiences associated with INVANZ in this study were generally comparable to those found in other clinical trials for INVANZ. During clinical trials, the most common side effects in adults related to treatment with INVANZ were diarrhea (5.5 percent), infused vein complication (3.7 percent), nausea (3.1 percent), headache (2.2 percent), vaginitis in females (2.1 percent), phlebitis/thrombophlebitis (1.3 percent), and vomiting (1.1 percent). Pseudomembranous colitis has been reported with nearly all antibacterial agents, including INVANZ, and may range in severity from mild to life threatening. For additional information, please refer to the prescribing information.

About INVANZ

INVANZ, a carbapenem related to the class of antibiotics known as beta-lactams, is generally given to adults as a 1-gram dose, once-a-day, by intravenous infusion or intramuscular injection. Dosage adjustment of INVANZ is required in patients with reduced renal function (creatinine clearance ≤ 30 mL/min/1.73m2). In addition to the new indication, INVANZ is also indicated for the treatment of adults and pediatric patients over three months of age for the following moderate to severe infections caused by susceptible isolates of the designated pathogens:

> Complicated intra-abdominal infections: Due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis.
> Complicated skin and skin structure infections including diabetic foot infections without osteomyelitis: Due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotella bivia. Invanz has not been studied in diabetic foot infections with concomitant osteomyelitis.
> Community-acquired pneumonia: Due to Streptococcus pneumoniae (penicillin susceptible isolates only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates only), or Moraxella catarrhalis.
> Complicated urinary tract infections, including pyelonephritis (kidney infections): Due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae.
> And acute pelvic infections, including postpartum endomyometritis, septic abortion and post-surgical gynecologic infections: Due to Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella bivia.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to ertapenem. Therapy with INVANZ may be initiated empirically before results of these tests are known; once results become available, antimicrobial therapy should be adjusted accordingly.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of INVANZ and other antibacterial drugs, INVANZ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. 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.

Seizures and other central nervous system (CNS) adverse experiences have been reported during treatment with INVANZ. During clinical investigations in adult patients treated with INVANZ (1 g once a day), seizures, irrespective of drug relationship, occurred in 0.5 percent of patients during study therapy plus 14-day follow-up period. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function. Close adherence to the recommended dosage regimen is urged, especially in patients with known factors that predispose to convulsive activity.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also published unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

Full prescribing information for INVANZ is attached.

INVANZ is a registered trademark of Merck & Co., Inc.