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

December 20, 2006

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.

INVANZ(R) 9709701 (ERTAPENEM FOR INJECTION)

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 bacteria.

For Intravenous or Intramuscular Use

DESCRIPTION

INVANZ** (Ertapenem for Injection) is a sterile, synthetic, parenteral, 1-(beta) methyl-carbapenem that is structurally related to beta-lactam antibiotics. Chemically, INVANZ is described as (4R-(3(3S*,5S*),4(alpha),5(beta),6(beta)(R*)))-3-((5-(((3-carboxypheny l)amino)carbonyl)-3-pyrrolidinyl)thio)-6-(1-hydroxyethyl)-4-methyl-7-o xo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid monosodium salt. Its molecular weight is 497.50. The empirical formula is C22H24N3O7SNa, and its structural formula is:

(GRAPHIC OMITTED)

Ertapenem sodium is a white to off-white hygroscopic, weakly crystalline powder. It is soluble in water and 0.9% sodium chloride solution, practically insoluble in ethanol, and insoluble in isopropyl acetate and tetrahydrofuran.

INVANZ is supplied as sterile lyophilized powder for intravenous infusion after reconstitution with appropriate diluent (see DOSAGE AND ADMINISTRATION, PREPARATION OF SOLUTION) and transfer to 50 mL 0.9% Sodium Chloride Injection or for intramuscular injection following reconstitution with 1% lidocaine hydrochloride. Each vial contains 1.046 grams ertapenem sodium, equivalent to 1 gram ertapenem. The sodium content is approximately 137 mg (approximately 6.0 mEq).

Each vial of INVANZ contains the following inactive ingredients: 175 mg sodium bicarbonate and sodium hydroxide to adjust pH to 7.5.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Average plasma concentrations (mcg/mL) of ertapenem following a single 30-minute infusion of a 1 g intravenous (IV) dose and administration of a single 1 g intramuscular (IM) dose in healthy young adults are presented in Table 1.

Table 1 Plasma Concentrations of Ertapenem in Adults After Single Dose Administration ———————————————————————- Average Plasma Concentrations (mcg/mL) Dose/Route 0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 18 hr 24 hr ———————————————————————- 1 g IV* 155 115 83 48 31 20 9 3 1 1 g IM 33 53 67 57 40 27 13 4 2 ———————————————————————- *Infused at a constant rate over 30 minutes ———————————————————————-

The area under the plasma concentration-time curve (AUC) of ertapenem in adults increased less-than dose-proportional based on total ertapenem concentrations over the 0.5 to 2 g dose range, whereas the AUC increased greater-than dose proportional based on unbound ertapenem concentrations. Ertapenem exhibits non-linear pharmacokinetics due to concentration-dependent plasma protein binding at the proposed therapeutic dose. (See CLINICAL PHARMACOLOGY, Distribution.) There is no accumulation of ertapenem following multiple IV or IM 1 g daily doses in healthy adults. Average plasma concentrations (mcg/mL) of ertapenem in pediatric patients are presented in Table 2.

Table 2 Plasma Concentrations of Ertapenem in Pediatric Patients After Single IV* Dose Administration ———————————————————————- Age Group Dose Average Plasma Concentrations (mcg/mL) ———————————————————————- 0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr ———————————————————————- 3 to 23 months 15 mg/kg+ 103.8 57.3 43.6 23.7 13.5 8.2 2.5 – 20 mg/kg+ 126.8 87.6 58.7 28.4 – 12.0 3.4 0.4 40 mg/kg++ 199.1 144.1 95.7 58.0 – 20.2 7.7 0.6 ———————————————————————- 2 to 12 years 15 mg/kg+ 113.2 63.9 42.1 21.9 12.8 7.6 3.0 – 20 mg/kg+ 147.6 97.6 63.2 34.5 – 12.3 4.9 0.5 40 mg/kg++ 241.7 152.7 96.3 55.6 – 18.8 7.2 0.6 ———————————————————————- 13 to 17 years 20 mg/kg+ 170.4 98.3 67.8 40.4 – 16.0 7.0 1.1 1 g ss. 155.9 110.9 74.8 – 24.0 – 6.2 – 40 mg/kg++ 255.0 188.7 127.9 76.2 – 31.0 15.3 2.1 ———————————————————————- * Infused at a constant rate over 30 minutes + up to a maximum dose of 1 g/day ++ up to a maximum dose of 2 g/day ss. Based on three patients receiving 1 g ertapenem who volunteered for pharmacokinetic assessment in one of the two safety and efficacy studies ———————————————————————-

Absorption

Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (in saline without epinephrine), is almost completely absorbed following intramuscular (IM) administration at the recommended dose of 1 g. The mean bioavailability is approximately 90%. Following 1 g daily IM administration, mean peak plasma concentrations (Cmax) are achieved in approximately 2.3 hours (Tmax).

Distribution

Ertapenem is highly bound to human plasma proteins, primarily albumin. In healthy young adults, the protein binding of ertapenem decreases as plasma concentrations increase, from approximately 95% bound at an approximate plasma concentration of less than 100 micrograms (mcg)/mL to approximately 85% bound at an approximate plasma concentration of 300 mcg/mL.

The apparent volume of distribution at steady state (Vss) of ertapenem in adults is approximately 0.12 liter/kg, approximately 0.2 liter/kg in pediatric patients 3 months to 12 years of age and approximately 0.16 liter/kg in pediatric patients 13 to 17 years of age.

The concentrations of ertapenem achieved in suction-induced skin blister fluid at each sampling point on the third day of 1 g once daily IV doses are presented in Table 3. The ratio of AUC0-24 in skin blister fluid/AUC0-24 in plasma is 0.61.

Table 3 Concentrations (mcg/mL) of Ertapenem in Adult Skin Blister Fluid at each Sampling Point on the Third Day of 1-g Once Daily IV Doses ——————————————— 0.5 hr 1 hr 2 hr 4 hr 8 hr 12 hr 24 hr ——————————————— 7 12 17 24 24 21 8

The concentration of ertapenem in breast milk from 5 lactating women with pelvic infections (5 to 14 days postpartum) was measured at random time points daily for 5 consecutive days following the last 1 g dose of intravenous therapy (3-10 days of therapy). The concentration of ertapenem in breast milk within 24 hours of the last dose of therapy in all 5 women ranged from less than 0.13 (lower limit of quantitation) to 0.38 mcg/mL; peak concentrations were not assessed. By day 5 after discontinuation of therapy, the level of ertapenem was undetectable in the breast milk of 4 women and below the lower limit of quantitation (less than 0.13 mcg/mL) in 1 woman.

Metabolism

In healthy young adults, after infusion of 1 g IV radiolabeled ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the inactive ring-opened derivative formed by hydrolysis of the beta-lactam ring. In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. (See DRUG INTERACTIONS.) In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport. (See PRECAUTIONS, Drug Interactions.)

Elimination

Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults is approximately 4 hours and the plasma clearance is approximately 1.8 L/hour. The mean plasma half-life in pediatric patients 13 to 17 years of age is approximately 4 hours and approximately 2.5 hours in pediatric patients 3 months to 12 years of age. Following the administration of 1 g IV radiolabeled ertapenem to healthy young adults, approximately 80% is recovered in urine and 10% in feces. Of the 80% recovered in urine, approximately 38% is excreted as unchanged drug and approximately 37% as the ring-opened metabolite. In healthy young adults given a 1 g IV dose, the mean percentage of the administered dose excreted in urine was 17.4% during 0-2 hours postdose, 5.4% during 4-6 hours postdose, and 2.4% during 12-24 hours postdose.

Special Populations

Renal Insufficiency

Total and unbound fractions of ertapenem pharmacokinetics were investigated in 26 adult subjects (31 to 80 years of age) with varying degrees of renal impairment. Following a single 1 g IV dose of ertapenem, the unbound AUC increased 1.5-fold and 2.3-fold in subjects with mild renal insufficiency (CLCR 60-90 mL/min/1.73 m2) and moderate renal insufficiency (CLCR 31-59 mL/min/1.73 m2), respectively, compared with healthy young subjects (25 to 45 years of age). No dosage adjustment is necessary in patients with CLCR (greater than=)31 mL/min/1.73 m2. The unbound AUC increased 4.4-fold and 7.6-fold in subjects with advanced renal insufficiency (CLCR 5-30 mL/min/1.73 m2) and end-stage renal insufficiency (CLCR less than 10 mL/min/1.73 m2), respectively, compared with healthy young subjects. The effects of renal insufficiency on AUC of total drug were of smaller magnitude. The recommended dose of ertapenem in adult patients with CLCR (less than=)30 mL/min/1.73 m2 is 0.5 grams every 24 hours. Following a single 1 g IV dose given immediately prior to a 4 hour hemodialysis session in 5 adult patients with end-stage renal insufficiency, approximately 30% of the dose was recovered in the dialysate. A supplementary dose of 150 mg is recommended if ertapenem is administered within 6 hours prior to hemodialysis. (See DOSAGE AND ADMINISTRATION.) There are no data in pediatric patients with renal insufficiency.

Hepatic Insufficiency

The pharmacokinetics of ertapenem in patients with hepatic insufficiency have not been established. However, ertapenem does not appear to undergo hepatic metabolism based on in vitro studies and approximately 10% of an administered dose is recovered in the feces. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

Gender

The effect of gender on the pharmacokinetics of ertapenem was evaluated in healthy male (n=8) and healthy female (n=8) subjects. The differences observed could be attributed to body size when body weight was taken into consideration. No dose adjustment is recommended based on gender.

Geriatric Patients

The impact of age on the pharmacokinetics of ertapenem was evaluated in healthy male (n=7) and healthy female (n=7) subjects (greater than=)65 years of age. The total and unbound AUC increased 37% and 67%, respectively, in elderly adults relative to young adults. These changes were attributed to age-related changes in creatinine clearance. No dosage adjustment is necessary for elderly patients with normal (for their age) renal function.

Pediatric Patients

Plasma concentrations of ertapenem are comparable in pediatric patients 13 to 17 years of age and adults following a 1 g once daily IV dose. Following the 20 mg/kg dose (up to a maximum dose of 1 g), the pharmacokinetic parameter values in patients 13 to 17 years of age (N=6) were generally comparable to those in healthy young adults. Plasma concentrations at the midpoint of the dosing interval following a single 15 mg/kg IV dose of ertapenem in patients 3 months to 12 years of age are comparable to plasma concentrations at the midpoint of the dosing interval following a 1 g once daily IV dose in adults (see Pharmacokinetics). The plasma clearance (mL/min/kg) of ertapenem in patients 3 months to 12 years of age is approximately 2-fold higher as compared to that in adults. At the 15 mg/kg dose, the AUC value (doubled to model a twice daily dosing regimen, i.e., 30 mg/kg/day exposure) in patients 3 months to 12 years of age was comparable to the AUC value in young healthy adults receiving a 1 g IV dose of ertapenem.

Microbiology

Ertapenem has in vitro activity against gram-positive and gram-negative aerobic and anaerobic bacteria. The bactericidal activity of ertapenem results from the inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin binding proteins (PBPs). In Escherichia coli, it has strong affinity toward PBPs 1a, 1b, 2, 3, 4 and 5 with preference for PBPs 2 and 3. Ertapenem is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and cephalosporinases and extended spectrum beta-lactamases. Ertapenem is hydrolyzed by metallo-beta-lactamases. Ertapenem has been shown to be active against most isolates of the following microorganisms in vitro and in clinical infections. (See INDICATIONS AND USAGE):

Aerobic and facultative gram-positive microorganisms:

Staphylococcus aureus (methicillin susceptible isolates only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin susceptible isolates only)

Streptococcus pyogenes

Note: Methicillin-resistant staphylococci and Enterococcus spp. are resistant to ertapenem.

Aerobic and facultative gram-negative microorganisms:

Escherichia coli

Haemophilus influenzae (Beta-lactamase negative isolates only)

Klebsiella pneumoniae

Moraxella catarrhalis

Proteus mirabilis

Anaerobic microorganisms:

Bacteroides fragilis

Bacteroides distasonis

Bacteroides ovatus

Bacteroides thetaiotaomicron

Bacteroides uniformis

Clostridium clostridioforme

Eubacterium lentum

Peptostreptococcus species

Porphyromonas asaccharolytica

Prevotella bivia

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ertapenem; however, the safety and effectiveness of ertapenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical studies:

Aerobic and facultative gram-positive microorganisms:

Staphylococcus epidermidis (methicillin susceptible isolates only)

Streptococcus pneumoniae (penicillin-intermediate isolates only)

Aerobic and facultative gram-negative microorganisms:

Citrobacter freundii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Haemophilus influenzae (Beta-lactamase positive isolates)

Haemophilus parainfluenzae

Klebsiella oxytoca (excluding ESBL producing isolates)

Morganella morganii

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Serratia marcescens

Anaerobic microorganisms:

Bacteroides vulgatus

Clostridium perfringens

Fusobacterium spp.

Susceptibility Test Methods:

When available, the results of in vitro susceptibility tests should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a broth dilution method(1,2) or equivalent with standardized inoculum concentrations and standardized concentrations of ertapenem powder. The MIC values should be interpreted according to criteria provided in Table 4.

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure(2,3) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-(mu)g ertapenem to test the susceptibility of microorganisms to ertapenem. The disk diffusion interpretive criteria should be interpreted according to criteria provided in Table 4.

Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to ertapenem as MICs can be determined by standardized test methods(4). The MIC values obtained should be interpreted according to criteria provided in Table 4.

Table 4 Susceptibility Interpretive Criteria for Ertapenem ———————————————————————- Pathogen Minimum Inhibitory Disk Diffusion(a) Concentrations(a) Zone Diameter (mm) MIC ( (mu)g/mL) ———————————————————————- S I R S I R ———————————————————————- Enterobacteriaceae (less (greater (greater (less and than=)2.0 than=)8.0 than=)19 than=)15 Staphylococcus spp. 4.0 16-18 ———————————————————————- Haemophilus spp. (less (greater than=)0.5 – – than=)19 – – ———————————————————————- Streptococcus (less (greater pneumoniae (b,c) than=)1.0 – – than=)19 – – ———————————————————————- Streptococcus spp. (less (greater other than than=)1.0 than=)19 Streptococcus pneumoniae(d,e) – – – – ———————————————————————- Anaerobes (less (greater than=)4.08.0 than=)16.0 – – – ———————————————————————- (a) The current absence of data in resistant isolates precludes defining any results other than “Susceptible”. Isolates yielding MIC results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing. (b) Streptococcus pneumoniae that are susceptible to penicillin (penicillin MIC (less than=)0.06 (mu)g/mL) can be considered susceptible to ertapenem. Testing of ertapenem against penicillin- intermediate or penicillin-resistant isolates is not recommended since reliable interpretive criteria for ertapenem are not available. (c) Streptococcus pneumoniae that are susceptible to penicillin (1- (mu)g oxacillin disk zone diameter (greater than=)20 mm), can be considered susceptible to ertapenem. Isolates with 1-(mu)g oxacillin zone diameter (less than=)19 mm should be tested against ertapenem using an MIC method. (d) Streptococcus spp. other than Streptococcus pneumoniae that are susceptible to penicillin (MIC (less than=)0.12 (mu)g/mL) can be considered susceptible to ertapenem. Testing of ertapenem against penicillin-intermediate or penicillin-resistant isolates is not recommended since reliable interpretive criteria for ertapenem are not available. (e) Streptococcus spp. other than Streptococcus pneumoniae that are susceptible to penicillin (10-units penicillin disk zone diameter (greater than=)24 mm), can be considered susceptible to ertapenem. Isolates with 10-units penicillin disk zone diameter less than 24 mm should be tested against ertapenem using an MIC method. Penicillin disk diffusion interpretive criteria are not available for viridans group streptococci and they should not be tested against ertapenem. ———————————————————————-

Note: Staphylococcus spp. can be considered susceptible to ertapenem if the penicillin MIC is (less than=)0.12 (mu)g/mL. If the penicillin MIC is greater than 0.12 (mu)g/mL, then test oxacillin. Staphylococcus aureus can be considered susceptible to ertapenem if the oxacillin MIC is (less than=)2.0 (mu)g/mL and resistant to ertapenem if the oxacillin MIC is (greater than=)4.0 (mu)g/mL. Coagulase negative staphylococci can be considered susceptible to ertapenem if the oxacillin MIC is (less than=)0.25 (mu)g/mL and resistant to ertapenem if the oxacillin MIC (greater than=)0.5 (mu)g/mL.

Staphylococcus spp. can be considered susceptible to ertapenem if the penicillin (10 U disk) zone is (greater than=)29 mm. If the penicillin zone is (less than=)28 mm, then test oxacillin by disk diffusion (1 (mu)g disk). Staphylococcus aureus can be considered susceptible to ertapenem if the oxacillin (1 (mu)g disk) zone is (greater than=)13 mm and resistant to ertapenem if the oxacillin zone is (less than=)10 mm. Coagulase negative staphylococci can be considered susceptible to ertapenem if the oxacillin zone is (greater than=)18 mm and resistant to ertapenem if the oxacillin (1 (mu)g disk) zone is (less than=)17 mm.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures(1,2,3,4). Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. Standard ertapenem powder should provide the following range of values noted in Table 5.

Table 5 Acceptable Quality Control Ranges for Ertapenem ———————————————————————- Microorganism Minimum Disk Inhibitory Diffusion Concentrations Zone MIC Range Diameter ((mu)g/mL) (mm) ———————————————————————- Escherichia coli ATCC 25922 0.004-0.016 29-36 ———————————————————————- Haemophilus influenzae ATCC 49766 0.016-0.06 27-33 ———————————————————————- Staphylococcus aureus ATCC 29213 0.06-0.25 – ———————————————————————- Staphylococcus aureus ATCC 25923 – 24-31 ———————————————————————- Streptococcus pneumoniae ATCC 49619 0.03-0.25 28-35 ———————————————————————- Bacteroides fragilis ATCC 25285 0.06-0.5(f) 0.06-0.25(g) – ———————————————————————- Bacteroides thetaiotaomicron ATCC 29741 0.5-2.0(f) 0.25-1.0(g) – ———————————————————————- Eubacterium lentum ATCC 43055 0.5-4.0(f) 0.5-2.0(g) – ———————————————————————- (f) Quality control ranges for broth microdilution testing (g) Quality control ranges for agar microdilution testing ———————————————————————-

INDICATIONS AND USAGE

Treatment

INVANZ is indicated for the treatment of patients with the following moderate to severe infections caused by susceptible isolates of the designated microorganisms. (See DOSAGE AND ADMINISTRATION): 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 (see CLINICAL STUDIES). 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 due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae. 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.

Prevention

INVANZ is indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery. 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 (ertapenem) 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.

CONTRAINDICATIONS

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 a known hypersensitivity to local anesthetics of the amide type. (Refer to the prescribing information for lidocaine HCl.)

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY REACTIONS WHEN TREATED WITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY WITH INVANZ, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO INVANZ OCCURS, DISCONTINUE THE DRUG IMMEDIATELY. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE, OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION. OTHER THERAPY MAY ALSO BE ADMINISTERED AS INDICATED. Seizures and other CNS adverse experiences have been reported during treatment with INVANZ. (See PRECAUTIONS and ADVERSE REACTIONS.) Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ertapenem, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. Lidocaine HCl is the diluent for intramuscular administration of INVANZ. Refer to the prescribing information for lidocaine HCl.

PRECAUTIONS

General

During clinical investigations in adult patients treated with INVANZ (1 g once a day), seizures, irrespective of drug relationship, occurred in 0.5% of patients during study therapy plus 14-day follow-up period. (See ADVERSE REACTIONS.) 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. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of INVANZ re-examined to determine whether it should be decreased or the antibiotic discontinued. Dosage adjustment of INVANZ is recommended in patients with reduced renal function. (See DOSAGE AND ADMINISTRATION.) As with other antibiotics, prolonged use of INVANZ may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Prescribing INVANZ in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Caution should be taken when administering INVANZ intramuscularly to avoid inadvertent injection into a blood vessel. (See DOSAGE AND ADMINISTRATION.) Lidocaine HCl is the diluent for intramuscular administration of INVANZ. Refer to the prescribing information for lidocaine HCl for additional precautions.

Information for patients

Patients should be counseled that antibacterial drugs including INVANZ should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When INVANZ is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by INVANZ or other antibacterial drugs in the future.

Laboratory Tests

While INVANZ possesses toxicity similar to the beta-lactam group of antibiotics, periodic assessment of organ system function, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Drug Interactions

When ertapenem is co-administered with probenecid (500 mg p.o. every 6 hours), probenecid competes for active tubular secretion and reduces the renal clearance of ertapenem. Based on total ertapenem concentrations, probenecid increased the AUC by 25% and reduced the plasma and renal clearances by 20% and 35%, respectively. The half-life increased from 4.0 to 4.8 hours. Because of the small effect on half-life, the coadministration with probenecid to extend the half-life of ertapenem is not recommended. In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport. In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following six cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Drug interactions caused by inhibition of P-glycoprotein-mediated drug clearance or CYP-mediated drug clearance with the listed isoforms are unlikely. (See CLINICAL PHARMACOLOGY, Distribution and Metabolism.) Other than with probenecid, no specific clinical drug interaction studies have been conducted.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of ertapenem. Ertapenem was neither mutagenic nor genotoxic in the following in vitro assays: alkaline elution/rat hepatocyte assay, chromosomal aberration assay in Chinese hamster ovary cells, and TK6 human lymphoblastoid cell mutagenesis assay; and in the in vivo mouse micronucleus assay. In mice and rats, IV doses of up to 700 mg/kg/day (for mice, approximately 3 times the recommended human dose of 1 g based on body surface area and for rats, approximately 1.2 times the human exposure at the recommended dose of 1 g based on plasma AUCs) resulted in no effects on mating performance, fecundity, fertility, or embryonic survival.

Pregnancy: Teratogenic Effects

Pregnancy Category B: In mice and rats given IV doses of up to 700 mg/kg/day (for mice, approximately 3 times the recommended human dose of 1 g based on body surface area and for rats, approximately 1.2 times the human exposure at the recommended dose of 1 g based on plasma AUCs), there was no evidence of developmental toxicity as assessed by external, visceral, and skeletal examination of the fetuses. However, in mice given 700 mg/kg/day, slight decreases in average fetal weights and an associated decrease in the average number of ossified sacrocaudal vertebrae were observed. Ertapenem crosses the placental barrier in rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Ertapenem is excreted in human breast milk. (See CLINICAL PHARMACOLOGY, Distribution.) Caution should be exercised when INVANZ is administered to a nursing woman. INVANZ should be administered to nursing mothers only when the expected benefit outweighs the risk.

Labor and delivery

INVANZ has not been studied for use during labor and delivery.

Pediatric Use

Safety and effectiveness of INVANZ in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from comparator-controlled studies in pediatric patients 3 months to 17 years of age with the following infections (see INDICATIONS AND USAGE and CLINICAL STUDIES):

— Complicated Intra-abdominal Infections

— Complicated Skin and Skin Structure Infections

— Community Acquired Pneumonia

— Complicated Urinary Tract Infections

— Acute Pelvic Infections

INVANZ is not recommended in infants under 3 months of age as no data are available. INVANZ is not recommended in the treatment of meningitis in the pediatric population due to lack of sufficient CSF penetration.

Geriatric Use

Of the 1,835 patients in Phase IIb/III studies treated with INVANZ, approximately 26 percent were 65 and over, while approximately 12 percent were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See DOSAGE AND ADMINISTRATION.)

Hepatic Insufficiency

The pharmacokinetics of ertapenem in patients with hepatic insufficiency have not been established. Of the total number of patients in clinical studies, 37 patients receiving ertapenem 1 g daily and 36 patients receiving comparator drugs were considered to have Child-Pugh Class A, B, or C liver impairment. The incidence of adverse experiences in patients with hepatic impairment was similar between the ertapenem group and the comparator groups.

ANIMAL PHARMACOLOGY

In repeat-dose studies in rats, treatment-related neutropenia occurred at every dose-level tested, including the lowest dose of 2 mg/kg (approximately 2% of the human dose on a body surface area basis). Studies in rabbits and Rhesus monkeys were inconclusive with regard to the effect on neutrophil counts.

ADVERSE REACTIONS

Adults

Clinical studies enrolled 1954 patients treated with ertapenem; in some of the clinical studies, parenteral therapy was followed by a switch to an appropriate oral antimicrobial. (See CLINICAL STUDIES.) Most adverse experiences reported in these clinical studies were described as mild to moderate in severity. Ertapenem was discontinued due to adverse experiences in 4.7% of patients. Table 6 shows the incidence of adverse experiences reported in (greater than=)1.0% of patients in these studies. The most common drug-related adverse experiences in patients treated with INVANZ, including those who were switched to therapy with an oral antimicrobial, were diarrhea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache (2.2%), vaginitis in females (2.1%), phlebitis/thrombophlebitis (1.3%), and vomiting (1.1%).

Table 6 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Adult Patients Treated With INVANZ in Clinical Studies ———————————————————————- Piperacillin/ INVANZ* Tazobactam* INVANZ+ Ceftriaxone+ 1 g 3.375 g q6h 1 g 1 or 2 g Adverse Events daily (N=774) daily daily (N=802) (N=1152) (N=942) ———————————————————————- Local: Extravasation 1.9 1.7 0.7 1.1 Infused vein complication 7.1 7.9 5.4 6.7 Phlebitis/thrombophlebitis 1.9 2.7 1.6 2.0 ———————————————————————- Systemic: Asthenia/fatigue 1.2 0.9 1.2 1.1 Death 2.5 1.6 1.3 1.6 Edema/swelling 3.4 2.5 2.9 3.3 Fever 5.0 6.6 2.3 3.4 Abdominal pain 3.6 4.8 4.3 3.9 Chest pain 1.5 1.4 1.0 2.5 Hypertension 1.6 1.4 0.7 1.0 Hypotension 2.0 1.4 1.0 1.2 Tachycardia 1.6 1.3 1.3 0.7 Acid regurgitation 1.6 0.9 1.1 0.6 Oral candidiasis 0.1 1.3 1.4 1.9 Constipation 4.0 5.4 3.3 3.1 Diarrhea 10.3 12.1 9.2 9.8 Dyspepsia 1.1 0.6 1.0 1.6 Nausea 8.5 8.7 6.4 7.4 Vomiting 3.7 5.3 4.0 4.0 Leg pain 1.1 0.5 0.4 0.3 Anxiety 1.4 1.3 0.8 1.2 Altered mental status++ 5.1 3.4 3.3 2.5 Dizziness 2.1 3.0 1.5 2.1 Headache 5.6 5.4 6.8 6.9 Insomnia 3.2 5.2 3.0 4.1 Cough 1.6 1.7 1.3 0.5 Dyspnea 2.6 1.8 1.0 2.4 Pharyngitis 0.7 1.4 1.1 0.6 Rales/rhonchi 1.1 1.0 0.5 1.0 Respiratory distress 1.0 0.4 0.2 0.2 Erythema 1.6 1.7 1.2 1.2 Pruritus 2.0 2.6 1.0 1.9 Rash 2.5 3.1 2.3 1.5 Vaginitis 1.4 1.0 3.3 3.7 ———————————————————————- * Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections studies + Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa studies ++ Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor ———————————————————————-

In patients treated for complicated intra-abdominal infections, death occurred in 4.7% (15/316) of patients receiving ertapenem and 2.6% (8/307) of patients receiving comparator drug. These deaths occurred in patients with significant co-morbidity and/or severe baseline infections. Deaths were considered unrelated to study drugs by investigators. In clinical studies, seizure was reported during study therapy plus 14-day follow-up period in 0.5% of patients treated with ertapenem, 0.3% of patients treated with piperacillin/tazobactam and 0% of patients treated with ceftriaxone. (See PRECAUTIONS.) Additional adverse experiences that were reported with INVANZ with an incidence greater than 0.1% within each body system are listed below: Body as a whole: abdominal distention, pain, chills, septicemia, septic shock, dehydration, gout, malaise, necrosis, candidiasis, weight loss, facial edema, injection site induration, injection site pain, flank pain, and syncope; Cardiovascular System: heart failure, hematoma, cardiac arrest, bradycardia, arrhythmia, atrial fibrillation, heart murmur, ventricular tachycardia, asystole, and subdural hemorrhage; Digestive System: gastrointestinal hemorrhage, anorexia, flatulence, C. difficile associated diarrhea, stomatitis, dysphagia, hemorrhoids, ileus, cholelithiasis, duodenitis, esophagitis, gastritis, jaundice, mouth ulcer, pancreatitis, and pyloric stenosis; Nervous System & Psychiatric: nervousness, seizure (see WARNINGS and PRECAUTIONS), tremor, depression, hypesthesia, spasm, paresthesia, aggressive behavior, and vertigo; Respiratory System: pleural effusion, hypoxemia, bronchoconstriction, pharyngeal discomfort, epistaxis, pleuritic pain, asthma, hemoptysis, hiccups, and voice disturbance; Skin & Skin Appendage: sweating, dermatitis, desquamation, flushing, and urticaria; Special Senses: taste perversion; Urogenital System: renal insufficiency, oliguria/anuria, vaginal pruritus, hematuria, urinary retention, bladder dysfunction, vaginal candidiasis, and vulvovaginitis.

In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were treated with ertapenem, the adverse experience profile was generally similar to that seen in previous clinical trials.

In a clinical study in adults for the prophylaxis of surgical site infection following elective colorectal surgery in which 476 patients received a 1 g dose of ertapenem 1 hour prior to surgery and were then followed for safety 14 days post surgery, the overall adverse experience profile was generally comparable to that observed for ertapenem in previous clinical trials. Table 7 shows the incidence of adverse experiences other than those previously described above for ertapenem, regardless of causality, reported in (greater than=)1.0% of patients in this study.

Table 7 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Adult Patients Treated With INVANZ for Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery ———————————————————————- INVANZ Cefotetan 1 g 2 g Adverse Events (N= 476) (N= 476) ———————————————————————- Anemia 5.7 6.9 Small intestinal obstruction 2.1 1.9 Cellulitis 1.5 1.5 C. difficile infection or colitis 1.7 0.6 Pneumonia 2.1 4.0 Postoperative infection 2.3 4.0 Urinary tract infection 3.8 5.5 Wound infection 6.5 12.4 Anastomotic leak 1.5 1.3 Seroma 1.3 1.9 Wound complication 2.9 2.3 Wound dehiscence 1.3 1.5 Wound secretion 1.9 2.1 Dysuria 1.1 1.3 Atelectasis 3.4 1.9 ———————————————————————-

Additional adverse experiences that were reported in this prophylaxis study with INVANZ, regardless of causality, with an incidence less than 1.0% and greater than 0.5% within each body system are listed below: Gastrointestinal Disorders: dry mouth, hematochezia; General Disorders and Administration Site Condition: crepitations; Infections and Infestations: abdominal abscess, fungal rash, pelvic abscess; Injury, Poisoning and Procedural Complications: incision site complication, incision site hemorrhage, intestinal stoma complication; Musculoskeletal and Connective Tissue Disorders: muscle spasms; Nervous System Disorders: cerebrovascular accident; Renal and Urinary Disorders: pollakiuria; Respiratory, Thoracic and Mediastinal Disorders: crackles lung, lung infiltration, pulmonary congestion, pulmonary embolism, wheezing.

Pediatric Patients

Clinical studies enrolled 384 patients treated with ertapenem; in some of the clinical studies, parenteral therapy was followed by a switch to an appropriate oral antimicrobial. (See CLINICAL STUDIES.) The overall adverse experience profile in pediatric patients is comparable to that in adult patients. Table 8 shows the incidence of adverse experiences reported in (greater than=)1.0% of pediatric patients in clinical studies. The most common drug-related adverse experiences in pediatric patients treated with INVANZ, including those who were switched to therapy with an oral antimicrobial, were diarrhea (6.5%), infusion site pain (5.5%), infusion site erythema (2.6%), vomiting (2.1%).

Table 8 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Pediatric Patients Treated With INVANZ in Clinical Studies ———————————————————————- Ticarcillin/ INVANZ*+ Ceftriaxone* Clavulanate+ Adverse Events (N=384) (N=100) (N=24) ———————————————————————- Local: Infusion Site Erythema 3.9 3.0 8.3 Infusion Site Induration 1.0 1.0 0.0 Infusion Site Pain 7.0 4.0 20.8 Infusion Site Phlebitis 1.8 3.0 0.0 Infusion Site Swelling 1.8 1.0 4.2 Infusion Site Warmth 1.3 1.0 4.2 ———————————————————————- Systemic: Abdominal Pain 4.7 3.0 4.2 Upper Abdominal Pain 1.0 2.0 0.0 Constipation 2.3 0.0 0.0 Diarrhea 11.7 17.0 4.2 Loose Stools 2.1 0.0 0.0 Nausea 1.6 0.0 0.0 Vomiting 10.2 11.0 8.3 Pyrexia 4.9 6.0 8.3 Abdominal Abscess 1.0 0.0 4.2 Herpes Simplex 1.0 1.0 4.2 Nasopharyngitis 1.6 6.0 0.0 Upper Respiratory Tract Infection 2.3 3.0 0.0 Viral Pharyngitis 1.0 0.0 0.0 Hypothermia 1.6 1.0 0.0 Dizziness 1.6 0.0 0.0 Headache 4.4 4.0 0.0 Cough 4.4 3.0 0.0 Wheezing 1.0 0.0 0.0 Dermatitis 1.0 1.0 0.0 Pruritus 1.6 0.0 0.0 Diaper Dermatitis 4.7 4.0 0.0 Rash 2.9 2.0 8.3 ———————————————————————- * Includes Phase IIb Complicated skin and skin structure infections, Community acquired pneumonia and Complicated urinary tract infections studies in which patients 3 months to 12 years of age received INVANZ 15 mg/kg IV twice daily up to a maximum of 1 g or ceftriaxone 50 mg/kg/day IV in two divided doses up to a maximum of 2 g, and patients 13 to 17 years of age received INVANZ 1 g IV daily or ceftriaxone 50 mg/kg/day IV in a single daily dose. + Includes Phase IIb Acute pelvic infections and Complicated intra- abdominal infections studies in which patients 3 months to 12 years of age received INVANZ 15 mg/kg IV twice daily up to a maximum of 1 g and patients 13 to 17 years of age received INVANZ 1 g IV daily or ticarcillin/clavulanate 50 mg/kg for patients less than 60 kg or ticarcillin/clavulanate 3.0 g for patients greater than 60 kg, 4 or 6 times a day. ———————————————————————-

Additional adverse experiences that were reported with INVANZ with an incidence 1.0% and greater than 0.5% within each body system are listed below:

General Disorders and Administration Site Condition: chest pain, infusion site pruritus; Infections and Infestations: candidiasis, ear infection, oral candidiasis; Metabolism and Nutrition Disorders: decreased appetite; Musculoskeletal and Connective Tissue Disorders: arthralgia; Nervous System Disorders: somnolence; Psychiatric Disorders: insomnia; Reproductive System and Breast Disorders: genital rash; Respiratory, Thoracic and Mediastinal Disorders: pleural effusion, rhinitis, rhinorrhea; Skin and Subcutaneous Tissue Disorders: dermatitis atopic, rash erythematous, skin lesion; Vascular Disorders: phlebitis.

Post-Marketing Experience:

The following post-marketing adverse experiences have been reported: Immune System: anaphylaxis including anaphylactoid reactions Nervous System & Psychiatric: hallucinations Adverse Laboratory Changes

Adults

Laboratory adverse experiences that were reported during therapy in (greater than=)1.0% of adult patients treated with INVANZ in clinical studies are presented in Table 9. Drug-related laboratory adverse experiences that were reported during therapy in 1.0% of adult patients treated with INVANZ, including those who were switched to therapy with an oral antimicrobial, in clinical studies were ALT increased (6.0%), AST increased (5.2%), serum alkaline phosphatase increased (3.4%), platelet count increased (2.8%), and eosinophils increased (1.1%). Ertapenem was discontinued due to laboratory adverse experiences in 0.3% of patients.

Table 9 Incidence* (%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in (greater than=)1.0% of Adult Patients Treated With INVANZ in Clinical Studies —————————————————————




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