INVANZ * (Ertapenem for Injection) is a sterile, synthetic, parenteral, 1-b methyl-carbapenem that is structurally related to beta-lactam antibiotics. Chemically, INVANZ is described as [4R-[3(3S *,5S *),4a,5b,6b(R *)]]-3-[[5-[[(3- carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-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:

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

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 After Single Dose Administration Average Plasma Concentrations (mcg/mL)

*Infused at a constant rate over 30 minutes The area under the plasma concentration-time curve (AUC) of ertapenem 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.

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).

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 <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 is approximately 8.2 liters. 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 2. The ratio of AUC0-24 in skin blister fluid/AUC0-24 in plasma is 0.61. Table 2 Concentrations (mcg/mL) of Ertapenem in Skin Blister Fluid at each Sampling Point on the Third Day of 1-g Once Daily IV Doses

24 hr 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 <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 (<0.13 mcg/mL) in 1 woman.

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.

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.)

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. 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.

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 331 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 <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 patients with CLCR PS30 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 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.)

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.)

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.

The impact of age on the pharmacokinetics of ertapenem was evaluated in healthy male (n=7) and healthy female (n=7) subjects 365 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.

The pharmacokinetics of ertapenem in pediatric patients have not been established.

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 strains of the following microorganisms in vitro and in clinical infections. (See INDICATIONS AND USAGE):

Aerobic gram-positive microorganisms:

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

Aerobic gram-negative microorganisms:

Anaerobic microorganisms: Bacteroides fragilis Bacteroides distasonis Bacteroides ovatus Bacteroides thetaiotaomicron Bacteroides uniformis Clostridium clostridioforme Eubacterium lentum Peptostreptococcus

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 gram-positive microorganisms:

Aerobic gram-negative microorganisms:

Citrobacter freundii Citrobacter koseri Enterobacter aerogenes Enterobacter cloacae

Anaerobic microorganisms: Clostridium perfringens Fusobacterium

Susceptibility Tests:

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.

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 method1,4 or equivalent with standardized inoculum concentrations and standardized concentrations of ertapenem powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae and Staphylococcus spp. : MIC (mg/mL) Interpretation

Note: Staphylococcus spp. can be considered susceptible to ertapenem if the penicillin MIC is PS 0.12 mg/mL. If the penicillin MIC is >0.12 mg/mL, then test oxacillin. Staphylococcus aureus can be considered susceptible to ertapenem if the oxacillin MIC is PS2.0 mg/mL and resistant to ertapenem if the oxacillin MIC is 34.0 mg/mL. Coagulase negative staphylococci can be considered susceptible to ertapenem if the oxacillin MIC is PS0.25 mg/mL and resistant to ertapenem if the oxacillin MIC 30.5 mg/mL. For testing Haemophilus spp.a:

aThis interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Test Medium (HTM)1 inoculated with a direct colony suspension and incubated in ambient air at 35degC for 20-24 hrs.

The current absence of data in resistant strains precludes defining any results other than "Susceptible".

Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing. For testing Streptococcus pneumoniaec,d: MIC (mg/mL) Interpretationb

This interpretive standard is applicable only to broth microdilution susceptibility tests using cation- adjusted Mueller-Hinton broth with 2-5% lysed horse blood inoculated with direct colony suspension and incubated in ambient air at 35degC for 20-24 hrs.

dStreptococcus pneumoniae that are susceptible to penicillin (penicillin MIC PS0.06 mg/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. For testing Streptococcus spp. other than Streptococcus pneumoniaec,e: MIC (mg/mL) Interpretationb

eStreptococcus spp. that are susceptible to penicillin (MIC PS0.12 mg/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. 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. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. 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 MIC values.

fThis quality control range is applicable to only H. influenzae ATCC 49766 tested by the broth microdilution procedure using HTM1 inoculated with a direct colony suspension and incubated in ambient air at 35degC for 20-24 hrs. gThis quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35degC for 20-24 hrs.

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,4 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-mg ertapenem to test the susceptibility of microorganisms to ertapenem. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-mg ertapenem disk should be interpreted according to the following criteria: For testing Enterobacteriaceae and Staphylococcus spp. :

Note: Staphylococcus spp. can be considered susceptible to ertapenem if the penicillin (10 U disk) zone is 329 mm. If the penicillin zone is PS28 mm, then test oxacillin by disk diffusion (1ug disk). Staphylococcus aureus can be considered susceptible to ertapenem if the oxacillin (1ug disk) zone is 313 mm and resistant to ertapenem if the oxacillin zone is PS10 mm. Coagulase negative staphylococci can be considered susceptible to ertapenem if the oxacillin zone is 318 mm and resistant to ertapenem if the oxacillin (1ug disk) zone is PS17 mm. For testing Haemophilus spp.h:

hThis zone diameter standard is applicable only to tests performed by disk diffusion with Haemophilus spp. using HTM2 inoculated with a direct colony suspension and incubated in 5% CO2 at 35degC for 16- 18 hrs. For testing Streptococcus pneumoniaei,j:

iThese zone diameter standards apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood inoculated with a direct colony suspension and incubated in 5% CO2 at 35degC for 20-24 hrs. jStreptococcus pneumoniae that is susceptible to penicillin (1-mg oxacillin disk zone diameter 320 mm), can be considered susceptible to ertapenem. Isolates with 1-mg oxacillin zone diameter PS19 mm should be tested against ertapenem using an MIC method. For testing Streptococcus spp. other than Streptococcus pneumoniaek,l: Zone Diameter (mm) Interpretationb

These zone diameter standards apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood inoculated with a direct colony suspension and in ambient air at 35degC for 20-24 hrs.

lBeta-hemolytic Streptococcus spp. that are susceptible to penicillin (10-units penicillin disk zone diameter 324 mm), can be considered susceptible to ertapenem. Isolates with 10-units penicillin disk zone diameter <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. Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ertapenem. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains that will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. For the diffusion technique, the 10-mg ertapenem disk should provide the following zone diameters in these laboratory quality control strains:

mThis quality control range is applicable to Haemophilus influenzae ATCC 49766 tested by disk diffusion using HTM2 agar inoculated with a direct colony suspension and incubated in 5% CO2 at 35degC for 16-18 hrs. nThis quality control range is applicable to Streptococcus pneumoniae ATCC 49619 tested by disk diffusion using Mueller-Hinton agar supplemented with 5% sheep blood inoculated with a direct colony suspension and incubated in 5% CO2 at 35degC for 20-24 hrs.

Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to ertapenem as MICs can be determined by standardized test methods3. The MIC values obtained should be interpreted according to the following criteria:

Interpretation is identical to that stated above for results using dilution techniques. As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ertapenem powder should provide the following MIC values: Microorganism MICo (mg/mL)

OThese quality control ranges are applicable only to agar dilution using Brucella agar supplemented with hemin, vitamin K1 and 5% defibrinated or laked sheep blood inoculated with a direct colony suspension or a 6- to 24-hour fresh culture in enriched thioglycollate medium and incubated in an anaerobic jar or chamber at 35-37degC for 42-48 hrs.

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

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. 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.

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.

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.

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.

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.

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.

Safety and effectiveness in pediatric patients have not been established. Therefore, use in patients under 18 years of age is not recommended.

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.)

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 (2 mg/kg, 12 mg/m2). Studies in rabbits and Rhesus monkeys were inconclusive with regard to the effect on neutrophil counts.

ADVERSE REACTIONS

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 3 shows the incidence of adverse experiences reported in 31.0% 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 3 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in

1.0% of Patients

Treated With INVANZ in Clinical Studies

Adverse Events	INVANZ * 1 g daily (N=802)	Piperacillin/ Tazobactam * 3.375 g q6h (N=774)	INVANZ + 1 g daily (N=1152)	Ceftriaxone + 1 or 2 g daily (N=942)
Local:			0.7	1.1
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:			1.2	1.1
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 >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.

Adverse Laboratory Changes

Laboratory adverse experiences that were reported during therapy in 31.0% of patients treated with INVANZ in clinical studies are presented in Table 4. Drug-related laboratory adverse experiences that were reported during therapy in 31.0% of 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 4 Incidence * (%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14- Day Follow-Up

Adverse laboratory experiences	INVANZ ++ 1 g daily (n + =766)	Piperacillin/ Tazobactam ++ 3.375 g q6h (n =755)	INVANZ SS 1 g daily (n + =1122)	Ceftriaxone SS 1 or 2 g daily (n + =920)
ALT increased	8.8	7.3	8.3	6.9
AST increased	8.4	8.3	7.1	6.5
Serum albumin	1.7	1.5	0.9	1.6
decreased
Serum alkaline	6.6	7.2	4.3	2.8
phosphatase increased
Serum creatinine	1.1	2.7	0.9	1.2
increased
Serum glucose	1.2	2.3	1.7	2.0
increased
Serum potassium	1.7	2.8	1.8	2.4
decreased
Serum potassium	1.3	0.5	0.5	0.7
increased
Total serum bilirubin	1.7	1.4	0.6	1.1
increased
Eosinophils increased	1.1	1.1	2.1	1.8
Hematocrit decreased	3.0	2.9	3.4	2.4
Hemoglobin	4.9	4.7	4.5	3.5
decreased
Platelet count	1.1	1.2	1.1	1.0
decreased
Platelet count	6.5	6.3	4.3	3.5
increased
Segmented	1.0	0.3	1.5	0.8
neutrophils decreased
Prothrombin time	1.2	2.0	0.3	0.9
increased
WBC decreased	0.8	0.7	1.5	1.4
Urine RBCs increased	2.5	2.9	1.1	1.0
Urine WBCs	2.5	3.2	1.6	1.1
increased			1.6	1.1

in 31.0% of Patients Treated With INVANZ in Clinical Studies

*Number of patients with laboratory adverse experiences/Number of patients with the laboratory test

Number of patients with one or more laboratory tests

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

Additional laboratory adverse experiences that were reported during therapy in >0.1% but <1.0% of patients treated with INVANZ in clinical studies include: increases in BUN, direct and indirect serum bilirubin, serum sodium, monocytes, PTT, urine epithelial cells; decreases in serum bicarbonate.

OVERDOSAGE

No specific information is available on the treatment of overdosage with INVANZ. Intentional overdosing of INVANZ is unlikely. Intravenous administration of INVANZ at a dose of 2 g over 30 min or 3 g over 1-2h in healthy volunteers resulted in an increased incidence of nausea. In clinical studies, inadvertent administration of three 1 g doses of INVANZ in a 24 hour period resulted in diarrhea and transient dizziness in one patient. In the event of an overdose, INVANZ should be discontinued and general supportive treatment given until renal elimination takes place. INVANZ can be removed by hemodialysis; the plasma clearance of the total fraction of ertapenem was increased 30% in subjects with end-stage renal insufficiency when hemodialysis (4 hour session) was performed immediately following administration. However, no information is available on the use of hemodialysis to treat overdosage.

DOSAGE AND ADMINISTRATION

The dose of INVANZ in adults is 1 gram (g) given once a day. INVANZ may be administered by intravenous infusion for up to 14 days or intramuscular injection for up to 7 days. When administered intravenously, INVANZ should be infused over a period of 30 minutes. Intramuscular administration of INVANZ may be used as an alternative to intravenous administration in the treatment of those infections for which intramuscular therapy is appropriate.

DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (a-D-GLUCOSE).

Table 5 presents dosage guidelines for INVANZ. Table 5 Dosage Guidelines for Adults With Normal Renal Function * and Body Weight Infection+ Daily Dose (IV or IM) Recommended Duration of Total Antimicrobial Treatment Complicated intra-abdominal infections 1 g 5 to 14 days Complicated skin and skin structure infections 1 g 7 to 14 days Community acquired pneumonia 1 g 10 to 14 days++ Complicated urinary tract infections, including pyelonephritis 1 g 10 to 14 days++ Acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecologic 1 g 3 to 10 days

duration includes a possible switch to an appropriate oral therapy, after at least 3 days of

Patients with Renal Insufficiency: INVANZ may be used for the treatment of infections in patients with renal insufficiency. In patients whose creatinine clearance is >30 mL/min/1.73 m2, no dosage adjustment is necessary. Patients with advanced renal insufficiency (creatinine clearance PS30 mL/min/1.73 m2) and end- stage renal insufficiency (creatinine clearance PS10 mL/min/1.73 m2) should receive 500 mg daily.

: When patients on hemodialysis are given the recommended daily dose of 500 mg of INVANZ within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended following the hemodialysis session. If INVANZ is given at least 6 hours prior to hemodialysis, no supplementary dose is needed. There are no data in patients undergoing peritoneal dialysis or hemofiltration.

When only the serum creatinine is available, the following formula * * may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function.

Cockcroft and Gault equation: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976

Males: (weight in kg) x (140-age in years) (72) x serum creatinine (mg/100 mL) Females: (0.85) x (value calculated for males)

Patients with Hepatic Insufficiency: No dose adjustment recommendations can be made in patients with impaired hepatic function. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency and PRECAUTIONS.) No dosage adjustment is recommended based on age or gender. (See CLINICAL PHARMACOLOGY, Special Populations.)

PREPARATION OF SOLUTION

Preparation for intravenous administration: DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (a-D-GLUCOSE).

INVANZ MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION.

INVANZ MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use, whenever solution and container permit. Solutions of INVANZ range from colorless to pale yellow. Variations of color within this range do not affect the potency of the product.

STORAGE AND STABILITY

The reconstituted solution, immediately diluted in 0.9% Sodium Chloride Injection (see DOSAGE AND ADMINISTRATION, PREPARATION OF SOLUTION), may be stored at room temperature (25degC) and used within 6 hours or stored for 24 hours under refrigeration (5degC) and used within 4 hours after removal from refrigeration. Solutions of INVANZ should not be frozen.

HOW SUPPLIED

INVANZ is supplied as a sterile lyophilized powder in single dose vials containing ertapenem for intravenous infusion or for intramuscular injection as follows: No. 3843--1 g ertapenem equivalent NDC 0006-3843-71 in trays of 10 vials No. 3843--1 g ertapenem equivalent NDC 0006-3843-45 in trays of 25 vials.

CLINICAL STUDIES

Ertapenem was evaluated in adults for the treatment of complicated intra-abdominal infections in a clinical trial. This study compared ertapenem (1 g intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 5 to 14 days and enrolled 665 patients with localized complicated appendicitis, and any other complicated intra-abdominal infection including colonic, small intestinal, and biliary infections and generalized peritonitis. The combined clinical and microbiologic success rates in the microbiologically evaluable population at 4 to 6 weeks posttherapy (test of cure) were 83.6% (163/195) for ertapenem and 80.4% (152/189) for piperacillin/tazobactam.

Ertapenem was evaluated in adults for the treatment of complicated skin and skin structure infections in a clinical trial. This study compared ertapenem (1 g intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 7 to 14 days and enrolled 540 patients including patients with deep soft tissue abscess, posttraumatic wound infection and cellulitis with purulent drainage. The clinical success rates at 10 to 21 days posttherapy (test of cure) were 83.9% (141/168) for ertapenem and 85.3% (145/170) for piperacillin/tazobactam.

Ertapenem was evaluated in adults for the treatment of community acquired pneumonia in two clinical trials. Both studies compared ertapenem (1 g parenterally once a day) with ceftriaxone (1 g parenterally once a day) and enrolled a total of 866 patients. Both regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of 10 to 14 days of treatment (parenteral and oral). In the first study the primary efficacy parameter was the clinical success rate in the clinically evaluable population and success rates were 92.3% (168/182) for ertapenem and 91.0% (183/201) for ceftriaxone at 7 to 14 days posttherapy (test of cure). In the second study the primary efficacy parameter was the clinical success rate in the microbiologically evaluable population and success rates were 91% (91/100) for ertapenem and 91.8% (45/49) for ceftriaxone at 7 to 14 days posttherapy (test of cure).

Ertapenem was evaluated in adults for the treatment of complicated urinary tract infections including pyelonephritis in two clinical trials. Both studies compared ertapenem (1 g parenterally once a day) with ceftriaxone (1 g parenterally once a day) and enrolled a total of 850 patients. Both regimens allowed the option to switch to oral ciprofloxacin (500 mg twice daily) for a total of 10 to 14 days of treatment (parenteral and oral). The microbiological success rates (combined studies) at 5 to 9 days posttherapy (test of cure) were 89.5% (229/256) for ertapenem and 91.1% (204/224) for ceftriaxone.

Acute Pelvic Infections Including Endomyometritis, Septic Abortion And Post-Surgical Gynecological Infections

Ertapenem was evaluated in adults for the treatment of acute pelvic infections in a clinical trial. This study compared ertapenem (1 g intravenously once a day) with piperacillin/tazobactam (3.375 g intravenously every 6 hours) for 3 to 10 days and enrolled 412 patients including 350 patients with obstetric/postpartum infections and 45 patients with septic abortion. The clinical success rates in the clinically evaluable population at 2 to 4 weeks posttherapy (test of cure) were 93.9% (153/163) for ertapenem and 91.5% (140/153) for piperacillin/tazobactam.

REFERENCES

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Microorganism	MIC Range ( m g/mL)
Enterococcus faecalis ATCC 29212	4.0-16.0
Escherichia coli ATCC 25922	0.004-0.016
Haemophilus influenzae f ATCC 49766	0.016-0.06
Pseudomonas aeruginosa ATCC 27853	2.0-8.0
Staphylococcus aureus ATCC 29213	0.06-0.25
Streptococcus pneumoniae g ATCC 49619	0.03-0.25

INVANZ

(ERTAPENEM FOR INJECTION)

DESCRIPTION

CLINICAL PHARMACOLOGY

Aerobic gram-positive microorganisms:

Aerobic gram-negative microorganisms:

Anaerobic microorganisms: Bacteroides fragilis Bacteroides distasonis Bacteroides ovatus Bacteroides thetaiotaomicron Bacteroides uniformis Clostridium clostridioforme Eubacterium lentum Peptostreptococcus

Aerobic gram-positive microorganisms:

Aerobic gram-negative microorganisms:

Anaerobic microorganisms: Clostridium perfringens Fusobacterium

Susceptibility Tests:

Anaerobic Techniques:

INDICATIONS AND USAGE

CONTRAINDICATIONS

WARNINGS

THERAPY MAY ALSO BE ADMINISTERED AS INDICATED.

PRECAUTIONS

ANIMAL PHARMACOLOGY

ADVERSE REACTIONS

OVERDOSAGE

DOSAGE AND ADMINISTRATION

DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (a-D-GLUCOSE).

PREPARATION OF SOLUTION

INVANZ MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION.

INVANZ MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION.

STORAGE AND STABILITY

HOW SUPPLIED

CLINICAL STUDIES

REFERENCES

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