Date of Revision: October 24, 2007

Submission Control No: 115563

INVANZ(r) is a Registered Trademark of Merck & Co., Inc. Used under license.

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 18 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 24 DOSAGE FORMS, COMPOSITION AND PACKAGING 24

PART II: SCIENTIFIC INFORMATION 25

PHARMACEUTICAL INFORMATION 25 CLINICAL TRIALS 26 DETAILED PHARMACOLOGY 38 MICROBIOLOGY 47 TOXICOLOGY 59 BIBLIOGRAPHY 70

PART III: CONSUMER INFORMATION 73

PrINVANZ(r) ertapenem sodium for injection

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

INVANZ(r) (ertapenem sodium) 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. For a complete listing of components, see the Dosage Forms, Composition and Packaging section of the product monograph. Due to the use of lidocaine HCl as a diluent, INVANZ(r) administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type and in patients with severe shock or heart block (refer to the Product Monograph for lidocaine HCl).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS, (see WARNINGS AND PRECAUTIONS, Hypersensitivity) Seizures and other CNS (Central Nervous System) adverse experiences have been reported during treatment with INVANZ(r). These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function (see WARNINGS AND PRECAUTIONS, Neurologic, Renal and ADVERSE REACTIONS).

General

As with other antibiotics, prolonged use of INVANZ(r) 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(r) intramuscularly to avoid inadvertent injection into a blood vessel (see DOSAGE AND ADMINISTRATION - Administration). Lidocaine HCl is the diluent for intramuscular administration of INVANZ(r). Refer to the Product Monograph for lidocaine HCl for additional precautions.

Gastrointestinal

Pseudomembranous colitis

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ertapenem, which may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of Clostridium. Studies indicate that a toxin produced by Clostridium difficile is one 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.

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 1g 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.

Hypersensitivity

HYPERSENSITIVITY (ANAPHYLACTIC) 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(r) (ERTAPENEM SODIUM), CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO INVANZ(r) 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.

Neurologic

During clinical investigations in adult patients treated with INVANZ(r) (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(r) re-examined to determine whether it should be decreased or the antibiotic discontinued (see ADVERSE REACTIONS).

Renal

Dosage adjustment of INVANZ(r) is recommended in patients with reduced renal function (see DOSAGE AND ADMINISTRATION). A supplementary dose may be recommended in patients following hemodialysis (see DOSAGE AND ADMINISTRATION - Patients on Hemodialysis).

Special Populations

Pregnant Women: There are no adequate and well-controlled studies in pregnant women. INVANZ(r) should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. Nursing Women: Ertapenem is excreted in human milk. INVANZ(r) should be administered to nursing mothers only when the potential benefit outweighs the potential risk (see ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics).

Pediatrics (< 18 years of age)

:

Safety and effectiveness of INVANZ(r) 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 CLINICAL TRIALS, Pediatric Patients).

• Complicated Intra-Abdominal Infections

• Complicated Skin and Skin Structure Infections

• Community Acquired Pneumonia

• Complicated Urinary Tract Infections

• Acute Pelvic Infections

INVANZ(r) is not recommended in infants under 3 months of age as no data are available. INVANZ(r) is not recommended in the treatment of meningitis in the pediatric population due to lack of sufficient CSF penetration. Geriatrics (>= 65 years of age): In clinical studies, the efficacy and safety of INVANZ(r) in the elderly >= 65 years) was comparable to that seen in younger patients (<65 years). 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).

Monitoring and Laboratory Tests

While INVANZ(r) 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

Overview

When ertapenem is administered with probenecid (500 mg of probenecid every 6 hours), probenecid competes for active tubular secretion and reduces the renal excretion of ertapenem. This leads to small but statistically significant increases in the elimination half-life (19%, mean half-life with probenecid is 4.8 hours and mean half-life without probenecid is 4.0 hours) and in the extent of systemic exposure (25%, mean AUC0-[?] of total ertapenem with probenecid is 767.6 ug *hr/mL and mean AUC0-[?] of total ertapenem without probenecid is 616.2 ug *hr/mL). The coadministration of ertapenem with probenecid is not recommended, unless clinically necessary, due to the small effect on half-life. No dosage adjustment is recommended when patients receive probenecid concomitantly with ertapenem.

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 ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics). In vitro studies indicate that ertapenem, over its therapeutic concentration range, has little effect on the unbound fraction of warfarin in human plasma. Other than with probenecid, no specific clinical drug interaction studies have been conducted. Decreased serum levels of valproic acid with co-administration of ertapenem have been reported as post-marketing experiences and in some cases breakthrough seizures have occurred. Careful monitoring of serum levels of valproic acid should be considered if ertapenem is to be co- administered with valproic acid.

DOSAGE AND ADMINISTRATION

Treatment

Recommended Dose and Dosage Adjustment

The recommended dose of INVANZ(r) (ertapenem sodium) in patients 13 years of age and older is 1 gram (g) given once a day. The recommended dose of INVANZ(r) in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1 g/day). Table 7 presents treatment guidelines for INVANZ(r).

Table 7

Daily Treatment Guidelines for Adult and Pediatric Patients with Normal Renal Function *

Special Populations

Patients with Renal Insufficiency

INVANZ(r) may be used for the treatment of infections in adult patients with renal insufficiency. In patients whose creatinine clearance is >30 mL/min/1.73 m2 (SI = >0.5 mL/s/1.73 m2), no dosage adjustment is necessary. Adult patients with advanced renal insufficiency (creatinine clearance <= 30 mL/min/1.73 m2 (SI = <= 0.5 mL/s/1.73 m2)), and end-stage renal insufficiency on hemodialysis (creatinine clearance <= 10mL/min/1.73m2 (SI = <= 0.17 mL/s/1.73 m2)) should receive 500 mg daily. There are no data in pediatric patients with renal insufficiency. This recommended dosage reduction is based on pharmacokinetic modeling of data collected from a clinical safety and pharmacokinetic study in adult patients with varying degrees of renal insufficiency (including those with creatinine clearance <30 mL/min/1.73 m2 (SI = <0.5 mL/s/1.73 m2)) receiving a single 1 g IV dose of ertapenem (see ACTION AND CLINICAL PHARMACOLOGY - Renal Insufficiency). The efficacy of the recommended adjusted dose (500 mg) for adult patients with advanced or end-stage renal insufficiency has not been established.

Patients on Hemodialysis

When adult patients on hemodialysis are given the recommended daily dose of 500 mg of INVANZ(r) within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended following the hemodialysis session. If INVANZ(r) is given at least 6 hours prior to hemodialysis, no supplementary dose is recommended. There are no data in patients undergoing peritoneal dialysis or hemofiltration. There are no data in pediatric patients on hemodialysis. When only the serum creatinine is available, the following formula * * may be used to estimate creatinine clearance (mL/min). The serum creatinine should represent a steady state of renal function. Males: (weight in kg) x (140-age in years) (72) x serum creatinine (mg/100 mL) Females: (0.85) x (value calculated for males) When using the International System of units (SI), the estimated creatinine clearance (mL/s) can be calculated as follows: Males: (weight in kg) x (140-age in years) x 1.4736 (72) x serum creatinine (umol/L) Females: (0.85) x (value calculated for males)

Patients with Hepatic Impairment

No dosage adjustment recommendation can be made in patients with impaired hepatic function (see ACTION AND CLINICAL PHARMACOLOGY - Special Population and WARNINGS AND PRECAUTIONS - Hepatic Insufficiency).

Age/Gender

No dosage adjustment is recommended based on age (13 years of age and older) or gender. Dosing adjustment is needed based on age 3 months to 12 years of age (see ACTION AND CLINICAL PHARMACOLOGY - Special Population and WARNINGS AND PRECAUTIONS - Pediatrics).

* *

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

1976.

Prevention

Table 8 presents prophylaxis guidelines for INVANZ(r).

Table 8

Prophylaxis Guidelines for Adults

Missed Dose

The injection schedule will be set by the physician, who will monitor the response and condition to determine what treatment is needed.

Administration

INVANZ(r) may be administered by intravenous infusion or intramuscular injection. When administered intravenously, INVANZ(r) should be infused over a period of 30 minutes. Intramuscular administration of INVANZ(r) may be used as an alternative to intravenous administration in the treatment of those infections for which intramuscular therapy is appropriate.

Reconstitution

Patients 13 years of age and older

Preparation for Intravenous Administration:

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

INVANZ(r) MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION.

1. Reconstitute the contents of a 1 g vial of INVANZ(r) with 10 mL Water for Injection, 0.9% Sodium Chloride Injection or Bacteriostatic Water for Injection to yield a reconstituted solution of approximately 100 mg/mL. Shake well to dissolve.

2. To withdraw a 1 gram dose, immediately withdraw 9.8 mL of the reconstituted vial and transfer to 50 mL of 0.9% Sodium Chloride Injection.

3. The reconstituted IV solution should be used within 6 hours after preparation.

Preparation for Intramuscular Administration:

INVANZ(r) MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION.

1. Reconstitute the contents of a 1 g vial of INVANZ(r) with 3.2 mL of 1.0% lidocaine HCl injection * * * (without epinephrine) to yield a reconstituted solution of approximately 280 mg/mL. Shake vial thoroughly to form solution. To withdraw a 1 gram dose, the contents of the reconstituted vial should be withdrawn as completely as possible.

2. Immediately withdraw the contents of the vial and administer by deep intramuscular injection into a large muscle mass (such as the gluteal muscles or lateral part of the thigh).

3. The reconstituted IM solution should be used within 1 hour after preparation. Note: The reconstituted solution should not be administered intravenously.

Pediatric patients 3 months to 12 years of age

Preparation for Intravenous Administration:

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

INVANZ(r) MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION.

1. Reconstitute the contents of a 1 g vial of INVANZ(r) with 10 mL Water for Injection, 0.9% Sodium Chloride Injection or Bacteriostatic Water for Injection to yield a reconstituted solution of approximately 100 mg/mL. Shake well to dissolve.

2. Immediately withdraw a volume equal to 15 mg/kg of body weight (not to exceed 500 mg per dose) and dilute in 0.9% Sodium Chloride Injection to a final concentration of 20 mg/mL or less (not to exceed 1g/day).

3. The reconstituted IV solution should be used within 6 hours after preparation. Discard unused portion of the vial.

Preparation for Intramuscular Administration:

INVANZ(r) MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION.

1. Reconstitute the contents of a 1 g vial of INVANZ(r) with 3.2 mL of 1.0% lidocaine HCl injection * * * (without epinephrine) to yield a reconstituted solution of approximately 280

* * * .

Refer to the prescribing information for lidocaine HCl

* * * .

Refer to the prescribing information for lidocaine HCl

mg/mL. Shake vial thoroughly to form solution. Immediately withdraw a volume equal to 15 mg/kg of body weight (not to exceed 500 mg per dose and 1g/day) and administer by deep intramuscular injection into a large muscle mass (such as the gluteal muscles or lateral part of the thigh). The reconstituted IM solution should be used within 1 hour after preparation. Note: The reconstituted solution should not be administered intravenously. Discard unused portion of the vial. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use, whenever solution and container permit. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. Discard unused portion. Solutions of INVANZ(r) range from colorless to pale yellow. Variations of color within this range do not affect the potency of the product. The vials are for single use only. Unused portions should be discarded.

OVERDOSAGE

No specific information is available on the treatment of overdosage with INVANZ(r) (ertapenem sodium). Intentional overdosing of INVANZ(r) is unlikely. Intravenous administration of INVANZ(r) at a 3 g daily dose for 8 days to healthy adult volunteers did not result in significant toxicity. In clinical studies in adults, inadvertent administration of up to 3 g in a day did not result in clinically important adverse experiences. In pediatric clinical studies, a single IV dose of 40 mg/kg up to a maximum of 2 g did not result in toxicity. In the event of an overdose, INVANZ(r) should be discontinued and general supportive treatment given until renal elimination takes place. INVANZ(r) can be removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

INVANZ(r) (ertapenem sodium) is a sterile, synthetic, parenteral, 1-ss methyl-carbapenem that is structurally related to beta-lactam antibiotics, such as penicillins and cephalosporins, with in vitro activity against a range of 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 (see MICROBIOLOGY).

Pharmacokinetics

Overall, ertapenem pharmacokinetics were approximately linear. The plasma concentration of total ertapenem declines in a poly-exponential fashion following single 30-minute intravenous infusion. Area under the plasma concentration curve (AUC) of ertapenem increased slightly less than dose-proportionally based on total ertapenem concentrations over the 0.5 to 2 g dose range and that the AUC increased slightly greater than dose proportionally based on unbound ertapenem concentrations over the 0.5 to 2 g dose range. The slight deviations from strict dose proportionality are thought to be due to concentration-dependent plasma protein binding at the proposed therapeutic dose. The departure from dose-proportionality is very slight and, given the apparent wide therapeutic index of ertapenem, is not considered clinically relevant. The apparent volume of distribution of ertapenem at steady state is approximately 8.2 liters. The major metabolite of ertapenem is the bacteriologically inactive ring-opened derivative formed predominantly by the kidney by hydrolysis of the beta-lactam ring. Ertapenem is eliminated primarily by the kidneys. Plasma radioactivity consists predominantly (94%) of ertapenem. The mean plasma half-life of ertapenem in healthy young adults and 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. The mean bioavailability of 1 g IM dose is approximately 92%. There is no accumulation of ertapenem following multiple IV doses ranging from 0.5 to 2 g daily or IM doses of 1 g daily. Average plasma concentrations (ug/mL) and mean AUC0-[?] of total ertapenem following a single 30-minute IV infusion of a 1 or 2 g dose and IM administration of a single 1 g dose in healthy young adults are presented in Table 9.

Table 9

Plasma Concentrations and Mean AUC0-[?] of Total Ertapenem After Single Dose Administration in Healthy Young Adults

Mean AUC0-[?] values (ug *hr/mL) of unbound ertapenem for intravenous doses of 1 g and 2 g are 33.2 and 76.6, respectively. Average plasma concentrations (ug/mL) of ertapenem in pediatric patients are presented in Table 10.

Table 10

Plasma Concentrations of Ertapenem in Pediatric Patients After Single IV * Dose Administration

Absorption: Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (in saline without epinephrine), is well absorbed following IM administration at the recommended dose of 1 g. The mean bioavailability is approximately 92%. Following 1 g daily IM administration, mean peak plasma concentrations (mean Cmax= 70.6 ug/mL) are reached in approximately 2 hours (mean Tmax= 2.2 hours) [see Table 9].

Distribution:

Ertapenem is highly bound to human plasma proteins. In healthy young adults, the proportion of protein binding of ertapenem decreases as plasma concentrations of total ertapenem increase, from approximately 95% bound at an approximate plasma concentration of

<100 micrograms (ug)/mL to approximately 85% protein bound at an approximate plasma concentration of 300 ug/mL. The apparent volume of distribution (Vdss) of ertapenem in adults at steady state is approximately 8.2 liters (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. Concentrations of ertapenem achieved in skin blister fluid at each sampling point on the third day of 1 g once daily IV doses are presented in Table 11. The ratio of AUC0-24 of total ertapenem in skin blister fluid to AUC0-24 of total ertapenem in plasma is 0.61.

Table 11

Concentrations (ug/mL) of Total Ertapenem in Adult Skin Blister Fluid at Each Sampling Point on the Third Day of 1 g Once Daily IV Doses

The concentration of ertapenem in breast milk of 5 lactating women was measured at random time points daily for 5 consecutive days following the last 1 g dose of a 3- to 6-day, once daily intravenous therapy. The measured concentration of ertapenem in breast milk on the last day of therapy (5 to 14 days postpartum) in all 5 women was < 0.38 ug/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 was detected at trace levels (< 0.13 ug/mL) in 1 woman.

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 DRUG INTERACTIONS).

Metabolism:

In healthy young adults, after IV infusion of radiolabeled 1 g ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the bacteriologically inactive ring-opened derivative formed predominantly by the kidney by hydrolysis of the beta-lactam ring. This metabolite is found in urine (approximately 37% of the administered dose).

In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the six major cytochrome P450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (see - DRUG INTERACTIONS). In vitro studies in human liver microsomes indicate that ertapenem is a poor substrate of cytochrome P450 (CYP) isoforms. Coadministration of cilastatin (renal dehydropeptidase-1 inhibitor) significantly reduced the plasma clearance of ertapenem and increased the urinary excretion of ertapenem in rats and mice consistent with the view that dehydropeptidase-1 catalyzed the metabolism of ertapenem.

Excretion:

Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults and 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 administration of a 1 g radiolabeled IV dose of 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 bacteriologically inactive ring-opened metabolite. In healthy young adults given a 1 g IV dose, average concentrations of ertapenem in urine exceed 984 ug/mL during the period 0 to 2 hours postdose and exceed 52 ug/mL during the period 12 to 24 hours postdose.

Special Populations and Conditions

Pediatrics:

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 were generally comparable to those in healthy young adults. Three out of six patients 13 to 17 years of age received less than a 1 g dose. To provide an estimate of the pharmacokinetic data if all patients in this age group were to receive a 1 g dose, the pharmacokinetic data were calculated adjusting for a 1 g dose, assuming linearity. A comparison of results shows that a 1 g once daily dose of ertapenem achieves a pharmacokinetic profile in patients 13 to 17 years of age comparable to that of adults. The ratios (13 to 17 years/Adults) for AUC, the end of infusion concentration and the concentration at the midpoint of the dosing interval were 0.99, 1.20, and 0.84 respectively. 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 ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics - Distribution). 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 1g IV dose of ertapenem.

Geriatrics:

Plasma concentrations (AUC) following a 1 g and 2 g IV dose of ertapenem are slightly higher (approximately 39% and 22% for total ertapenem, respectively, and approximately 71% and 65% for unbound ertapenem, respectively) in elderly adults (>= 65 years) relative to young adults (< 65 years). These differences could be attributed partly to age-related changes in renal function. No dosage adjustment is necessary for elderly patients with normal (for their age) renal function.

Gender:

The plasma concentration profiles of ertapenem are comparable in healthy men and women when body weight differences are taken into consideration. No dosage adjustment is recommended based on gender.

Hepatic Insufficiency: The pharmacokinetics of ertapenem in patients with hepatic insufficiency have not been established. In vitro studies indicate that ertapenem is metabolically stable in human liver microsomes. Following administration of a 1 g radiolabeled IV dose of ertapenem to healthy young adults, only 10% of 14C-ertapenem was recovered in feces (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics - Metabolism and Excretion). Due to the limited extent of hepatic metabolism of ertapenem, its pharmacokinetics are not expected to be affected by hepatic impairment. No dosage adjustment recommendations can be made in patients with hepatic impairment. Renal Insufficiency: Single 1 g IV doses of ertapenem were administered to 26 adult subjects with varying degrees of renal impairment, AUC was similar in patients with mild renal insufficiency (Clcr 60-90 mL/min/1.73 m2 (when using International System of Units (SI), SI = 1.0 - 1.5 mL/s/1.73 m2)) compared with healthy subjects (ages 25 to 82 years). AUC was increased in patients with moderate renal insufficiency (Clcr 31-59 mL/min/1.73 m2 (SI = 0.52- 0.98 mL/s/1.73 m2)) approximately 1.5-fold compared with healthy subjects. AUC was increased in patients with advanced renal insufficiency (Clcr 5-30 mL/min/1.73 m2 (SI = 0.08-0.50 mL/s/1.73 m2)) approximately 2.6-fold compared with healthy subjects. AUC was increased in patients with end-stage renal insufficiency (Clcr <10 mL/min/1.73 m2 (SI = < 0.17 mL/s/1.73 m2)) approximately 2.9-fold compared with healthy subjects. There are no data in pediatric patients with renal insufficiency. A dosage adjustment (500 mg once daily) is recommended for adult patients with advanced or end-stage renal insufficiency (see DOSAGE AND ADMINISTRATION). The recommended dosage reduction is based on pharmacokinetic modeling of data collected from the clinical safety and pharmacokinetic study in patients with varying degrees of renal insufficiency (including those with creatinine clearance < 30 mL/min/1.73 m2 (SI = < 0.5 mL/s/1.73 m2)) receiving a single 1 g IV dose of ertapenem. Pharmacokinetic modeling was used to determine a dosing regimen, which would provide equivalent drug exposure for which clinical efficacy has been demonstrated. Following a single 1 g IV dose in 5 patients with end-stage renal insufficiency given immediately prior to a 4-hour hemodialysis session, approximately 30% of the dose was recovered in the dialysate. When patients on hemodialysis are given the recommended daily dose of 500 mg of INVANZ(r) (ertapenem sodium) within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended following the hemodialysis session (see DOSAGE AND ADMINISTRATION). Table 12 displays the mean plasma AUCs and the geometric mean AUC ratios (RI/Pooled Control) for total and unbound ertapenem in adult patients with varying degrees of renal insufficiency (RI).

Table 12

Mean Plasma AUCs and Geometric Mean Ratios (GMR) for Total and Unbound Ertapenem Following a 1 g Intravenous Dose of Ertapenem in Adult Patients with Varying

Degrees of Renal Insufficiency (RI) Versus the Pooled Control Group

STORAGE AND STABILITY

Before Reconstitution

Store lyophilized powder between 15degC and 25degC (59degF and 77degF).

Reconstituted and Infusion Solutions

The reconstituted solution, immediately diluted in 0.9% Sodium Chloride Injection (see DOSAGE AND ADMINISTRATION - Administration), 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(r) (ertapenem sodium) should not be frozen (see DOSAGE AND ADMINISTRATION - Reconstitution).

DOSAGE FORMS, COMPOSITION AND PACKAGING

INVANZ(r) (ertapenem sodium) is supplied as a sterile lyophilized powder in single dose glass vials containing 1 g of ertapenem as free acid for intravenous infusion or for intramuscular injection. Each vial of INVANZ(r) contains the following inactive ingredients: sodium bicarbonate and sodium hydroxide to adjust pH to 7.5. The sodium content is approximately 137 mg (approximately 6.0 mEq).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ertapenem sodium Chemical name: [1] 1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 3-[[5-[[[3- carboxyphenyl]amino]carbonyl]-3-pyrrolidinyl]thio]-6-[1- hydroxyethyl]-4-methyl-7-oxo-, monosodium salt, [4R-[3[3S *,5S *], 4a,5b,6b[R *]]]-; [2][4R,5S,6S]-3-[[[3S,5S]-5-[[m- carboxyphenyl]carbamoyl]-3-pyrrolidinyl]thio]-6-[[1R]-1- hydroxyethyl]-4-methyl-7-oxo-1-azabi-cyclo[3.2.0]hept-2-ene-2- carboxylic acid, monosodium salt. Molecular formula: C22H24N3NaO7S Molecular mass: 497.50 Structural formula:

H3C

OH

CH3 _

H H COO

S

Na+

NH

H2

O

Physicochemical properties: 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.

CLINICAL TRIALS

Adult Patients

Complicated Intra-Abdominal Infections

Table 13

Summary of Patient Demographics for the Pivotal Trial in Complicated Intra-Abdominal Infections

Table 14

Clinical and Microbiological Success Rates in Complicated Intra-Abdominal Infections for Study 017

+ Percentages and the 95% CI for study 017 (Test of Cure) were computed from a statistical model adjusting for strata.

Table 15

Clinical Success Rates at the Test of Cure by Pathogen for Microbiologically Evaluable Adult Patients with Complicated Intra-Abdominal Infections For Study 017

Complicated Skin and Skin Structure-Infections

Table 16

Summary of Patient Demographics for the Pivotal Trial in Complicated Skin and Skin- Structure Infections

Including patients with deep soft tissue abscess, posttraumatic wound infection and cellulitis with purulent drainage.

Table 17

Clinical Success Rates at the Test of Cure in Complicated Skin and Skin-Structure Infections for Study 016

+ Percentages and the 95% CI for study 016 (Test of Cure) were computed from a statistical model adjusting for strata.

Table 18

Clinical Success Rates at the Test of Cure by Pathogen for Clinically Evaluable Adult Patients with Complicated Skin and Skin-Structure Infections for Study 016

Diabetic Foot Infections

Table 19

Summary of Patient Demographics for the Clinical Trial in Diabetic Foot Infections

1 Both regimens allowed the option to switch to oral amoxicillin/clavulanate beyond day 5 of the maximal 28 day treatment (parenteral and oral). Most patients received appropriate adjunctive treatments such as debridement, wound off-loading and saline compresses as is typically required in the treatment of diabetic foot infections. Patients with suspected osteomyelitis could be enrolled if all the infected bone was removed within 2 days of initiation of study therapy, and preferably within the prestudy period. Investigators had the option to add open-label vancomycin if enterococci or methicillin-resistant Staphylococcus aureus (MRSA) were among the pathogens isolated in polymicrobial infections or fi patients had a history of MRSA infection and, such additional therapy was indicated in the opinion of the investigator.

Five hundred and eighty-six (586) patients were randomized into 1 of 2 treatment groups: 289 patients received ertapenem and 287 patients received piperacillin/tazobactam. Ten (10) patients were randomized to 1 of the 2 treatment arms (6 to ertapenem and

4 to piperacillin/tazobactam) but received no parenteral study therapy.

Table 20

Clinical Success Rates at the Test of Cure1 in Diabetic Foot Infections for Study 034

Test-of-cure was defined as a favorable clinical response (resolution of all or most of the signs and symptoms of the index infection) in the clinically evaluable population at a follow-up visit 10-days posttherapy.

Table 21

Clinical Success Rates at the Posttherapy Visit by Pathogen for Clinically Evaluable Adult Patients With Diabetic Foot Infections for Study 034

Community-Acquired Pneumonia

Table 22

Summary of Patient Demographics for the Clinical Trials in Community Acquired Pneumonia

Both regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of 10 to 14 days of treatment (parenteral and oral).

Table 23

Clinical Success Rates at the Test of Cure in Community Acquired Pneumonia for Combined Studies 018 and 020

+

Percentages and the 95% confidence interval for the combined studies 018 and 020 (Test of Cure) were calculated from a statistical model adjusting for strata.

Table 24

Clinical Success Rates at the Test of Cure by Pathogen for Microbiologically Evaluable Adult Patients with Community-Acquired Pneumonia For Combined Studies 018 and 020

Complicated Urinary Tract Infections Including Pyelonephritis

Table 25

Summary of Patient Demographics for the Clinical Trials in Complicated Urinary Tract Infections Including Pyelonephritis

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).

Table 26

Microbiological Success Rates in Complicated Urinary Tract Infections Including Pyelonephritis for Combined Studies 014 and 021

+

Percentages and the 95% confidence interval for the combined studies 014 and 021 (Test of Cure) were calculated from a statistical model adjusting for strata.

Table 27

Eradication Rates at the Test of Cure by Pathogen for Microbiologically Evaluable Adult Patients with Complicated Urinary Tract Infections For Combined Studies 014 and 021

Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post- surgical Gynecologic Infections

Table 28

Summary of Patient Demographics for the Pivotal Clinical Trial in Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post-Surgical Gynecologic Infections

Table 29

Clinical Success Rate at the Test of Cure in Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post-Surgical Gynecologic Infections for Study 023

+

Percentages and the 95% confidence interval for Study 023 (Test of Cure) were calculated from a statistical model adjusting for strata.

Table 30

Clinical Success Rates at the Test of Cure by Pathogen for Microbiologically Evaluable Adult Patients with Acute Pelvic Infections for Study 023

Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery

Table 31

Summary of Patient Demographics For the Clinical Trial in Colorectal Surgical Prophylaxis (Evaluable Population)

Study Results

Table 32

Proportion of Patients With Favorable Clinical Response Assessment at 4-Weeks Post- Treatment (Evaluable Population) (Estimated+) For Study 039

Table 33

Proportion of Patients With Favorable Clinical Response Assessment at 4-Weeks Post- Treatment Displayed by Surgical Procedure (Evaluable Population) For Study 039

Table 34

Proportion of Patients With Favorable Clinical Response Assessment at 4-Weeks Post Treatment (MITT Population) (Estimated +) For Study 039

Table 35

Proportion of Patients who Failed Prophylaxis at 4-Weeks Post-Treatment Displayed by Reason for Failure (Evaluable Population) For Study 039

Pediatric Patients

Ertapenem was evaluated primarily for pediatric safety and secondarily for efficacy in randomized comparative, multicenter studies in patients 3 months to 17 years of age with community acquired pneumonia (CAP), urinary tract infections (UTI), skin and soft tissue infections (SSTI), intraabdominal infections (IAI) and acute pelvic infections (API).

Study Demographics and Trial Design Table 36

Summary of Patient Demographics For Clinical Trials in Pediatric Patients

Study Results

Table 37

The Proportion of Pediatric Patients in the Evaluable Per Protocol (EPP) Analysis With a Favorable Assessment+ at the Test-of-cure Visit For Studies 036 (CAP, UTI, SSTI) and 038 (IAI, API):

rate is displayed for UTI.

++

Included patients with perforated or complicated appendicitis.

SS

Included patients with post-operative or spontaneous obstetrical endomyometritis, or septic abortion.

DETAILED PHARMACOLOGY

Animal Pharmacology

The pharmacologic assays were part of a screening effort to assess potential liabilities of the compound.

In Vivo

Pharmacokinetics

Ertapenem showed no interaction with the cardiovascular system, respiratory system, or gastrointestinal function. Tissue distribution was assessed in rats by measuring the concentration of total radioactivity in various tissues after single dose administration of radiolabeled ertapenem. Following administration of a single 15 mg/kg IV dose of [14C] ertapenem, concentrations declined with time in all tissues (Table 38). At 0.5 hr postdose, the concentrations (radioequivalents) were highest in the liver, kidneys, small intestine, and plasma. The kidneys consistently contained the highest concentrations, which occurred most likely because ertapenem radioequivalents are eliminated primarily by renal excretion. With the exception of the kidney (~6 ug/g), ertapenem radioequivalent concentrations at 72 hr postdose had declined to less than 0.7 ug/g in all tissues.

Table 38

Tissue Concentrations of Radioactivity in Rats After IV Administration of 15 mg/kg [14C] Ertapenem

Shown as the mean and S.D. of three animals per time point. Ertapenem was transferred from the maternal to the fetal circulation (3% and 174% of maternal plasma concentrations at 5 and 240 minutes after dosing, respectively), when administered at 700 mg/kg/day to pregnant rats.

Cardiovascular and Respiratory System

Ertapenem was evaluated for cardiovascular response in the conscious, remote monitored dog. Measurements of blood pressure (BP) and heart rate (HR) were conducted to determine indicators of potential cardiovascular effects outside the normal sphere of the test compound's actions. Ertapenem administered at 10 mg/kg IV had no effect on BP and/or HR when compared to the placebo controls. Arterial BP and HR responses to ertapenem (100 mg/kg IV) were also determined in the hypertensive rat. No significant effects on either systolic or diastolic BP or HR were detected when compared to vehicle controls. Furthermore, BP, HR, electrocardiogram (ECG), air flow, and respiratory rate were also measured in the anesthetized cat as indicators of potential cardiovascular and respiratory effects in response to ertapenem. A 100 mg/kg IV dose showed no effect on either systolic or diastolic BP. At 1 minute postdose, a transitory increase in HR was detected but was not considered significant. No effects on respiratory parameters were observed in the cat. Respiratory parameters measured in anesthetized guinea pigs also were not statistically different in baseline values between groups following a 100 mg/kg IV dose of ertapenem.

Central Nervous System

To assess any behavioral changes brought on by ertapenem (100 mg/kg IV dose), parameters including locomotor activity, muscle tone, stereotypy, straub tail, salivation, ptosis, tremors, righting reflex, mydriasis, convulsions, lethality, body temperature circulation, respiration, and other measurements were evaluated and showed no significant changes over vehicle-treated mice. Central nervous system (CNS) stimulation or depression due to ertapenem was assessed by measuring decrease or increase in barbiturate-induced sleep time in mice. Ertapenem was reported inactive in all instances.

Gastrointestinal System

A direct measure of intestinal motility and gastrointestinal function was explored in mice with the use of the charcoal meal test. This analysis determines the possible side effects of ertapenem on intestinal transit. No changes at a dose of 100 mg/kg IV of ertapenem were observed when compared to the (water) control animals. The influence of ertapenem on gastric acid secretion was evaluated in anesthetized rats. No significant activity over normal was detected based on acid secretion over time in response to the 100 mg/kg IV dose of ertapenem.

Urinary Tract

The diuretic evaluation of ertapenem administered IV at 100 mg/kg body weight was conducted in conscious Wistar rats. Compared to the control group, ertapenem demonstrated no change in water, sodium, potassium, and chloride excretion and osmolality over a period of up to 6 hours after IV administration.

Other Systems

To determine the sedative liability or muscle relaxant properties of ertapenem, 8 trained male Wistar rats were administered 100 mg/kg IV and then placed on a rotating rod for a 1-minute period at 15, 30, 60, 90, and 120 minutes after dosing to assess motor coordination. All rats were able to perform this coordinated locomotor task and, thus, ertapenem was inactive in this study. To evaluate its effect on acute inflammatory edema, ertapenem was administered at 100 mg/kg IV 1 hour prior to injection of edema-producing carrageenin into the right hind paw of male Wistar rats. Edema was inhibited 14% by ertapenem; this level of inhibition was not significant compared to vehicle-treated animals (student's t-test, p<0.05). The dose rate of 100 mg/kg ertapenem was evaluated in 10 Swiss Webster male mice for local anesthetic activity following intramuscular injection in the area of the sciatic nerve. All animals were able to use the injected limb to walk normally both upright and inverted on a wire mesh screen. Therefore, ertapenem was devoid of effects in this assay. No significant activities were observed in a variety of in vitro tissue preparations to assess potential antagonist and agonist effects. Biochemical assays further demonstrate the specificity of ertapenem as an antibacterial agent. Specifically, ertapenem (100 uM) did not demonstrate lipoxygenase or cyclooxygenase activity as evidenced by a lack of effect on LTB4 and TXB2 generation in human whole blood. Ertapenem (100 uM) also did not alter ADP-induced aggregation of human citrated platelet rich plasma. Growth rates of tumor cells (KB nasopharyngeal carcinoma cell line and HeLa cells) were not influenced by 10 and 100 uM ertapenem, and no significant inhibition of microsomal squalene synthetase was observed at 25 uM ertapenem. Ertapenem exhibited no cytotoxicity in COLO 205 cells at concentrations from 10-8 to 10-3 M. The effect of ertapenem on the intrinsic and extrinsic coagulation pathways was determined using the plasma from male Sprague Dawley (SD) or Alderly Park (AP) rats administered 100 mg/kg IV and measured by the activated partial thromboplastin time (APTT) and prothrombin time (PT) assays, respectively. In these tests, the ertapenem-treated group was not significantly different from vehicle control. The effect of ertapenem on the fibrinolytic system was determined using the plasma from male SD or AP rats dosed with 100 mg/kg IV and measured by the Euglobulin Clot Lysis (ECLT) assay. The ertapenem-treated group was not significantly different from vehicle control and, therefore, no profibrinolytic or antifibrinolytic activity was detected.

Human Pharmacology In Vivo Pharmacokinetics Table 39

Clinical Pharmacology and Biopharmaceutics Studies

Human Pharmacology (cont'd)

Table 39

Clinical Pharmacology and Biopharmaceutics Studies (cont'd)

Human Pharmacology (cont'd) Table 39

Clinical Pharmacology and Biopharmaceutics Studies (cont'd)

Human Pharmacology (cont'd) Table 39

Clinical Pharmacology and Biopharmaceutics Studies (cont'd)

Human Pharmacology (cont'd) Table 39

Clinical Pharmacology and Biopharmaceutics Studies (cont'd)

+

Active treatment only (subjects on placebo not included in number entered).

++ Gender and race provided for analyzed subjects/patients: S = healthy subjects, P = patients, M = male, F = female, A = Asian, B = Black, C = Caucasian, CB = Cuban, H = Hispanic, I = South Pacific Islander, MZ = Mestizo, NA = Native

American, O = Other.

SS

Counted as patients due to organ dysfunction, not due to bacterial infection.

Renal Elimination/Hemodialysis

Renal clearance of unbound ertapenem was reduced by approximately 54% in the presence of probenecid (mean renal clearance = 203.7 mL/min without probenecid and 94.5 mL/min with probenecid), an inhibitor of renal tubular secretion. The results suggest that tubular secretion and passive glomerular filtration are significant pathways of the renal clearance of ertapenem. In a clinical study, following a single 1 g IV dose of ertapenem given immediately prior to a hemodialysis session, approximately 30% of the dose was recovered in the dialysate.

In Vitro

Pharmacokinetics

Ertapenem penetrated poorly into erythrocytes. This may be due to the extensive plasma protein binding and polarity of the compound (log10 p<-2) that limit the ability of the drug to cross the erythrocyte cell membrane.

MICROBIOLOGY

The antibacterial spectrum of ertapenem was evaluated using standard in vitro microbiological procedures. Table 40 displays the in vitro antibacterial activity of ertapenem against 9911 isolates from surveillance studies and from the clinical studies. The ratios of MBC to MIC in broth (inoculum 105 CFU/mL) are shown in Table 41. Ertapenem was found to have limited activity against Corynebacterium jeikeium, Pseudomonas spp., Burkholderia cepacia, Stenotrophomonas maltophilia, Acinetobacter spp., Bacteroides distasonis, and Clostridium difficile. Enterococci and methicillin-resistant staphylococci are resistant to ertapenem.

Table 40

Summation of in Vitro Activity of Ertapenem Including Aerobic and Anaerobic Isolates Obtained in the Phase II to Phase III Clinical Efficacy Trials (North American Isolates Only)

Table 40 (cont'd)

Summation of in Vitro Activity of Ertapenem Including Aerobic and Anaerobic Isolates Obtained in the Phase II to Phase III Clinical Efficacy Trials (North American Isolates Only)

Table 40 (cont'd)

Summation of in Vitro Activity of Ertapenem Including Aerobic and Anaerobic Isolates Obtained in the Phase II to Phase III Clinical Efficacy Trials (North American Isolates Only)

Table 40 (cont'd)

Summation of in Vitro Activity of Ertapenem Including Aerobic and Anaerobic Isolates Obtained in the Phase II to Phase III Clinical Efficacy Trials (North American Isolates Only)

Table 41

RATIOS OF MBC TO MIC IN BROTH (INOCULUM 105 CFU/mL)

INVANZ(r)

Organism

with Multiple Isolates ug/mL ug/mL

Enterococcus faecalis

20 32 32 1

Resistance to Ertapenem

In vitro studies, which have focused on gram-negative pathogens, have partially elucidated the mechanisms of resistance to ertapenem. These studies suggest that the main forms of resistance to ertapenem in gram-negative bacilli, involve combinations of reduced accumulation (due to decreased influx and/or increased efflux) and b-lactamase hydrolysis. In vitro development of resistance to ertapenem has been studied in Pseudomonas aeruginosa and in Escherichia coli strains. In a P. aeruginosa strain, resistance rates ranged from 2x10-7 at 2 times MIC to 2.2x10-9 at 8 times the MIC. In E. coli strains expressing either low levels of AmpC b-lactamase or significant amounts of b-lactamases TEM-1 or SHV-1, frequencies at 4 to 8 times MIC were in the range of 4x10-8 to 3x10-9. Frequencies obtained with E. coli clinical strains containing ESbLs ranged from 3.3x10-7 to 8x10-8 (Table 42). Although cross-resistance between ertapenem and other carbapenems is possible, in vitro studies and surveillance studies indicate that cross-resistance between ertapenem and other carbapenems is not complete. Target-based cross-resistance with non-b-lactam antimicrobials is not anticipated as b-lactams do not share common mechanisms of actions with these agents.

Stability of Ertapenem to Beta-Lactamases

Ertapenem is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, cephalosporinases, and extended spectrum beta-lactamases. Ertapenem is hydrolyzed by metallo- beta-lactamases. Table 42 shows in vitro activity of ertapenem against strains producing extended spectrum b-lactamase (ESbLs) and AmpC b-lactamase.

Table 42

In Vitro Activity of Ertapenem Against Strains Producing Extended Spectrum Beta-Lactamases (ESbLs) and AmpC beta- Lactamases

Product Monograph - INVANZ(r)

Page 53 of 75

Parameters of in Vitro Susceptibility Testing

MIC values of ertapenem against Staphylococcus aureus increased 4- to 8-fold in the presence of 50% human serum while they increased 2- to 4-fold against Klebsiella pneumoniae. Heat inactivation of human serum did not alter the serum effects on MIC values, suggesting that increases were most likely attributable to the effects of plasma protein binding. The low serum effect on the susceptibility of K. pneumoniae against ertapenem is consistent with the concept of reversible serum protein binding of ertapenem. Although the presence of serum increased the MIC of ertapenem by 2- to 8-fold, the bactericidal effect as demonstrated by the MBC/MIC ratio was unaffected by serum (equal to 2-fold). The activity of ertapenem was not affected by the addition of the standard 5% sheep blood or 3% horse blood. A significant decrease in the activity of ertapenem was observed in thioglycollate broth and in brain heart infusion broth containing L-cysteine. Sets of trays containing serial dilutions of ertapenem in cation-adjusted Mueller-Hinton broth (MHB) (pH 7.3) were stored in sealed plastic bags at various temperatures and for various periods of time and thereafter assayed for activity by the broth microdilution method. The activity of ertapenem was unchanged following storage for at least 3 months at -70degC, for at least 4 weeks at -20degC, for at least 7 days at 4degC and at 23deg to 25degC and for at least 2 to 3 days at 37degC. The effects of incubation in MHB at 37degC on the stability of ertapenem were determined. Over 80% of intact ertapenem remained after 7 hours of incubation, which decreased to about 67.3% by 24 hours. The effect of inoculum on in vitro susceptibility was studied against a variety of organisms including Staphylococcus aureus, members of the Enterobacteriaceae (including those producing ESbLs and/or AmpC b-lactamases), Pseudomonas aeruginosa, and Acinetobacter species. The inocula evaluated varied in different studies with the highest inoculum tested being 1000-fold greater than the control inoculum. No inoculum effect was demonstrated for S. aureus. For Enterobacteriaceae, an inoculum effect was demonstrated against some, but not all, organisms studied, but in all cases the ertapenem MIC90 values remained <= 2 ug/mL at the higher inocula. The greatest increase in MIC values was observed in Enterobacteriaceae expressing one or more extended-spectrum and/or broad-spectrum b-lactamase. For example, in one study the inocula tested ranged from 6x105 to 6x106 cfu/mL to 1.8x106 to 1.8x107 cfu/mL. In each case, the higher inoculum was 10-fold higher than the lower inoculum. In a study of a panel including E. coli clinical isolates containing broad-spectrum b-lactamases (BDSbLs) TEM-1 and SHV-1, and the ESssLs TEM-7, TEM-12, and TAZ-25 and K. pneumoniae isolates containing the ESssLs TEM-5, TEM-10, TAZ-3 and TAZ-10, as well as 1 unidentified b-lactamase, ertapenem MICs at the lower inoculum ranged from <= 0.03 ug/mL to 0.12 ug/mL. At 10-fold higher inocula, increased MICs for ertapenem were noted against many of the strains containing BDSbLs and ESssLs; however, in all cases the ertapenem MIC values remained <= 2 ug/mL. In another study, the activity of ertapenem was evaluated in routine MIC tests and at 100 times the standard inocula against 100 well characterized clinical and laboratory strains of Enterobacteriaceae expressing the following enzymes: TEM-1, 3-10, 12, 16, 24, 26, 50, SHV-1, 2-5, 7, Toho-1 and 2, OXA-2, K1, inducible AmpC, MIR-1, LAT-2, ACT-1, FOX-3 and several unidentified plasmid-borne AmpC enzymes and TEM-derived ESssLs. The MIC90 of ertapenem against these strains was 0.5 ug/mL at the lower inoculum; at the higher inocula, the MIC90 of ertapenem increased to 1 ug/mL. A broth microdilution checkerboard study of synergy was carried out for combinations of ertapenem and ciprofloxacin, and of ertapenem and gentamicin against methicillin-sensitive S. aureus, methicillin-sensitive coagulase-negative staphylococci, E. coli, and K. pneumoniae. No antagonism was demonstrated. Synergy, complete or partial, was seen with <50% of the strains for either combination.

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 dilution method(a) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ertapenem powder. The MIC values should be interpreted according to criteria provided in Table 43.

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(b) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 ug ertapenem to test the susceptibility of microorganisms to ertapenem. The disk diffusion interpretive criteria are provided in Table 43.

Anaerobic Techniques

For anaerobic bacteria, susceptibility to ertapenem as MICs can be determined by standardized test methods (c)(d). The MIC values obtained should be interpreted according to the criteria provided in Table 43.

Table 43

NCCLS Interpretive Susceptibility Criteria for Ertapenem

The current absence of data on resistant strains precludes defining any category other than "susceptible". If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.

Isolates of Streptococcus pneumoniae should be tested against a 1 ug oxacillin disk. Isolates with oxacillin zone sizes of

>= 20 mm are susceptible to penicillin and can be considered susceptible to ertapenem.

Streptococcus pneumoniae that are susceptible to penicillin (MIC <= 0.06ug/mL) and Streptococcus spp. other than S. pneumoniae that are susceptible to penicillin (MIC <= 0.12 ug/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.

Streptococcus

spp. should be tested with a 10-unit penicillin disk. Isolates with penicillin zone sizes of >= 24 mm are susceptible to penicillin and can be considered susceptible to ertapenem.

These interpretive standards are applicable to the broth microdilution procedure using Haemophilus Test Medium (HTM)

inoculated with a direct colony suspension and incubated in ambient air at 35degC for 20-24 hrs.

These zone diameters are applicable to tests performed by disk diffusion using Haemophilus Test Medium (HTM) agar inoculated with a direct colony suspension and incubated in 5% CO2 at 35degC for 16-18 hrs.

These interpretative standards 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.

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 (QC)

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard ertapenem powder should provide the following range of values noted in Table 44. 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.

Table 44

Acceptable Quality Control (QC) Ranges for Ertapenem

This organism is used for quality control of susceptibility testing of Streptococcus pneumoniae and Streptococcus spp.

These quality control ranges are applicable to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35degC for 20-24

hrs.

These quality control ranges are applicable to tests performed 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.

These quality control ranges are applicable to the broth microdilution procedure using Haemophilus Test Medium (HTM)

inoculated with a direct colony suspension and incubated in ambient air at 35degC for 20-24 hrs.

These quality control ranges are applicable to tests performed by disk diffusion using Haemophilus Test Medium (HTM) agar inoculated with a direct colony suspension and incubated in 5% CO2 at 35degC for 16-18 hrs.

These 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.

Quality control ranges applicable for broth microdilution method.

ATCC(r) is a registered trademark of the American Type Culture Collection.

TOXICOLOGY

Animal Toxicology

Acute Toxicity

In rats and mice, the approximate LD50 was greater than 700 mg/kg IV of ertapenem for both species since all animals survived until the end of the 14-day observation period. In an additional study in mice conducted as a range-finding study, the approximate 3-day LD50 was >2000 mg/kg. In mice that received a single oral dose of 500 mg/kg ertapenem, all mice survived through the 7-day observation period, and therefore the approximate LD50 was >500 mg/kg. An acute nephrotoxicity study in rabbits indicated that the drug was not nephrotoxic at a dose of 225 mg/kg. A treatment-related decrease in absolute neutrophil count was first observed in a 5-week intravenous toxicity study in rats at doses of 30, 60, and 180 mg/kg/day. The lowest dose in repeat-dose studies in rats in which a treatment-related decrease in neutrophils occurred was 2 mg/kg/day. The decrease in neutrophil count did not progress with continued dosing, and for most groups, the magnitude of the change diminished over the course of the study. Similar changes occurred in the 14-week and 27- week studies in rats. In each study, there was no evidence of a compensatory left shift, and there were no histopathologic changes in any organ, including the bone marrow. Furthermore, this change occurred in the absence of any treatment-related physical signs (except for slight injection site irritation at 675 mg/kg/day) or changes in body weight gain. This change in neutrophil count was shown to require at least 2 doses of ertapenem and to be reversible after discontinuation of treatment. It was not accompanied by changes in the bones, bone marrows, or bone marrow smears. Rats that had an ertapenem-induced decrease in neutrophils had this change reversed by subcutaneous injections of granulocyte colony stimulating factor (G-CSF; NEUPOGEN(r)). Following a 6-day treatment with G-CSF, the neutrophil counts returned to the levels of controls, and remained in that range following cessation of the G-CSF treatment. Studies in rhesus monkeys were inconclusive with regard to the effect on neutrophil counts. Table 45 reports long term (repeat-dose) studies in several species.

(r)

NEUPOGEN (filgrastim), Registered Trademark of Amgen Canada Inc.

Table 45

Long-Term Toxicity

General Toxicology

Table 45

Long-Term Toxicity (cont'd)

Subacute Toxicity Studies

Table 45

Long-Term Toxicity (cont'd)

Subacute Toxicity Studies (cont'd)

Table 45

Long-Term Toxicity (cont'd)

Subacute Toxicity Studies (cont'd)

Table 45

Long-Term Toxicity (cont'd)

Chronic Toxicology Stud

ies

IV = Intravenous

Table 45

Long-Term Toxicity (cont'd)

Reproductive Toxicology Studies

GD = Gestation Day IV= Intravenous

Table 45

Long-Term Toxicity (cont'd)

Embryo-Fetal & Perinatal Toxicology Studies

Table 45

Long-Term Toxicity (cont'd)

Embryo-Fetal & Perinatal Toxicology Studies (cont'd)

GD = Gestation Day LD = Lactation Day IV = Intravenous

In a 14-week rat study, 2 of 15 males that received 675 mg/kg/day and 1 of 15 females that received 225 mg/kg/day had a thrombocytopenia, usually associated with decreases in the erythron in Drug Weeks 4, 8, and/or 12. The no-effect level for this change was 75 mg/kg/day. Similar changes were not observed in rats that received 30, 60, and 180 mg/kg/day for 5 weeks, or in rats that received doses as high as 540 mg/kg/day for 27 weeks. There were no microscopic changes in any tissues, including the bone marrow, of the rats on study, including the ones that had the thrombocytopenias (except for slight injection site irritation in some rats at 675 mg/kg/day). Slight increases in serum ALT were observed both in monkeys and in female rabbits. There was a slight, non-dose-related increase in mean serum ALT in monkeys that received 30, 60, or 180 mg/kg/day in a 5-week study, and 40, 120, or 360 mg/kg/day in 14- and 27-week studies. These increases were not progressive and not accompanied by any histopathologic change in the livers. In a 27-week study in monkeys at doses of 40, 120, and 360 mg/kg/day, and in a 5-week study in monkeys at doses of 500, 750, and 1250 mg/kg/day, similar increases in serum ALT also occurred, as well as increases in serum triglycerides and phosphorus. There were treatment-related liver weight increases at doses of 500, 750 and 1250 mg/kg/day in monkeys in a 5-week study. The 5-week study also showed decreases in chloride in the high-dose group. There were increases in kidney weights and renal tubular cytoplasmic rarefaction in both the 27-week and higher dose 5-week study. The 27- week study also had luminal eosinophilic granularity observed, whereas the higher dose 5-week study had renal cortical tubular vacuolation. This slight difference may be due to a more severe change in the 5-week study resulting from the same process. Furthermore, in the higher dose 5-week study the kidneys were removed from the body cavity first because of the expectation that there were treatment-related renal changes. The higher dose 5-week study also had hepatocellular swelling at all doses and hepatocellular single cell necrosis at doses >=750 mg/kg/day.

Carcinogenesis

No long-term studies in animals have been performed to evaluate the carcinogenic potential of ertapenem.

Mutagenesis

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.

Reproduction

In the female fertility study in rats, ertapenem was administered at dosages of 70, 350, 700 mg/kg/day. There were no deaths or treatment-related physical signs. There were no treatment- related effects on mating, fertility, or fecundity indices, or embryonic/fetal survival. The no-effect level of ertapenem for effects on female fertility was >= 700 mg/kg/day. In the male fertility study in rats, ertapenem was administered at dosages of 175, 350, and 700 mg/kg/day. There were no treatment-related effects on mating index, fertility index, fecundity index, embryonic/fetal survival, sperm count and motility, and testicular/epididymal organ weights or histology. The no-effect level of ertapenem for effects on male fertility was >= 700 mg/kg/day.

Development

A developmental toxicity study was conducted in rats at doses of 70, 350, and 700 mg/kg/day to assess the effects of ertapenem on fetal survival, growth, and development. There were no treatment- related changes at any dose. An additional developmental toxicity study was conducted at the same doses in rats to assess ertapenem on reproductive performance of F0 females and to evaluate the effects on development, growth, behavior, reproductive performance and fertility of the F1 generation. During lactation there were significant treatment-related increases in mean maternal body weight gain at all doses (63 to 111% above controls). There were no treatment-related changes, including on reproductive performance, and effects on the F1 or F2 generations. A toxicokinetic study was conducted in rats to determine concentrations of ertapenem in maternal and fetal plasma and in maternal milk following intravenous administration of 700 mg/kg/day of ertapenem to pregnant rats from Gestation Day 6 through 20 or through Lactation Day 14. Ertapenem was transferred from the maternal to the fetal circulation (3% and 174% of maternal plasma concentrations at 5 and 240 minutes after dosing, respectively). Doses of 70, 350, and 700 mg/kg/day of ertapenem were used in the mouse developmental toxicity study. There was no maternal toxicity up to the highest dose. Developmental toxicity was observed only in the 700-mg/kg/day group in the form of slight decreases in average fetal weight and an associated decrease in the number of ossified sacrocaudal vertebrae. There were no effects on embryo survival or fetal morphology. Based on these results, the no-effect level in mice for maternal toxicity was >=700 mg/kg/day and for developmental toxicity was 350 mg/kg/day (approximately 1.5-fold the typical human dose based on body surface area).

BIBLIOGRAPHY

1. Solomkin JS, Yellin AE, Rotstein OD, Christou NV, Dellinger EP, Tellado JM, Malafaia O, Fernandez A, Choe KA, Carides A, Satishchandran V, Teppler H. Ertapenem Versus Piperacillin/Tazobactam in the Treatment of Complicated Intraabdominal Infections: Results of a Double-Blind, Randomized Comparative Phase III Trial. The Protocol 017 Study Group, Ann Surg 2003; 237(2):235-45.

2. Teppler H, McCarrol K, Gesser RM, Woods GL. Surgical Infections with enterococcus: Outcomes of patients treated with ertapenem and piperacillin/tazobactam. Surgical Infections 2002; 3(4):337-49.

3. Yellin AE, Hassett JM, Fernandez A, Geib J, Adeyi B, Woods Gl, Teppler H. Ertapenem monotherapy versus combination therapy with ceftriaxone plus metronidazole for treatment of complicated intra-abdominal infections in adults. The 004 Intra abdominal Infection Study Group. Int J Antimicrob Agents 2002; 20(3):165-73.

4. Pelak BA, Woods Gl, Teppler H, Friedland I, Bartizal K, Motyl M. Comparative in vitro activities of ertapenem against aerobic bacterial pathogens isolated from patients with complicated intra-abdominal infections. J Chemother 2002; 14(3):227-33.

5. Tellado J, Woods GL, Gesser R, McCarroll K, Teppler H. Ertapenem versus Piperacillin- Tazobactam for Treatment of Mixed Anaerobic Complicated Intra-Abdominal, Complicated Skin and Skin Structure, and Acute Pelvic Infections. Surgical Infections 2002; 3(4):303-14.

6. Pelak B, Bartizal K, Woods GL, Gesser RM, Motyl M. Comparative in vitro Activities of Ertapenem against Aerobic and Facultative Bacterial Pathogens from Patients with Complicated Skin and Skin Structure Infections. Diagn Microbiol Infect Dis 2002; 43(2):129- 33.

7. Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell KL, Gesser RM. General microbiology and in vitro susceptibility of anaerobes isolated from complicated skin and skin structure infections in patients enrolled in a comparative trial of ertapenem versus piperacillin/tazobactam. Clin Infect Dis 2002; 35:119-25.

8. Ortiz-Ruiz G, Caballero-Lopez J, Friedland IR, Woods GL, Carides A, Protocol 018 ertapenem Community-Acquired Pneumonia Study group. A prospective, multicenter, double-blind, randomized, comparative study to evaluate the safety, tolerability and efficacy of ertapenem versus ceftriaxone in the treatment of serious community-acquired pneumonia in adults. Clin Infect Dis 2002; 34:1076-83.

9. Vetter N, Cambronero-Hernandez E, Rohlf J, Simon S, Carides A, Oliveria T, Isaacs R, Protocol 020 Study group. A prospective, randomized, double-blind multicenter comparison of parenteral ertapenem and ceftriazone for the treatment of hospitalized adults with community-acquired pneumonia. Clin Ther 2002; 24(11): 1770-85.

10. Jimenez-Cruz F, Jasovich A, Cajigas J, Jiang Q, Imbeault D, Woods GL, Gesser RM, Protocol 021 Study Group. A Prospective, Multicenter, Randomized, double-blind Study Comparing Ertapenem and Ceftriaxone Followed by Appropriate Oral Therapy for Treatment of Complicated Urinary Tract Infections in Adults. Urology 2002; 60(1):16-22.

11. Tomera KM, Burdmann EA, Pamo Reyna OG, Jiang Q, Wimmer WM, Woods GL, Gesser RM, Protocol 014 Study Group. Ertapenem versus Ceftriaxone Followed by Appropriate Oral Therapy for Treatment of Complicated Urinary Tract Infections in Adults: Results of a Prospective, Randomized, double-blind Multicenter Study. Antimicrob Agents Chemother 2002; 46:2895-900.

12. Aldridge KE. Antimicrobial Susceptibility Studies Ertapenem (MK-0826), a new carbapenem: comparative in vitro activity against clinically significant anaerobes. Diagn Microbiol Infect Dis 2002; 44:181-6.

13. Betriu C, Sanchez A, Palau ML, Gomez M, Picazo JJ. In Vitro Activities of MK-0826 and 16 Other Antimicrobials against Bacteroides fragilis Group Strains. Antimicrob Agents Chemother 2001; 45:2372-4.

14. Livermore DM, Oakton KJ, Carter MW, Warner M. Activity of Ertapenem (MK-0826) versus Enterobacteriaceae with Potent b-Lactamases. Antimicrob Agents Chemother 2001; 45:2831-7.

15. Fuchs PC, Barry AL, Brown SD. In Vitro Activities of Ertapenem (MK-0826) against Clinical Bacterial. Isolates from 11 North American Medical Centers. Antimicrob Agents Chemother 2001; 45:1915-18.

16. Goldstein EJC, Citron DM, Merriam CV. Comparative In Vitro Activities of Ertapenem (MK-0826) against 1,001 Anaerobes Isolated from Human Intra-Abdominal Infections. Antimicrob Agents Chemother 2000; 44:2389-94.

17. Pelak BA, Citron DM, Motel M, Goldstein EJC, Woods GL, Teppler H. Comparative in vitro activities of ertapenem against bacterial pathogens from patients with acute pelvic infection. J Antimicrob Chemother 2002; 50:735-41.

18. Wexler HM, Molitoris D, Finegold SM. In Vitro Activities of MK-826 (L-749,345) against 363 Strains of Anaerobic Bacteria. Antimicrob Agents Chemother 2000; 44:2222-4.

19. Mazuski JE, Sawyer RG, Nathens AB, Dipiro JT, Schein M, Kudsk KA, Yowler C. The Surgical Infection Society Guidelines on Antimicrobial Therapy for Intra-Abdominal Infections: An Executive Summary. Surgical Infections 2002; 3: 161-73.

20. Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004; 39:885-910.

21. Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE, Abramson MA. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial The Lancet 2005; 366:1695-703.

22. Lavery LA, Armstrong DG, Harkless LB, Classification of diabetic foot wounds. J. Foot Ankle Surg 1996; 35:528-31.

References from the National Committee for Clinical Laboratory Standards

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Sixth Edition. Approved Standard NCCLS Document M7- A6, Vol. 20, No. 2 NCCLS, Wayne, PA, January 2003.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. Eight Edition. Approved Standard NCCLS Document M2- A8, Vol. 20, No. 1 NCCLS, Wayne, PA, January 2003.

3. National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria, Fifth Edition. NCCLS Document M11-A 5, Vol. 17, No. 22 NCCLS, Wayne, PA, December 2001.

4. Performance Standards for Antimicrobial Susceptibility Testing of Anaerobic bacteria: Informational Supplement. M100-S13 (M11) NCCLS, Wayne, PA, January 2003.

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrINVANZ(r)

ertapenem sodium for injection

This leaflet is part III of a three-part "Product Monograph" published when INVANZ(r) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about INVANZ(r). Contact your physician or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Your physician has prescribed INVANZ(r) to treat one of the following infections:

Intra-abdominal infection

Skin infection, including diabetic foot infections in adults

Community acquired pneumonia

Urinary tract infection, including kidney infection

Acute pelvic infection

Prevention of surgical site infections following surgery of the colon or rectum in adults

What it does:

INVANZ(r) is an antibiotic that has the ability to kill a wide range of bacteria that cause infections.

When it should not be used:

You or your child should not receive INVANZ(r) intravenously if you:

are allergic to any of its ingredients (See, What the important nonmedicinal ingredients are.)

are allergic to beta-lactams, such as penicillins or

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Serious and occasionally fatal allergic reactions (anaphylaxis) have been reported in patients taking other beta-lactam antibiotics

such as penicillins and cephalosporins and could occur for INVANZ(r).

Seizures and other central nervous system adverse effects have been reported during treatment with INVANZ(r) and occurred most frequently in patients with central nervous system disorders (brain lesions, history of seizures) and/or kidney disorders.

BEFORE you or your child use INVANZ(r) talk to your physician or pharmacist about any medical condition you or your child has now or has had including:

kidney disease in order that your physician prescribes the correct dose of INVANZ(r)

allergies to any drugs, including antibiotics

colitis or any other gastrointestinal disease

are pregnant as INVANZ(r) has not been studied in pregnant women. INVANZ(r) should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

are breast-feeding as INVANZ(r) is secreted in human milk.

As the breast-fed baby may be affected, women who are receiving INVANZ(r) should not breast-feed. If you intend to breast-feed, talk to you physician.

history of seizures or other brain disorders

Children

INVANZ(r) can be given to children 3 months of age and older. However, it is not approved for prevention of surgical site infections following

cephalosporins

surgery of the colon or rectum in children. INVANZ

is not

You or your child should not receive INVANZ(r) intramuscularly if you:

are allergic to any of its ingredients (See, What the important nonmedicinal ingredients are.)

are allergic to beta-lactams, such as penicillins or cephalosporins

are allergic to local anesthetics of the amide type, particularly lidocaine hydrochloride, which is used during intramuscular administration of INVANZ(r).

What the medicinal ingredient is:

Ertapenem sodium is the active ingredient.

What the important nonmedicinal ingredients are: INVANZ(r) contains the following inactive ingredients: sodium bicarbonate and sodium hydroxide.

What dosage forms it comes in:

INVANZ(r) is supplied as a sterile lyophilized powder in single dose glass vials containing 1g of ertapenem as free acid for intravenous infusion or for intramuscular injection.

recommended in children under 3 months of age as no data are available.

INTERACTIONS WITH THIS MEDICATION

In general, INVANZ(r) can be used with other drugs. No specific clinical interaction studies have been conducted with INVANZ(r), other than probenecid. You should tell your physician about all drugs that you or your child is taking or plans to take, including those obtained without a prescription, as some drugs may affect each other's action.

Probenecid may interact with the actions of ertapenem and should not be taken with INVANZ(r).

PROPER USE OF THIS MEDICATION

Usual dose:

INVANZ(r) may be infused into a vein (intravenous infusion) or injected into a muscle (intramuscular injection). When

administered intravenously, INVANZ(r) should be infused over a

period of 30 minutes.

How much INVANZ(r) should I receive?

INVANZ(r) will be given to you or your child by a physician or another healthcare professional who will determine the most

appropriate method and dose.

How long do I need to receive INVANZ(r)?

It is very important that you or your child continues to receive INVANZ(r) for as long as your physician prescribes it.

Your physician will let you know when you or your child may stop receiving INVANZ(r).

Overdose:

The injection schedule will be set by your physican, who will monitor your response and condition to determine what treatment

is needed. However, if you are concerned that you or your child may have been given too much INVANZ(r), contact your physician or another healthcare professional immediately.

Missed Dose:

The injection schedule will be set by your physician, who will

monitor your response and condition to determine what treatment is needed. However, if you are concerned that you or your child may have missed a dose, contact your physician or another healthcare professional immediately.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Any medicine may have unintended or undesirable effects, so- called side effects. The most common side effects in adults are diarrhea, inflammation of the vein, nausea, and headache.

Other side effects in adults include: irritation of the vein at the infusion site, vomiting, rash, vaginitis, dizziness, sleepiness, sleeplessness, seizure, confusion, swelling at injection site, low blood pressure, slow heart rate, shortness of breath, oral thrush, constipation, acid regurgitation, dry mouth, indigestion, loss of appetite, skin redness, itching, severe allergic reactions (anaphylaxis), abdominal pain, fungal infections, abnormal taste, fatigue, swelling of the lower limbs, feeling unwell, fever, pain, chest pain, vaginal itching, and alterations in some laboratory blood tests.

Side effects in children are generally similar to those in adults. The most common side effects in children are diarrhea, pain and redness at the infusion site. If you develop severe diarrhea while taking INVANZ(r), contact your doctor as this may be a sign of a serious condition.

Other side effects in children include: inflammation of the vein at the infusion site, vomiting, rash, swelling, formation of a lump, itching and warmth at the infusion site, inflammation of the vein and alterations in some laboratory blood tests.

Some people may have other reactions. If you notice any unusual effect, check with your physician or pharmacist.

HOW TO STORE IT

Store the dry powder at room temperature below 25degC.

Please consult the Product Monograph for information on storage periods for reconstituted solutions.

Keep INVANZ(r) and all medicines safely away from children.

Consumer Information - INVANZ(r) Page 74 of 75 IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this vaccine you may notify Health Canada by:

Toll-free telephone: 1-866-234-2345

Toll-free fax: 1-866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

or Merck Frosst Canada Ltd. by: Toll-free telephone: 1-800-567-2594

Toll-free fax: 1-877-428-8675 By regular mail:

Merck Frosst Canada Ltd.

P.O. Box 1005

Pointe-Claire - Dorval, QC H9R 4P8

NOTE: Before contacting Health Canada or Merck Frosst, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.merckfrosst.com

or by contacting the sponsor, Merck Frosst Canada Ltd., at: 1-800-567-2594,

This leaflet was prepared by Merck Frosst Canada Ltd. Last revised: October 24, 2007

INVANZ(r) is a Registered Trademark of Merck & Co., Inc. Used under license.