Ertapenem for Injection (Eugia Pharma) Product Monograph

RECENT MAJOR LABEL CHANGES

N/A

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ......................................................................................... 2

TABLE OF CONTENTS ........................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ................................................................... 5

1 INDICATIONS .................................................................................................................... 5

1.1 Pediatrics .......................................................................................................................... 6

1.2 Geriatrics .......................................................................................................................... 6

2 CONTRAINDICATIONS ....................................................................................................... 7

3 SERIOUS WARNINGS AND PRECAUTIONS BOX .................................................................. 7

4 DOSAGE AND ADMINISTRATION ....................................................................................... 8

4.2 Recommended Dose and Dosage Adjustment ................................................................. 8

4.3 Reconstitution ................................................................................................................ 10

4.4 Administration ................................................................................................................ 12

4.5 Missed Dose ................................................................................................................... 12

5 OVERDOSAGE ................................................................................................................. 12

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING...................................... 13

7 WARNINGS AND PRECAUTIONS ...................................................................................... 13

7.1 Special Populations......................................................................................................... 16

7.1.1 Pregnant Women .................................................................................................. 16

7.1.2 Breast-feeding ....................................................................................................... 16

7.1.3 Pediatrics ............................................................................................................... 16

7.1.4 Geriatrics ............................................................................................................... 17

8 ADVERSE REACTIONS ...................................................................................................... 17

8.1 Adverse Reaction Overview .......................................................................................... 17

8.2 Clinical Trial Adverse Reactions ..................................................................................... 17

8.2.1 Clinical Trial Adverse Reactions – Pediatrics .............................................................. 18

8.3 Less Common Clinical Trial Adverse Reactions ............................................................. 19

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics ....................................... 21

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................................ 21

8.5 Post-Market Adverse Reactions ..................................................................................... 23

9 DRUG INTERACTIONS ..................................................................................................... 23

9.2 Drug Interactions Overview ........................................................................................... 23

9.3 Drug-Behavioural Interactions ....................................................................................... 23

9.4 Drug-Drug Interactions ................................................................................................... 24

9.5 Drug-Food Interactions .................................................................................................. 24

9.6 Drug-Herb Interactions ................................................................................................... 24

9.7 Drug-Laboratory Test Interactions ................................................................................. 24

10 CLINICAL PHARMACOLOGY ........................................................................................... 24

10.1 Mechanism of Action ................................................................................................... 24

10.2 Pharmacodynamics ...................................................................................................... 25

10.3 Pharmacokinetics ......................................................................................................... 25

11 STORAGE, STABILITY AND DISPOSAL ............................................................................. 36

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................... 36

PART II: SCIENTIFIC INFORMATION .................................................................................... 37

13 PHARMACEUTICAL INFORMATION ................................................................................ 37

14 CLINICAL TRIALS............................................................................................................ 37

14.1 Clinical Trials by Indication ........................................................................................... 37

Adult Patients ....................................................................................................................... 37

Complicated Intra-Abdominal Infections ............................................................................. 37

Diabetic Foot Infections ....................................................................................................... 40

Community Acquired Pneumonia ........................................................................................ 42

Complicated Urinary Tract Infections Including Pyelonephritis .......................................... 43

Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post-Surgical Gynecologic Infections ............................................................................................. 44

Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery ..................... 46

Pediatric Patients.................................................................................................................. 48

14.2 Comparative Bioavailability Studies ............................................................................. 49

15 MICROBIOLOGY ............................................................................................................ 49

16 NON-CLINICAL TOXICOLOGY ......................................................................................... 60

17 SUPPORTING PRODUCT MONOGRAPHS ........................................................................ 73

PATIENT MEDICATION INFORMATION ............................................................................... 74

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Treatment

ERTAPENEM FOR INJECTION (ertapenem monosodium) is indicated for the treatment of patients with the following moderate to severe infections caused by susceptible strains of the designated microorganisms (see 4 DOSAGE AND ADMINISTRATION).

• Complicated intra-abdominal infections due to Escherichia coli, Clostridium clostridioforme, Eubacteriumlentum, Peptostreptococcus species, Bacteroidesfragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides uniformis, or Bacteroides thetaiotaomicron.

• Complicated skin and skin structure infections due to Staphylococcus aureus

  (methicillin- susceptible strain only), Streptococcus pyogenes, Escherichia coli and Peptostreptococcus species, as well as, diabetic foot infections due to Staphylococcus aureus (methicillin-susceptible strain only) and Peptostreptococcus species. Ertapenem has not been studied in diabetic foot infections with concomitant osteomyelitis or severe ischemia (see 14 CLINICAL TRIALS).

• Community acquired pneumonia due to Streptococcus pneumoniae (penicillin-susceptible strain only), Haemophilus influenzae (β-lactamase negative strain only), or Moraxella catarrhalis.

• Complicated urinary tract infections including pyelonephritis due to Escherichia coli,

  Klebsiella pneumoniae or Proteusmirabilis.

• Acute pelvic infections including postpartum endomyometritis, septic abortion and post-surgical gynecologic infections due to Streptococcus agalactiae, Escherichia coli, Peptostreptococcus species, Bacteroides fragilis, Porphyromonas asaccharolytica, or Prevotella species.

Prevention

ERTAPENEM FOR INJECTION is indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ERTAPENEM FOR INJECTION and other antibacterial drugs, ERTAPENEM FOR INJECTION should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to ertapenem. Initial therapy with ERTAPENEM FOR INJECTION may be instituted empirically for the treatment of bacterial infections, including mixed infections, while awaiting the results of these tests. Once these results become available, antimicrobial therapy should be adjusted accordingly.

1.1 Pediatrics

Pediatrics (3 months - 17 years of age): Safety and effectiveness of ertapenem 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 7 WARNINGS AND PRECAUTIONS, 7.1.3 Pediatrics and 14 CLINICAL TRIALS, Pediatric Patients):

• Complicated Intra-Abdominal Infections
• Complicated Skin and Skin Structure Infections
• Community Acquired Pneumonia
• Complicated Urinary Tract Infections
• Acute Pelvic Infections

ERTAPENEM FOR INJECTION is not recommended in the treatment of meningitis in the pediatric population due to lack of sufficient cerebrospinal fluid (CSF) penetration.

Pediatrics (< 3 months of age): ERTAPENEM FOR INJECTION is not recommended in infants under 3 months of age as no data are available. Therefore, Health Canada has not authorized an indication for this population.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): In clinical studies, the efficacy and safety of ertapenem 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 7 WARNINGS AND PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION).

2 CONTRAINDICATIONS

ERTAPENEM FOR INJECTION (ertapenem monosodium) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Due to the use of lidocaine HCl as a diluent, ERTAPENEM FOR INJECTION 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).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) AND

  OTHER

  SERIOUS SKIN REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS, INCLUDING ERTAPENEM (see 7 WARNINGS AND PRECAUTIONS, Immune and 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Drug Reactions

• Seizures and other CNS (Central Nervous System) adverse experiences, have been reported during treatment with ertapenem. 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 7 WARNINGS AND PRECAUTIONS, Neurologic, Renal and 8 ADVERSE REACTIONS).
• Case reports in the literature have shown that co-administration of carbapenems, including ertapenem, to patients receiving valproic acid or divalproex sodium results in a reduction in serum valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. In some cases of co-administration of ertapenem with valproic acid, breakthrough seizures have occurred. Increasing the dose of valproic acidor divalproex sodium may not be sufficient to overcome this interaction.
• The concomitant use of ertapenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of ERTAPENEM FOR INJECTION is necessary, supplemental anti-convulsant therapy should be considered (see 9 DRUG INTERACTIONS).

4 DOSAGE AND ADMINISTRATION

4.2 Recommended Dose and Dosage Adjustment

The recommended dose of ERTAPENEM FOR INJECTION (ertapenem) in patients 13 years of age and older is 1 gram (g) given once a day. The recommended dose of ERTAPENEM FOR INJECTION in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1 g/day).

Table 1 presents treatment guidelines for ERTAPENEM FOR INJECTION.

Table 1: Daily Treatment Guidelines for Adult and Pediatric Patients with Normal Renal Function*

Infection†

Patients

13 years of

age and

older

Patients 3 months to

12 years of age

Recommended

Duration of Total Antimicrobial Treatment Complicated Intra-abdominal Infections 1 g daily 15 mg/kg/dose

to a maximum of 500 mg twice daily^§

5 to 14 days

Complicated Skin and Skin Structure

Infections

1 g daily 15 mg/kg/dose

to a maximum of 500 mg twice daily§

7 to 14 days

Diabetic foot infections 1 g daily

(patients

≥ 18 years

old only)

not applicable 5 to 28 days‡

Community Acquired Pneumonia 1 g daily 15 mg/kg/dose

to a maximum of 500 mg twice daily§

10 to 14 days‡

Complicated Urinary Tract Infections

including pyelonephritis

1 g daily 15 mg/kg/dose

to a maximum of 500 mg twice daily§

10 to 14 days‡

Acute Pelvic Infections including

postpartum endomyometritis, septic

abortion and post-surgical gynecologic

infections

1 g daily 15 mg/kg/dose

to a maximum of 500 mg twice daily§

3 to 10 days

* Defined as creatinine clearance > 90 mL/min/1.73 m2.

† Due to the designated pathogens (see 1 INDICATIONS).

‡ Dura on includes a possible switch to an appropriate oral therapy once clinical improvement has been demonstrated.

§ Not to exceed 1 g/day.

Special Populations

Patients with Renal Insufficiency

ERTAPENEM FOR INJECTION 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 (International System of Units (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 ≤ 10 mL/min/1.73 m² (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 10 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 ERTAPENEM FOR INJECTION within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended following the hemodialysis session. If ERTAPENEM FOR INJECTION 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 (μ mol/L)

Females: (0.85) x (value calculated for males)

Patients with Hepatic Impairment

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

No dosage adjustment recommendation can be made in patients with impaired hepatic function (see 10 CLINICAL PHARMACOLOGY, Hepatic Insufficiency and 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

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 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions and 7.1.3 Pediatrics).

Prevention

Table 2 presents prophylaxis guidelines for ERTAPENEM FOR INJECTION.

Table 2: Prophylaxis Guidelines for Adults

Indication Daily Dose

(IV)

Adults

Recommended Duration of Total Antimicrobial Treatment

Prophylaxis of surgical site

infection following elective

colorectal surgery*

1 g Single intravenous dose given 1 hour prior to the surgical incision

* Limited data are available in patients with advanced renal insufficiency (creatinine clearance ≤ 30 mL/min/1.73 m² [SI = ≤ 0.5 mL/s/1.73 m²]) (see 8 ADVERSE REACTIONS, Prevention, Patients with Renal Insufficiency).

4.3 Reconstitution

Parenteral Products:

Patients 13 years of age and older

Preparation for Intravenous Administration:

DO NOT MIX OR CO-INFUSE ERTAPENEM FOR INJECTION WITH OTHER MEDICATIONS.

DO NOT USE DILUENTS CONTAINING DEXTROSE (α D-GLUCOSE).

ERTAPENEM FOR INJECTION MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION.

• Reconstitute the contents of a 1 g vial of ERTAPENEM FOR INJECTION 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.
• 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.
• The reconstituted IV solution should be used within 6 hours after preparation. Preparation for Intramuscular Administration:

ERTAPENEM FOR INJECTION MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION.

• Reconstitute the contents of a 1 g vial of ERTAPENEM FOR INJECTION 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.

• 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).

• 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 ERTAPENEM FOR INJECTION WITH OTHER MEDICATIONS.

DO NOT USE DILUENTS CONTAINING DEXTROSE (α D-GLUCOSE).

ERTAPENEM FOR INJECTION MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO ADMINISTRATION.

• Reconstitute the contents of a 1 g vial of ERTAPENEM FOR INJECTION 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.
• 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).
• The reconstituted IV solution should be used within 6 hours after preparation. Discard unused portion of the vial.

Preparation for Intramuscular Administration:

ERTAPENEM FOR INJECTION MUST BE RECONSTITUTED PRIOR TO ADMINISTRATION.

• Reconstitute the contents of a 1 g vial of ERTAPENEM FOR INJECTION 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.

• 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.

^∗ ** Refer to the prescribing information for lidocaine HCl

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 ERTAPENEM FOR INJECTION 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.

4.4 Administration

ERTAPENEM FOR INJECTION may be administered by intravenous infusion or intramuscular injection. When administered intravenously, ERTAPENEM FOR INJECTION should be infused over a period of 30 minutes.

Intramuscular administration of ERTAPENEM FOR INJECTION may be used as an alternative to intravenous administration in the treatment of those infections for which intramuscular therapy is appropriate.

4.5 Missed Dose

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

5 OVERDOSAGE

No specific information is available on the treatment of over dosage with ERTAPENEM FOR INJECTION (ertapenem monosodium). Intentional overdosing of ERTAPENEM FOR INJECTION is unlikely. Intravenous administration of ERTAPENEM FOR INJECTION 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, ERTAPENEM FOR INJECTION should be discontinued and general supportive treatment given until renal elimination takes place.

ERTAPENEM FOR INJECTION can be removed by hemodialysis; however, no information is available on the use of hemodialysis to treat over dosage.

For management of a suspected drug overdose, contact your regional poison control centre. 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 3: Dosage Forms, Strengths, Composition and Packaging

ERTAPENEM FOR INJECTION (ertapenem) is supplied as a sterile lyophilized powder in single dose glass vials. Each vial contains 1.046 grams Ertapenem Monosodium equivalent to 1 gram Ertapenem.

Each vial of ERTAPENEM FOR INJECTION contains the following non- medicinal ingredients: sodium hydrogen carbonate and sodium hydroxide. The sodium content is 130.15 mg - 178.1 mg.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

As with other antibiotics, prolonged use of ERTAPENEM FOR INJECTION may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If super infection occurs during therapy, appropriate measures should be taken.

Caution should be taken when administering ERTAPENEM FOR INJECTION intramuscularly to avoid inadvertent injection into a blood vessel (see 4 DOSAGE AND ADMINISTRATION, 4.4 Administration)

Lidocaine HCl is the diluent for intramuscular administration of ERTAPENEM FOR INJECTION Refer to the Product Monograph for lidocaine HCl for additional precautions.

Gastrointestinal

Clostridium difficile-associated disease

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including ertapenem. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic mega colon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see 8 ADVERSE REACTIONS).

Hepatic/Biliary/Pancreatic

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.

Immune

Hypersensitivity

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) AND OTHER SERIOUS SKIN REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING BETA-LACTAM ANTIBIOTICS, INCLUDING ERTAPENEM. 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. CROSS-REACTIVITIES BETWEEN BETA- LACTAM ANTIBIOTICS HAVE BEEN CLEARLY DOCUMENTED. BEFORE INITIATING THERAPY WITH ERTAPENEM FOR INJECTION (ertapenem) CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO ERTAPENEM FOR INJECTION 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 (see 2 CONTRAINDICATIONS and 8 ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Monitoring and Laboratory Tests

While ertapenem 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.

Neurologic

During clinical investigations in adult patients treated with ertapenem (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 8 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 ERTAPENEM FOR INJECTION re-examined to determine whether it should be decreased or the antibiotic discontinued (see 8 ADVERSE REACTIONS).

Renal

Dosage adjustment of ERTAPENEM FOR INJECTION is recommended in patients with reduced renal function (see 4 DOSAGE AND ADMINISTRATION). A supplementary dose may be recommended in patients following hemodialysis (see 4 DOSAGE AND ADMINISTRATION, Patients on Hemodialysis).

Reproductive Health: Female and Male Potential

• Fertility

  Insufficient clinical data are available to inform on drug-associated risks to fertility. Fertility studies were performed in rats. In the female fertility study in rats, there were no treatment-related effects on mating, fertility, or fecundity indices, or embryonic/fetal survival. In the male fertility study in rats, 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 (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).

• Function

  Insufficient data are available to inform on drug-associated risks to sexual desire, erection, orgasm or ejaculation.

• Teratogenic Risk

  Available data from a small number of post-marketing cases with ertapenem use in pregnancy are insufficient to inform any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see 7.1.1 Pregnant Women). Developmental toxicity studies were performed in rats and mice. There were no drug-related effects in rats at any dose level tested. In mice, the developmental toxicity study showed slight decreases in average fetal weight and an associated decrease in the number of ossified sacrocaudal vertebrae at 700 mg/kg/day. The no- effect level in mice for developmental toxicity was 350 mg/kg/day, which is approximately 1.5-fold the typical human dose based on body surface area (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology)

Sensitivity/Resistance

Development of Drug Resistant Bacteria

Prescribing ERTAPENEM FOR INJECTION in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

Skin

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported in association with beta-lactam treatment. When SCAR is suspected, ERTAPENEM FOR INJECTION should be discontinued and appropriate therapy and/or measures should be taken.

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate and well-controlled studies in pregnant women. ERTAPENEM FOR INJECTION should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

7.1.2 Breast-feeding

Ertapenem is excreted in human milk. ERTAPENEM FOR INJECTION should be administered to nursing mothers only when the potential benefit outweighs the potential risk (see 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics).

7.1.3 Pediatrics

Pediatrics (3 months - 17 years of age): Safety and effectiveness of ertapenem 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 1 INDICATIONS, 4 DOSAGE AND ADMINISTRATION and 14 CLINICAL TRIALS, Pediatric Patients):

• Complicated Intra-Abdominal Infections
• Complicated Skin and Skin Structure Infections
• Community Acquired Pneumonia
• Complicated Urinary Tract Infections
• Acute Pelvic Infections

ERTAPENEM FOR INJECTION is not recommended in the treatment of meningitis in the pediatric population due to lack of sufficient cerebrospinal fluid (CSF) penetration.

Pediatrics (< 3 months of age): ERTAPENEM FOR INJECTION is not recommended in infants under 3 months of age as no data are available. Therefore, Health Canada has not authorized an indication for this population.

7.1.4 Geriatrics

Geriatrics (≥ 65 years of age): In clinical studies, the efficacy and safety of ertapenem 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 4 DOSAGE AND ADMINISTRATION).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Adult Patients

The total number of patients treated with ertapenem in clinical studies was over 1900 of which over 1850 received a 1 g dose of ertapenem. Most adverse experiences reported in these clinical studies were described as mild to moderate in severity. Drug-related adverse experiences were reported in approximately 20% of patients treated with ertapenem. Ertapenem was discontinued due to adverse experiences thought to be drug-related in 1.3% of patients.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adult Patients

Table 4 shows the incidence of drug-related adverse experiences reported during parenteral therapy.

Table 4: Incidence (%) of Drug-Related Adverse Experiences* Reported During Parenteral Therapy in ≥ 1.0% of Adult Patients Treated with Ertapenem in Clinical Studies

Adverse Events Ertapenem

1 g daily (N=1866)

Piperacillin/ Tazobactam 3.375 g q6h (N=775)

Ceftriaxone

1 or 2 g daily

(N=912) Gastrointestinal disorders:

Diarrhea

Nausea

Vomiting

4.3

2.9

1.0

6.6

3.2

1.5

3.7 2.6 0.9 General disorders and administration site conditions:

Infused vein complication

3.9

5.5

4.3 Nervous system disorders:

Headache

2.1

1.0

2.2 Vascular disorders:

Phlebitis/thrombophlebitis

1.3

1.3

1.4 * Determined by the investigator to be possibly, probably, or definitely drug-related.

In clinical studies, seizure was reported during parenteral therapy in 0.2% of patients treated with ertapenem, 0.3% of patients treated with piperacillin/tazobactam and 0% of patients treated with ceftriaxone.

Prevention (prophylaxis of surgical site infection following elective colorectal surgery)

In a clinical study for the prophylaxis of surgical site infections following elective colorectal surgery in which 476 adult patients received a 1 g dose of ertapenem and 476 adult patients received a 2 g dose of cefotetan prior to surgery, the following additional (i.e., in addition to Adverse Experiences listed in Table 4) drug-related adverse experience was reported with an incidence of ≥ 1.0% (common): wound infection (1.7% for patients treated with ertapenem and 2.1% for patients treated with cefotetan).

Patients with Renal Insufficiency

There are limited data in adults patients with renal insufficiency from the study of prophylaxis of surgical site infection following elective colorectal surgery. In a clinical study in which 476 treated patients received a 1 g dose of ertapenem 1 hour prior to surgery, the AE profile observed in five patients with creatinine clearance ≤ 30 mL/min/1.73 m2 is consistent with their underlying renal condition and/or having just undergone major elective colorectal surgery.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

The total number of pediatric patients treated with ertapenem in clinical studies was 384. The overall safety profile is comparable to that in adult patients. In clinical trials, the most common drug-related clinical adverse experiences reported during parenteral therapy were diarrhea (5.5%), infusion site pain (5.5%) and infusion site erythema (2.6%).

Table 5 shows the incidence of drug-related adverse experiences reported during parenteral therapy.

Table 5: Incidence (%) of Drug-Related Adverse Experiences* Reported During Parenteral

Therapy in ≥ 1.0% of Pediatric Patients Treated with Ertapenem in Clinical Studies

Adverse Events

* Determined by the investigator to be possibly, probably or definitely drug-related.

In the pediatric clinical studies, the majority of the patients had parenteral therapy followed by a switch to an appropriate oral antimicrobial (see 14 CLINICAL TRIALS). During the entire treatment period and a 14 day post-treatment follow-up period, drug-related adverse experiences reported with an incidence of ≥ 1.0% in patients treated with ertapenem were no different than those listed in Table 5.

8.3 Less Common Clinical Trial Adverse Reactions

Adults

Table 6 lists the less common drug-related adverse experiences that were reported during parenteral therapy with ertapenem within each body system.

Table 6: Less Common Clinical Trial Adverse Drug Reactions (< 1%) in Adult Patients

Prevention (prophylaxis of surgical site infection following elective colorectal surgery)

The following additional (i.e., in addition to Adverse Experiences listed in Table 6) drug-related adverse experiences were reported with an incidence of < 1.0% (uncommon) as listed below:

Cardiac disorders: Sinus bradycardia

Infections and infestations: Cellulitis, clostridial infection, Clostridium colitis, postoperative infection.

Injury and poisoning: Wound complication.

Skin and sub cutaneous tissue disorders: Erythematous rash, urticaria. 8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

Additional drug-related adverse experiences that were reported during parenteral therapy with ertapenem with an incidence of > 0.2% but < 1% in pediatric studies within each body system are listed below in Table 7:

Table 7: Less Common Clinical Trial Adverse Drug Reactions (> 0.2% but < 1%) in Pediatric Patients

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Adult Patients

Table 8 shows the most frequently observed drug-related laboratory abnormalities during parenteral therapy in patients receiving ertapenem.

Table 8: Incidence* (%) of Specific Drug-Related Laboratory Adverse Experiences Reported During Parenteral Therapy in ≥ 1.0% of Adult Patients Treated With Ertapenem in Clinical Studies

Laboratory adverse experiences Ertapenem

1 g daily n†=1766

Piperacillin/Tazobactam

3.375 g q6h

n†=750

Ceftriaxone

1 or 2 g daily n†=870

Chemistry:

ALT ↑ 5.5 4.4 4.9 AST ↑ 4.8 4.5 4.2 Alkaline phosphatase ↑ 2.9 3.9 1.4 Hematology:

Platelet count ↑ 2.0 3.9 0.4 * Number of patients with laboratory adverse experiences/Number of patients with the laboratory test; where at least 1516 patients had the test.

† Number of pa ents with one or more laboratory tests.

Other drug-related laboratory abnormalities that were reported during parenteral therapy in > 0.1% but < 1.0% of patients treated with ertapenem in clinical studies included the following:

Chemistry: increases in direct serum bilirubin, total serum bilirubin, indirect serum bilirubin, BUN, serum creatinine, serum glucose.

Hematology: increases in eosinophils, PTT, monocytes; decreases in segmented neutrophils, white blood cells, hematocrit, hemoglobin and platelet count.

Urinalysis: increases in urine bacteria, urine epithelial cells, urine red blood cells.

In the majority of clinical studies, parenteral therapy was followed by a switch to an appropriate oral antimicrobial (see 14 CLINICAL TRIALS). During the entire treatment period and a 14-day post- treatment follow-up period, drug-related laboratory abnormalities in patients treated with ertapenem were no different than those listed in Table 8.

Prevention (prophylaxis of surgical site infection following elective colorectal surgery)

The following additional (i.e., in addition to adverse experiences listed in the Abnormal Laboratory Findings Section) drug related laboratory adverse experiences were reported with an incidence of < 1.0% (uncommon): increases in white blood cells and prothrombin time (PT). Pediatrics

Table 9 shows the most frequently observed drug-related laboratory abnormality during parenteral therapy in patients receiving ertapenem.

Table 9: Incidence* (%) of Specific Drug-Related Laboratory Adverse Experiences Reported During Parenteral Therapy in ≥ 1.0% of Pediatric Patients Treated With Ertapenem in Clinical Studies

Laboratory adverse

experiences

Ertapenem (N†=384)

Ceftriaxone

(N†=100)

Ticarcillin/clavulanate

(N†=24)

Chemistry:

ALT ↑ 1.9 0.0 4.3 AST ↑ 1.9 0.0 4.3 Hematology:

Neutrophil count ↓ 2.5 1.1 0.0 * Number of patients with laboratory adverse experiences/Number of patients with the laboratory test; where at least 300 patients had the test.

† Number of pa ents with one or more laboratory tests.

Additional drug-related laboratory adverse experiences that were reported during parenteral therapy in > 0.5% but < 1.0% of pediatric patients treated with ertapenem in clinical studies include: increase in eosinophils.

Post-Market Findings

Not applicable.

8.5 Post-Market Adverse Reactions

The following additional post-marketing adverse experiences have been reported:

Gastrointestinal Disorders: teeth staining.

Immune System: anaphylaxis including anaphylactoid reactions.

Musculoskeletal and Connective Tissue Disorders: muscular weakness.

Nervous System Disorders: depressed level of consciousness, dyskinesia, gait disturbance, myoclonus, tremor, encephalopathy (recovery was prolonged in patients with renal impairment).

Psychiatric Disorders: altered mental status (e.g., aggression, agitation, confusion/confusional state, delirium, disorientation, mental status changes), hallucinations.

Skin and Subcutaneous Tissue Disorders: Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), hypersensitivity vasculitis.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

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 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics). In vitro studies indicate that ertapenem, over its therapeutic concentration range, has little effect on the unbound fraction of warfarin in human plasma.

9.3 Drug-Behavioural Interactions

No formal drug-behavioural interaction studies were conducted with ertapenem.

9.4 Drug-Drug Interactions

Probenecid

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 μg•hr/mL and mean AUC0-∞ of total ertapenem without probenecid is 616.2 μg•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.

Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including ertapenem, to patients receiving valproic acid or divalproex sodium results in a reduction of serum valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. In some cases of co- administration of ertapenem with valproic acid, breakthrough seizures have occurred. The mechanism of this interaction is unknown (see 7 WARNINGS AND PRECAUTIONS).

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Ertapenem 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 15 MICROBIOLOGY).

10.2 Pharmacodynamics

See 15 MICROBIOLOGY.

10.3 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 (μg/mL) and mean AUC_0-∞ 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 10.

Table 10: Plasma Concentrations and Mean AUC_0-∞ of Total Ertapenem After Single Dose Administration in Healthy Young Adults

Route/Dose Average Plasma Concentrations (μg/mL) AUC_0-∞

(μg·hr/mL) 0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 18 hr 24 hr IV 1 g* 155 115 83 48 31 20 9 3 1 572 IV 2 g* 283 202 145 86 58 36 16 5 2 1011 IM 1 g 33 53 67 57 40 27 13 4 2 555 * IV doses were infused at a constant rate over 30 minutes.

Mean AUC0-∞ values (μg·hr/mL) of unbound ertapenem for intravenous doses of 1 g and 2 g are 33.2 and 76.6, respectively.

Average plasma concentrations (µg/mL) of ertapenem in pediatric patients are presented in Table 11.

Table 11: Plasma Concentrations of Ertapenem in Pediatric Patients After Single IV* Dose Administration

Age Group

(Dose)

Average Plasma Concentrations (μg/mL)

0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr 3 to 23 months

(15 mg/kg)†

(20 mg/kg)†

(40 mg/kg)‡

103.8 126.8 199.1

57.3

87.6

144.1

43.6

58.7

95.7

23.7

28.4

58.0

13.5

-

-

8.2 12.0 20.2

2.5 3.4 7.7

-

0.4 0.6 2 to 12 years

(15 mg/kg)†

(20 mg/kg)†

(40 mg/kg)‡

113.2 147.6 241.7

63.9

97.6

152.7

42.1

63.2

96.3

21.9

34.5

55.6

12.8

-

-

7.6 12.3 18.8

3.0 4.9 7.2

-

0.5 0.6 13 to 17 years

(20 mg/kg)†

(1 g)§

(40 mg/kg)‡

170.4 155.9 255.0

98.3

110.9

188.7

67.8

74.8

127.

9

40.4

-

76.2

-

24.0

-

16.0

-

31.0

7.0 6.2 15.3

1.1

-

2.1

* IV doses were infused at a constant rate over 30 minutes

† up to a maximum dose of 1g/day

‡ up to a maximum dose of 2 g/day

§ Based on three patients receiving 1 g ertapenem who volunteered for pharmacokinetic assessment in one of the two safety and efficacy studies

Absorption

Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (in saline without epinephrine), is 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 C_max = 70.6 µg/mL) are reached in approximately 2 hours (mean T_max = 2.2 hours) (see Table 10).

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 (μg)/mL to approximately 85% protein bound at an approximate plasma concentration of 300 μg/mL.

The apparent volume of distribution (V_dss) 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 12. The ratio of AUC0-24hr of total ertapenem in skin blister fluid to AUC0-24hr of total ertapenem in plasma is 0.61.

Table 12: Concentrations (μg/mL) of Total Ertapenem in Adult Skin Blister Fluid at Each Sampling Point on the Third Day of 1 g Once Daily IV Doses

0.5 hr 1 hr 2 hr 4 hr 8 hr 12 hr 24 hr 7 12 17 24 24 21 8

The concentration of ertapenem in breast milk 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 μg/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 μg/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 9 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 9 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.

Elimination

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 μg/mL during the period 0 to 2 hours post dose and exceed 52 μg/mL during the period 12 to 24 hours post dose.

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 10 CLINICAL PHARMACOLOGY, 10.3 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.

• Sex: 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 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Metabolism and Elimination). 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/1.73m²)) 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/1.73m²)) 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/1.73m²)) 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 4 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 ERTAPENEM FOR INJECTION within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended following the hemodialysis session (see 4 DOSAGE AND ADMINISTRATION).

  Table 13 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 13: 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

Pharmacokinetic

Parameter

Pooled

Control*

Mild

RI†

Moderate

RI†

Advanced

RI†

End-Stage RI

Total drug

AUC0-∞

(μg•hr/mL)

665.9 712.2 1016.5 1719.9 1941.5

GMR‡ -- 1.1 1.5 2.6 2.9 Unbound drug

AUC0-∞

(μg•hr/mL)

42.5 44.2 76.1 144.6 252.7

GMR -- 1.0 1.8 3.4 6.0 * Pooled Control: Healthy young adult and healthy elderly subjects.

† Mild RI = Cl_cr 60–90 mL/min/1.73 m²; Moderate RI = Cl_cr 31–59 mL/min/1.73 m²; Advanced RI= Cl_cr 5–30 mL/min/1.73 m²; End-Stage RI = Cl_cr < 10 mL/min/1.73 m². ‡ GMR = Geometric Mean Ra o of RI/Pooled Control.

Human Pharmacology

In Vivo Pharmacokinetics

Table 14: Clinical Pharmacology and Bio pharmaceutics Studies

An open-label, single IV

dose study in healthy male and female subjects.

Subjects received 1 g

14C-ertapenem IV, followed by the collection of blood samples for up to 48 hours post dose and urine samples for up to 168 hours post dose, for the measurement of ertapenem and radioactivity. Stool samples were also collected at specified times up to 168 hours post dose for the recovery of radioactivity.

1g ¹⁴C-ertapenem

Approximately 104 μCi of radioactivity per dose

20 mg/mL

¹⁴C-ertapenem (n=7)

7/7 S

(3F, 4 M/4B, 2C, 1H)

The plasma radioactivity consists predominantly of ertapenem (approximately 94%) after IV infusion of radiolabeled 1 g ertapenem. The recovery of total radioactivity in urine and feces indicates that the majority (approximately 80%) of the dose is excreted in urine and only a small percent (approximately 10%) is eliminated by biliary/fecal excretion. Mass balance is achieved after a single IV dose. Ertapenem and its ring- opened metabolite, L-774183, together account for about 95% of the radioactivity excreted in urine, each in turn accounting for about half of this. Several other minor radioactive components are detected in urine, each of which accounts for approximately 1% or less of the administered dose. An open-label, 2-period study to evaluate the pharmacokinetics, safety, and tolerability of

ertapenem in patients with defined degrees of renal function. In Period 1, ertapenem was administered as a single

30-minute IV dose of 1 g in 4 groups of patients. The

4 groups of renal insufficiency (RI) were: mild, moderate, advanced, and end stage. For end- stage RI patients, Period 1 was defined as a non-dialysis day.

In Period 2, patients with end-stage RI received a single 1 g dose of ertapenem immediately prior to the initiation of hemodialysis.

1 g

(n=6 mild; n=7 moderate; n=6 advanced; n=7 end- stage RI)

RI based on

creatinine

clearances in the following ranges: 60 to 90 mL/min/1.73 m² (mild RI), 31 to 59 mL/min/1.73 m² (moderate RI), 5 to 30 mL/min/1.73 m² (advanced RI), and < 10 mL/min/1.73 m²

(for patients with end- stage RI who were on

hemodialysis).

26/24 P^§

(13F, 11M/11B, 11C, 1H, 1NA)

Plasma concentrations of ertapenem are increased in patients with end-stage RI following a single 1 g IV dose as reflected by an AUC increase of approximately 2.9-fold relative to the pooled control group of healthy young adult and elderly subjects. A dosage adjustment to 0.5 g once daily is recommended for the standard dose (instead of 1 g). Plasma concentrations of ertapenem are increased in patients with advanced RI following a single 1 g IV dose as reflected by an AUC increase of approximately 2.6-fold relative to the pooled control group. A dosage adjustment to 0.5 g daily is recommended for the standard dose (1 g). Plasma concentrations of ertapenem are similar

(approximately 1.5- fold increase for AUC_0-∞) in patients with moderate RI relative to the pooled control group following a single 1 g IV dose. No dosage adjustment is recommended for the standard

dose. Plasma concentrations of ertapenem following a single 1 g IV dose are similar in patients with mild RI relative to the pooled control group. No dosage adjustment is recommended for the standard dose. Plasma concentrations of total

ertapenem are decreased in patients with end-stage RI following a single 1 g IV dose given immediately prior to a hemodialysis session relative to the dose given on a non-dialysis day and approximately 30% of the dose is recovered in the dialysate. If the ertapenem dose is given at least 6 hours prior to

hemodialysis, a supplementary

^† 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.

^§ 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.

11 STORAGE, STABILITY AND DISPOSAL

Before Reconstitution

Store lyophilized powder between 15°C and 25°C.

Reconstituted and Infusion Solutions

The reconstituted solution, immediately diluted in 0.9% Sodium Chloride Injection (see 4.4 DOSAGE AND ADMINISTRATION, Administration), may be stored at room temperature (25°C) and used within 6 hours or stored for 24 hours under refrigeration (5°C) and used within 4 hours after removal from refrigeration. Solutions of ERTAPENEM FOR INJECTION (ertapenem monosodium) should not be frozen (see 4.3 DOSAGE AND ADMINISTRATION, Reconstitution).

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ertapenem Monosodium

Chemical name: (4R,5S,6S)-3-[[(3S,5S)-5-[[(3- CARBOXYPHENYL)-AMINO]CARBONYL]-3- PYRROLIDINYL]THIO]-6-[(1R)-1- HYDROXYETHYL]-4-METHYL-7-OXO-1- AZABICYCLO[3.2.0]HEPT-2-ENE-2- CARBOXYLIC ACID SODIUM SALT

Molecular formula and molecular mass: C₂₂H₂₄N₃O₇SNa and 497.50 g/mol

Structural formula:

Physicochemical properties: Ertapenem monosodium is a white to off-white hygroscopic powder. Freely soluble in water and 0.9% sodium chloride solution and practically insoluble in ethanol. Ertapenem monosodium exhibits polymorphism. pH is in between 5.0 and 6.8.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Adult Patients

Complicated Intra-Abdominal Infections

Table 15: Summary of Patient Demographics for the Pivotal Trial in Complicated Intra-Abdominal Infections

Results

Table 16: Clinical and Microbiological Success Rates in Complicated Intra-Abdominal Infections for Study 017

Ertapenem

n/N (%)

Comparator n/N (%)

95% CI for the difference

At 1 to 2 weeks post

therapy

190/212 (89.6%) 162/196 (82.7%) --

4 to 6 weeks post

therapy (Test of Cure)†

176/203 (86.7%) 157/193 (81.2%) (-2.2, 13.1)

Test of Cure (Stratum

1)

85/94 (90.4%) 82/91 (90.1%) --

Test of Cure (Stratum

2)

91/109 (83.5%) 75/102 (73.5%) --

† Percentages and the 95% CI for study 017 (Test of Cure) were computed from a sta s cal model adjus ng for strata

Table 17: Clinical Success Rates at the Test of Cure by Pathogen for Microbiologically Evaluable Adult Patients with Complicated Intra-Abdominal Infections for Study 017 Pathogen Ertapenem

% (n/N)*

Comparator

% (n/N)*

Escherichia coli 86.7 (137/158) 80.0 (108/135) Clostridium clostridioforme 89.5 (17/19) 90.5 (19/21) Eubacterium lentum 90.5 (19/21) 83.3 (10/12) Peptostreptococcus species 80.6 (29/36) 88.5 (23/26) Bacteroides fragilis 82.9 (63/76) 82.4 (56/68) Bacteroides distasonis 78.9 (15/19) 96.0 (24/25) Bacteroides ovatus 95.2 (20/21) 90.9 (20/22) Bacteroides uniformis 95.5 (21/22) 90.5 (19/21) Bacteroides thetaiotaomicron 87.2 (41/47) 85.3 (29/34) * Number of isolates with favorable response assessment/Total number of isolates

Complicated Skin and Skin Structure Infections

Table 18: Summary of Patient Demographics for the Pivotal Trial in Complicated Skin and Skin Structure Infections

Study # Trial design Treatments: Dosage,

route of

administration

and duration

Number of patients

Age range Gender

(males/ females)

016 randomized,

multicenter, double-blind, controlled clinical trial.

ertapenem (1 g IV once a day)

for 7 to 14 days

versus

540

patients*

18–99 351/189 piperacillin/tazobactam (3.375 g IV every

6 hours)

for 7 to 14 days

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

Results

Table 19: Clinical Success Rates at the Test of Cure in Complicated Skin and Skin Structure Infections for Study 016

Ertapenem

n/N (%)

Comparator

n/N (%)

95% CI for the

difference

10 to 21 days post

therapy (Test of

Cure)†

152/185 (82.4%) 147/174 (84.4%) (-10.2, 6.2)

Deep soft tissue

abscess

29/30 (96.7%) 34/36 (94.4%) --

Posttraumatic

wound infection

25/30 (83.3%) 22/26 (84.6%) --

Cellulitis with

purulent drainage

27/29 (93.1%) 21/24 (87.5%) --

† Percentages and the 95% CI for study 016 (Test of Cure) were computed from a sta s cal model adjus ng for strata.

Table 20: 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

Pathogen Ertapenem

% (n/N)*

Comparator

% (n/N)* Staphylococcus aureus 76.1 (54/71) 78.9 (56/71) Streptococcus pyogenes 81.3 (13/16) 93.8 (15/16) Escherichia coli 94.1 (16/17) 80.0 (12/15) Peptostreptococcus species 87.1 (27/31) 90.9 (20/22) * Number of isolates with favorable response assessment/Total number of isolates.

Diabetic Foot Infections

Table 21: Summary of Patient Demographics for the Clinical Trial in Diabetic Foot Infections

Study # Trial design Treatments:

Dosage, route of

administration and duration*

Number of

patients

Mean age

(Range)

Gender (males/ females

034 multicenter,

randomized,

double- blind,

clinical trial

conducted in

the US.

ertapenem (1 g intravenously once a day)

versus

586 patients** Mean: 59.2

(22–94)

Ertapenem was evaluated in adults

treated for 28 days or less for diabetic foot infections

without

concomitant osteomyelitis. The large

majority of patients had non-ischemic grade 1 and 2 diabetic foot infections

graded

according to the Texas

Health

Sciences

Centre

classification system.

piperacillin/

tazobactam

(3.375 g

intravenously

every 6 hours).

* 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 if 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.

Results

Table 22: Clinical Success Rates at the Test of Cure* in Diabetic Foot Infections for Study 034 Ertapenem n/N (%) Comparator n/N (%) 95 % CI 10 days post therapy

(Test of Cure)

153/204 (75.0%) 143/202 (70.8%) (-4.5, 12.8)

* 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 post therapy.

Table 23: Clinical Success Rates at the Post therapy Visit by Pathogen for Clinically Evaluable

Adult Patients with Diabetic Foot Infections for Study 034

Pathogen Ertapenem

% (n/N)*

Comparator

% (n/N)* Staphylococcus aureus

(MSSA)**

70.8 (51/72) 71.0 (49/69)

Peptostreptococcus species 78.7 (48/61) 68.5 (37/54) * n/N = Number of pathogens with associated favorable assessment/number of pathogens with an assessment.

** MSSA = Methicillin sensitive Staphylococcus aureus.

Community Acquired Pneumonia

Table 24: 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).

Results

Table 25: Clinical Success Rates at the Test of Cure in Community Acquired Pneumonia for Combined Studies 018 and 020

Ertapenem

n/N (%)

Comparator

n/N (%)

95% CI for the difference 7 to 14 days post

therapy (Test of Cure)†

335/364 (91.9%) 270/294 (92.0%) (-4.5, 4.4)

† 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 26: 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

* Number of isolates with favorable response assessment/Total number of isolates.

Complicated Urinary Tract Infections Including Pyelonephritis

Table 27: 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).

Results

Table 28: 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 29: 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

* Number of isolates with favorable response assessment/Total number of isolates.

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

Table 30: Summary of Patient Demographics for the Pivotal Clinical Trial in Acute Pelvic

Infections Including Postpartum Endomyometritis, Septic Abortion and Post-Surgical Gynecologic Infections

Results

Table 31: 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 sta s cal model adjusting for strata.

Table 32: Clinical Success Rates at the Test of Cure by Pathogen for Microbiologically Evaluable Adult Patients with Acute Pelvic Infections for Study 023

* Number of isolates with favorable response assessment/Total number of isolates.

Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery

Table 33: Summary of Patient Demographics for the Clinical Trial in Colorectal Surgical Prophylaxis (Evaluable Population)

† This study included 500 patients randomized to ertapenem and 502 patients randomized to cefotetan. To be in the evaluable cohort, a patient must have received a complete dose of study therapy infused over 30 minutes within 2 hours prior to incision and within 6 hours of surgical closure with adequate time for completion of bowel preparation prior to surgery. Adequate bowel preparations included: osmotic oral bowel preparations containing polyethylene glycol solutions or oral sodium phosphate preparations. For the primary analysis, patients with documented surgical site infections, in addition to those with post- operative anastomotic leak or unexplained antibiotic use, were considered to have failed prophylaxis.

Results

Table 34: Proportion of Patients with Favorable Clinical Response Assessment at 4-Weeks Post- Treatment (Evaluable Popula on)(Es mated†) for Study 039

†Percents, confidence intervals and p-values were calculated from a methodology proposed by Miettinen and Nurminen, accounting for the surgical procedure performed (intraperitoneal procedure or abdominoperineal resection) using Cochran-Mantel-Haenszel weights. The treatment by surgical procedure interaction was not significant (p>0.10). N = Number of evaluable patients in each treatment group.

n = Number of evaluable patients with a favorable clinical response assessment in each treatment group. CI = Confidence interval.

Table 35: Proportion of Patients with Favorable Clinical Response Assessment at 4-Weeks Post- Treatment Displayed by Surgical Procedure (Evaluable Population) for Study 039

N = Number of evaluable patients in each treatment group.

n/m = Number of evaluable patients with favorable assessment / number of evaluable patients with assessment.

CI = Confidence Interval.

Table 36: Proportion of Patients with Favorable Clinical Response Assessment at 4-Weeks Post Treatment (MITT Popula on)(Es mated†) for Study 039

† Percents, confidence intervals and p-values were calculated from a methodology proposed by

Miettinen and Nurminen, accounting for the surgical procedure performed (intraperitoneal procedure or abdominoperineal resection) using Cochran-Mantel-Haenszel weights. The treatment by surgical procedure interaction was not significant (p>0.10).

MITT = Modified Intent To Treat.

N = Number of MITT qualified patients in each treatment group.

n = Number of MITT qualified patients with a favorable clinical response assessment in each treatment group. CI = Confidence interval.

Table 37: Proportion of Patients who Failed Prophylaxis at 4-Weeks Post-Treatment Displayed by Reason for Failure (Evaluable Population) for Study 039

† Percents, confidence intervals and p-values were calculated from a methodology proposed by Miettinen and Nurminen, accounting for the surgical procedure performed (intraperitoneal procedure or abdominoperineal resection) using Cochran-Mantel-Haenszel weights. The treatment by surgical procedure interaction was not significant (p>0.10).

‡ Sta s cal test for treatment difference was significant (p<0.001).

N = Number of evaluable patients in each treatment group. n = Number of evaluable patients within failure category.

CI = Confidence interval.

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), intra-abdominal infections (IAI) and acute pelvic infections (API).

Table 38: Summary of Patient Demographics for Clinical Trials in Pediatric Patients

† Study 036 allowed the op on to switch to oral amoxicillin/clavulanate a er at least 3 days of parenteral therapy if clinical response criteria were met, for a total of up to 14 days of treatment (parenteral and oral). Study 038 did not allow for an oral switch; suggested parenteral treatment duration was 3–14 days for API and 5–14 days for IAI.

‡ Number of patients that received at least 1 dose of parenteral study therapy.

Results:

Table 39: 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)

Disease Stratum Ertapenem

% (n/N)

Comparator

% (n/N)

CAP 96.1 (74/77) 96.4 (27/28) UTI 87.0 (40/46) 90.0 (18/20) SSTI 95.5 (64/67) 100 (26/26) IAI‡ 83.7 (36/43) 63.6 (7/11) API§ 100 (23/23) 100 (4/4) † A favorable clinical response rate is displayed for SSTI, CAP, IAI, and API. A favorable microbiological response rate is displayed for UTI.

‡ Included pa ents with perforated or complicated appendici s.

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

14.2 Comparative Bioavailability Studies

Not applicable.

15 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)

Ertapenem

MIC,

μg/mL

Organism

N Range MIC50 MIC90

Aerobic Gram-positive

Corynebacterium spp. 34 0.008 to 32 0.5 32 Enterococcus faecalis 595 0.06 to > 64 8 16 Enterococcus faecium 211 0.125 to 64 32 32 Enterococcus gallinarum 16 8 to > 64 16 32 Enterococcus spp. 32 0.125 to 32 16 16 Staphylococcus aureus (Methicillin-Susceptible*) 618 ≤ 0.008 to 4 0.125 0.25 Staphylococcus aureus (Methicillin-Resistant*) 210 0.125 to > 32 16 32 Staphylococcus spp. 75 ≤ 0.016 to 4 0.5 2 Staphylococcus, coagulase-negative (Methicillin-

Susceptible*)

373 0.03 to > 32 0.25 2

Staphylococcus, coagulase-negative (Methicillin-

Resistant*)

404 0.06 to > 32 8 32

Streptococcus agalactiae 269 0.008 to > 16 0.06 0.06 Streptococcus beta-hemolytic 82 0.008 to 0.5 0.03 0.25 Streptococcus milleri group 36 0.008 to 4 0.125 0.25 Streptococcus pneumoniae (Penicillin-Sensitive†) 475 0.004 to

0.125

0.016 0.03

Streptococcus pneumoniae (Penicillin-Intermediate†) 132 0.008 to 1 0.25 0.5 Streptococcus pneumoniae (Penicillin-Resistant†) 149 0.12 to 4 1 2 Streptococcus pyogenes 317 0.004 to 2 0.008 0.016 Streptococcus viridans 42 ≤ 0.016 to 8 0.125 1 Streptococcus viridans group 66 ≤ 0.016 to 4 0.25 2 Streptococcus spp. 37 ≤ 0.008 to 4 0.06 2 Aerobic Gram-negative

Achromobacter xylosoxidans 15 0.06 to 0.5 0.125 0.5 Acinetobacter anitratus 12 2 to 8 4 8 Acinetobacter baumannii 104 0.5 to > 32 8 16 Acinetobacter spp. 26 ≤ 0.016 to >

16

4 8

Aeromonas hydrophila 11 0.03 to 0.5 0.06 0.25 Burkholderia cepacia 18 4 to 32 16 32 Citrobacter diversus 33 0.008 to

0.125

0.008 0.016

Citrobacter freundii 190 0.008 to > 8 0.016 0.25 Citrobacter koserii 72 ≤ 0.008 to 2 0.008 0.016 Enterobacter aerogenes 168 ≤ 0.008 to >

32

0.06 0.25

Enterobacter cloacae 245 ≤ 0.008 to 32 0.06 1

Escherichia coli 741 0.008 to 0.5 0.016 0.016 Haemophilus influenzae 493 ≤ 0.008 to

0.5

0.03 0.06

Haemophilus parainfluenzae 76 ≤ 0.008 to 1 0.03 0.125 Haemophilus species (not influenzae) 40 0.008 to 0.5 0.016 0.25 Klebsiella oxytoca 169 ≤ 0.008 to 4 0.008 0.03 Klebsiella pneumoniae 460 0.008 to 32 0.016 0.03 Morganella morganii 142 ≤ 0.008 to 2 0.03 0.06 Moraxella catarrhalis 221 0.004 to 0.25 0.008 0.016 Neisseria gonorrhoeae 20 0.004 to 0.03 0.008 0.03 Neisseria meningitidis 42 0.008 to 0.03 0.008 0.03 Pasteurella multocida 24 0.008 to 0.03 0.016 0.03 Proteus mirabilis 192 0.008 to 0.25 0.016 0.03 Proteus vulgaris 52 0.008 to 0.06 0.016 0.03 Providencia rettgeri 36 0.008 to

0.125

0.03 0.06

Providencia stuartii 50 0.016 to 8 0.06 0.125 Pseudomonas aeruginosa (IPM-Sensitive) 233 0.125 to > 32 4 16 Pseudomonas aeruginosa (IPM-Resistant) 131 0.5 to > 32 16 32 Pseudomonas spp. 41 0.008 to 32 8 32 Salmonella group A 48 0.008 to 0.06 0.008 0.008 Salmonella typhimurium (B) 23 0.008 to 0.03 0.008 0.008 Salmonella spp. 71 0.008 to

0.120

0.008 0.03

Serratia marcescens 132 0.008 to 32 0.03 0.125 Serratia spp. 43 0.016 to 0.25 0.03 0.125 Shigella sonnei 27 0.008 0.008 0.008 Shigella spp. 35 0.008 to 0.5 0.008 0.016 Stenotrophomonas maltophilia 66 1 to 32 32 32 Anaerobes

Actinomyces israelii 11 0.06 to 2 0.125 1 Actinomyces odontolyticus 36 0.06 to 4 0.5 0.5 Actinomyces viscosus 15 0.06 to 1 0.125 0.5 Actinomyces spp. 15 0.008 to 2 0.25 1 Anaerobiospirillum thomasii 15 0.016 to 0.03 0.016 0.016 Bacteroides caccae 13 0.125 to 2 1 1 Bacteroides capillosus 12 0.03 to 0.25 0.06 0.25 Bacteroides distasonis 39 0.125 to 8 1 8 Bacteroides fragilis 206 0.016 to > 16 0.25 2 Bacteroides ovatus 55 0.25 to 8 1 2 Bacteroides tectum 17 0.016 to 0.25 0.03 0.125 Bacteroides thetaiotaomicron 92 0.06 to 4 1 2 Bacteroides uniformis 23 0.12 to 2 1 2 Bacteroides vulgatus 35 0.03 to 8 0.25 1 Bacteroides spp. 69 0.016 to > 16 0.125 1 Bilophila wadsworthia 22 0.016 to > 32 0.125 16 Campylobacter gracilis 11 0.016 to 0.25 0.06 0.125

Clostridium bifermentans 12 0.016 to

0.125

0.06 0.06

Clostridium butyricum 12 0.125 to 1 0.25 0.25 Clostridium cadaveris 11 0.008 to

0.016

0.016 0.0158

Clostridium clostridioforme 13 0.125 to 4 1 2 Clostridium difficile 39 0.004 to 8 1 4 Clostridium innocuum 20 0.008 to 8 2 4 Clostridium perfringens 57 0.004 to

0.125

0.03 0.125

Clostridium ramosum 18 0.25 to 2 1 2 Clostridium spp. 27 0.016 to 1 0.125 0.5 Eubacterium lentum 28 0.25 to 2 1 1 Fusobacterium mortiferum 11 0.06 to 0.125 0.06 0.125 Fusobacterium naviforme 10 0.016 0.016 0.016 Fusobacterium russii 12 0.016 to 0.03 0.016 0.0158 Fusobacterium varium 15 0.016 to 0.06 0.06 0.06 Fusobacterium spp. 14 0.008 to 2 0.25 0.5 Gardnerella vaginalis 11 0.06 to 2 0.125 2 Lactobacillus spp. 29 0.03 to > 32 1 16 Peptostreptococcus micros 12 0.016 to 0.06 0.03 0.06 Peptostreptococcus tetradius 30 ≤ 0.004 to 4 0.04 1 Porphyromonas canoris 10 0.016 0.016 0.016 Porphyromonas gingivalis 14 0.016 0.016 0.016 Porphyromonas macacae 15 0.016 to 0.03 0.016 0.03 Prevotella bivia (Bacteroides bivus) 14 0.016 to 0.5 0.125 0.25 Prevotella heparinolytica 14 0.06 to 0.25 0.125 0.125 Prevotella melaninogenica 12 0.03 to 0.5 0.125 0.5 Prevotella oralis 12 0.06 to 1 0.125 1 Prevotella oris 13 0.03 to 0.5 0.125 0.25 Prevotella spp. 19 0.016 to 1 0.06 0.25 Propionobacterium acnes 25 0.03 to 4 0.125 0.25 Veillonella spp. 21 0.016 to 4 0.125 1 Total 9911 Aerobic Gram-positive 4173 Aerobic Gram-negative 4502 Anaerobes 1236 * As per the NCCLS the term “methicillin-resistant” when applied to the staphylococci has referred to resistance to the antistaphylococcal β-lactamase stable penicillins while “methicillin-sensitive” meant susceptibility to these agents. Oxacillin, and not methicillin, is currently the agent of choice for screening for these organisms but the term “methicillin-resistant” is still commonly used to describe them. Staphylococcus aureus strains with oxacillin MICs ≤ 2 μg/mL and coagulase-negative staphylococci with oxacillin MICs ≤ 0.25 μg/mL can be considered methicillin-susceptible staphylococci (MSS) while S. aureus strains with oxacillin MICs ≥ 4 μg/mL and coagulase-negative staphylococci ≥ 5 μg/mL can be considered methicillin-resistant staphylococci (MRS). † As per the NCCLS Streptococcus pneumoniae strains are considered penicillin-susceptible if their MICs to penicillin are ≤ 0.06 μg/mL; they are considered penicillin-intermediate if the penicillin MICs are between 0.12 and 1 μg/mL and penicillin-resistant if their penicillin MICs are ≥ 2 μg/mL.

Table 41: Ratios of MBC to MIC in Broth (Inoculum 10⁵ CFU/mL)

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 β-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 β-lactamase or significant amounts of β-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 ESβLs 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-β-lactam antimicrobials is not anticipated as β- 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 β-lactamase (ESβLs) and AmpC β-lactamase.

Table 42: In Vitro Activity of Ertapenem Against Strains Producing Extended Spectrum Beta-Lactamases (ESβLs) and AmpCbeta- Lactamases

.

ERTAPENEM FOR INJECTION Product Monograph Page 57 of 80

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 -70 °C, for at least 4 weeks at -20 °C, for at least 7 days at 4 °C and at 23° to 25 °C and for at least 2 to 3 days at 37 °C. The effects of incubation in MHB at 37 °C 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 ESβLs and/or AmpC β-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 μg/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 β- 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 β-lactamases (BDSβLs) 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 β-lactamase, ertapenem MICs at the lower inoculum ranged from ≤ 0.03 μg/mL to 0.12 μg/mL. At 10-fold higher inocula, increased MICs for ertapenem were noted against many of the strains containing BDSβLs and ESßLs; however, in all cases the ertapenem MIC values remained ≤ 2 μg/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-ERTAPENEM FOR INJECTION Product Monograph Page 58 of 80

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 µg/mL at the lower inoculum; at the higher inocula, the MIC90 of ertapenem increased to 1 µg/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 μg 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

ERTAPENEM FOR INJECTION Product Monograph Page 59 of 80

S = Susceptible; I = Intermediate; R = Resistant.

a 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.

b Isolates of Streptococcus pneumoniae should be tested against a 1 μg oxacillin disk. Isolates with oxacillin zone sizes of ≥ 20 mm are susceptible to penicillin and can be considered susceptible to ertapenem. c Streptococcus pneumoniae that are susceptible to penicillin (MIC ≤ 0.06 μg/mL) and Streptococcus spp. other than S. pneumoniae that are susceptible to penicillin (MIC ≤ 0.12 μg/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.

d 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.

e 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 35 °C for 20–24 hrs. f 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 35 °C for 16–18 hrs. g 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 35–37 °C 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.

ERTAPENEM FOR INJECTION Product Monograph Page 60 of 80

Table 44: Acceptable Quality Control (QC) Ranges for Ertapenem

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

i 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 35 °C for 20–24 hrs.

j 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% CO 2 at 35 °C for 20–24 hrs.

k 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 35 °C for 20–24 hrs. l 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% CO 2 at 35 °C for 16–18 hrs. m 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 35–37 °C for 42–48 hrs.

n Quality control ranges applicable for broth microdilution method.

ATCC® is a registered trademark of the American Type Culture Collection.

16 NON-CLINICAL TOXICOLOGY

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 ERTAPENEM FOR INJECTION Product Monograph Page 61 of 80

administration of a single 15 mg/kg IV dose of [14C] ertapenem, concentrations declined with time in all tissues (Table 45). At 0.5 hr post dose, the concentrations (radio equivalents) were highest in the liver, kidneys, small intestine, and plasma. The kidneys consistently contained the highest concentrations, which occurred most likely because ertapenem radio equivalents are eliminated primarily by renal excretion. With the exception of the kidney (~6 μg/g), ertapenem radio equivalent concentrations at 72 hr post dose had declined to less than 0.7 μg/g in all tissues.

Table 45: 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 post dose, 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 carrageen in 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 μM) 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 μM) 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 μM ertapenem, and no significant inhibition of microsomal squalene synthetase was observed at 25 μM 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.

Animal Toxicology

General 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^*). 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 46 reports long term (repeat-dose) studies in several species.

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

Table 46: Long-Term Toxicity

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.

Genotoxicity:

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.

Reproductive and Developmental Toxicology:

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 bodyweight 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).

17 SUPPORTING PRODUCT MONOGRAPHS

INVANZ® powder for solution, 1 g/vial, submission control 260091, Product Monograph, Merck Canada Inc. JUNE 3, 2022.