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All about: Invanz

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Generic Name: ertapenem
Dosage Form: For injection

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

For Intravenous or Intramuscular Use

Invanz Description

Invanz1 (Ertapenem for Injection) is a sterile, synthetic, parenteral, 1-β methyl-carbapenem that is structurally related to beta-lactam antibiotics.

Chemically, Invanz is described as [4R-[3(3S *,5S*),4α,5β,6β(R *)]]-3-[[5-[[(3- carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt. Its molecular weight is 497.50. The empirical formula is C22H24N3O7SNa, and its structural formula is:

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

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

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

1

Registered trademark of MERCK & CO., Inc. COPYRIGHT © 2001, 2003, 2004, 2005 MERCK & CO., Inc. All rights reserved

Invanz - Clinical Pharmacology

Pharmacokinetics

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

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

The area under the plasma concentration-time curve (AUC) of ertapenem in adults increased less-than dose-proportional based on total ertapenem concentrations over the 0.5 to 2 g dose range, whereas the AUC increased greater-than dose proportional based on unbound ertapenem concentrations. Ertapenem exhibits non-linear pharmacokinetics due to concentration-dependent plasma protein binding at the proposed therapeutic dose. (See CLINICAL PHARMACOLOGY, Distribution.)

There is no accumulation of ertapenem following multiple IV or IM 1 g daily doses in healthy adults.

Average plasma concentrations (mcg/mL) of ertapenem in pediatric patients are presented in Table 2.

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

Absorption

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

Distribution

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

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

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

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

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

Metabolism

In healthy young adults, after infusion of 1 g IV radiolabeled ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the inactive ring-opened derivative formed by hydrolysis of the beta-lactam ring.

In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. (See Drug Interactions.)

In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport. (See PRECAUTIONS, Drug Interactions.)

Elimination

Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults is approximately 4 hours and the plasma clearance is approximately 1.8 L/hour. The mean plasma half-life in pediatric patients 13 to 17 years of age is approximately 4 hours and approximately 2.5 hours in pediatric patients 3 months to 12 years of age.

Following the administration of 1 g IV radiolabeled ertapenem to healthy young adults, approximately 80% is recovered in urine and 10% in feces. Of the 80% recovered in urine, approximately 38% is excreted as unchanged drug and approximately 37% as the ring-opened metabolite.

In healthy young adults given a 1 g IV dose, the mean percentage of the administered dose excreted in urine was 17.4% during 0-2 hours postdose, 5.4% during 4-6 hours postdose, and 2.4% during 12-24 hours postdose.

Special Populations

Renal Insufficiency

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

Hepatic Insufficiency

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

Gender

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

Geriatric Patients

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

Pediatric Patients

Plasma concentrations of ertapenem are comparable in pediatric patients 13 to 17 years of age and adults following a 1 g once daily IV dose.

Following the 20 mg/kg dose (up to a maximum dose of 1 g), the pharmacokinetic parameter values in patients 13 to 17 years of age (N=6) were generally comparable to those in healthy young adults.

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

Microbiology

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

Ertapenem has been shown to be active against most isolates of the following microorganisms in vitro and in clinical infections. (See INDICATIONS AND USAGE):

Aerobic and facultative gram-positive microorganisms:

Staphylococcus aureus (methicillin susceptible isolates only)
Streptococcus agalactiae
Streptococcus pneumoniae (penicillin susceptible isolates only)
Streptococcus pyogenes

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

Aerobic and facultative gram-negative microorganisms:

Escherichia coli
Haemophilus influenzae (Beta-lactamase negative isolates only)
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis

Anaerobic microorganisms:

Bacteroides fragilis
Bacteroides distasonis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Clostridium clostridioforme
Eubacterium lentum
Peptostreptococcus species
Porphyromonas asaccharolytica
Prevotella bivia

The following in vitro data are available, but their clinical significance is unknown.

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

Aerobic and facultative gram-positive microorganisms:

Staphylococcus epidermidis (methicillin susceptible isolates only)
Streptococcus pneumoniae (penicillin-intermediate isolates only)

Aerobic and facultative gram-negative microorganisms:

Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Enterobacter cloacae
Haemophilus influenzae (Beta-lactamase positive isolates)
Haemophilus parainfluenzae
Klebsiella oxytoca (excluding ESBL producing isolates)
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Serratia marcescens

Anaerobic microorganisms:

Bacteroides vulgatus
Clostridium perfringens
Fusobacterium spp.

Susceptibility Test Methods:

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

Dilution Techniques:

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

Diffusion Techniques:

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

Anaerobic Techniques:

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

Table 4 Susceptibility Interpretive Criteria for Ertapenem
*
The current absence of data in resistant isolates precludes defining any results other than“Susceptible”. Isolates yielding MIC results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing.
Streptococcus pneumoniae that are susceptible to penicillin (penicillin MIC ≤0.06 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.
Streptococcus pneumoniae that are susceptible to penicillin (1-μg oxacillin disk zone diameter ≥20 mm), can be considered susceptible to ertapenem. Isolates with 1-μg oxacillin zone diameter ≤19 mm should be tested against ertapenem using an MIC method.
§
Streptococcus spp. other than Streptococcus 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.
Streptococcus spp. other than Streptococcus pneumoniae that are susceptible to penicillin (10-units penicillin disk zone diameter ≥24 mm), can be considered susceptible to ertapenem. Isolates with 10-units penicillin disk zone diameter <24 mm should be tested against ertapenem using an MIC method. Penicillin disk diffusion interpretive criteria are not available for viridans group streptococci and they should not be tested against ertapenem.
Pathogen Minimum Inhibitory Concentrations*
MIC (μg/mL)
Disk Diffusion*
Zone Diameter (mm)
S I R S I R

Enterobacteriaceae and

Staphylococcus spp.
≤2.0 4.0 ≥8.0 ≥19 16-18 ≤15
Haemophilus spp. ≤0.5 - - ≥19 - -
Streptococcus pneumoniae, ≤1.0 - - ≥19 - -
Streptococcus spp. other than Streptococcus pneumoniae§, ≤1.0 - - ≥19 - -
 Anaerobes  ≤4.0 8.0 ≥16.0 - - -

Note: Staphylococcus spp. can be considered susceptible to ertapenem if the penicillin MIC is ≤0.12 µg/mL. If the penicillin MIC is >0.12 µg/mL, then test oxacillin. Staphylococcus aureus can be considered susceptible to ertapenem if the oxacillin MIC is ≤2.0 µg/mL and resistant to ertapenem if the oxacillin MIC is ≥4.0 µg/mL. Coagulase negative staphylococci can be considered susceptible to ertapenem if the oxacillin MIC is ≤0.25 µg/mL and resistant to ertapenem if the oxacillin MIC ≥0.5 µg/mL.

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

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

Quality Control

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

Table 5 Acceptable Quality Control Ranges for Ertapenem
*
Quality control ranges for broth microdilution testing
Quality control ranges for agar microdilution testing
Microorganism Minimum Inhibitory Concentrations
MIC Range (µg/mL)
Disk Diffusion
Zone Diameter (mm)
Escherichia coli ATCC 25922 0.004-0.016 29-36
Haemophilus influenzae ATCC 49766 0.016-0.06 27-33
Staphylococcus aureus ATCC 29213 0.06-0.25 -
Staphylococcus aureus ATCC 25923 - 24-31
Streptococcus pneumoniae ATCC 49619 0.03-0.25 28-35
Bacteroides fragilis ATCC 25285

0.06-0.5 *

0.06-0.25
-
Bacteroides thetaiotaomicron ATCC 29741

0.5-2.0 *

0.25-1.0 
-
Eubacterium lentum ATCC 43055

0.5-4.0 *

0.5-2.0 
-

Indications and Usage for Invanz

Treatment

Invanz is indicated for the treatment of patients with the following moderate to severe infections caused by susceptible isolates of the designated microorganisms. (See DOSAGE AND ADMINISTRATION):

Complicated Intra-abdominal Infections due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis.

Complicated Skin and Skin Structure Infections, including diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotella bivia. Invanz has not been studied in diabetic foot infections with concomitant osteomyelitis (see CLINICAL STUDIES).

Community Acquired Pneumonia due to Streptococcus pneumoniae (penicillin susceptible isolates only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates only), or Moraxella catarrhalis.

Complicated Urinary Tract Infections including pyelonephritis due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae.

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

Prevention

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

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

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

Contraindications

Invanz is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams.

Due to the use of lidocaine HCl as a diluent, Invanz administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type. (Refer to the prescribing information for lidocaine HCl.)

Warnings

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY REACTIONS WHEN TREATED WITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY WITH Invanz, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO Invanz OCCURS, DISCONTINUE THE DRUG IMMEDIATELY. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE, OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION. OTHER THERAPY MAY ALSO BE ADMINISTERED AS INDICATED.

Seizures and other CNS adverse experiences have been reported during treatment with Invanz. (See PRECAUTIONS and ADVERSE REACTIONS.)

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ertapenem, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

Lidocaine HCl is the diluent for intramuscular administration of Invanz. Refer to the prescribing information for lidocaine HCl.

Precautions

General

During clinical investigations in adult patients treated with Invanz (1 g once a day), seizures, irrespective of drug relationship, occurred in 0.5% of patients during study therapy plus 14-day follow-up period. (See ADVERSE REACTIONS.) These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function. Close adherence to the recommended dosage regimen is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of Invanz reexamined to determine whether it should be decreased or the antibiotic discontinued. Dosage adjustment of Invanz is recommended in patients with reduced renal function. (See DOSAGE AND ADMINISTRATION.)

As with other antibiotics, prolonged use of Invanz may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing Invanz in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Caution should be taken when administering Invanz intramuscularly to avoid inadvertent injection into a blood vessel. (See DOSAGE AND ADMINISTRATION.)

Lidocaine HCl is the diluent for intramuscular administration of Invanz. Refer to the prescribing information for lidocaine HCl for additional precautions.

Information for Patients

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

Laboratory Tests

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

Drug Interactions

When ertapenem is co-administered with probenecid (500 mg p.o. every 6 hours), probenecid competes for active tubular secretion and reduces the renal clearance of ertapenem. Based on total ertapenem concentrations, probenecid increased the AUC by 25% and reduced the plasma and renal clearances by 20% and 35%, respectively. The half-life increased from 4.0 to 4.8 hours. Because of the small effect on half-life, the coadministration with probenecid to extend the half-life of ertapenem is not recommended.

In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport. In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following six cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Drug interactions caused by inhibition of P-glycoprotein-mediated drug clearance or CYP-mediated drug clearance with the listed isoforms are unlikely. (See CLINICAL PHARMACOLOGY, Distribution and Metabolism.)

Other than with probenecid, no specific clinical drug interaction studies have been conducted.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Ertapenem was neither mutagenic nor genotoxic in the following in vitro assays: alkaline elution/rat hepatocyte assay, chromosomal aberration assay in Chinese hamster ovary cells, and TK6 human lymphoblastoid cell mutagenesis assay; and in the in vivo mouse micronucleus assay.

In mice and rats, IV doses of up to 700 mg/kg/day (for mice, approximately 3 times the recommended human dose of 1 g based on body surface area and for rats, approximately 1.2 times the human exposure at the recommended dose of 1 g based on plasma AUCs) resulted in no effects on mating performance, fecundity, fertility, or embryonic survival.

Pregnancy

Teratogenic Effects

Pregnancy Category B

In mice and rats given IV doses of up to 700 mg/kg/day (for mice, approximately 3 times the recommended human dose of 1 g based on body surface area and for rats, approximately 1.2 times the human exposure at the recommended dose of 1 g based on plasma AUCs), there was no evidence of developmental toxicity as assessed by external, visceral, and skeletal examination of the fetuses. However, in mice given 700 mg/kg/day, slight decreases in average fetal weights and an associated decrease in the average number of ossified sacrocaudal vertebrae were observed. Ertapenem crosses the placental barrier in rats.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

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

Labor and Delivery

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

Pediatric Use

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

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

Invanz is not recommended in infants under 3 months of age as no data are available.

Invanz is not recommended in the treatment of meningitis in the pediatric populatio

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Albalon Albalon
Generic Name: naphazoline ophthalmic (na FAZ oh leen) Brand Names: AK-Con, Albalon, Allerest Eye Drops, Clear Eyes, Degest 2, Estivin II, Nafazair, Naphcon, Naphcon Forte, VasoClear, Vasocon What is Albalon (naphazoline ophthalmic)? Naphazoline ophthalmic causes constriction of blood ve more...

Antihemophilic Factor/von Willebrand Factor (Human) Antihemophilic Factor/von Willebrand Factor (Human)
Generic Name: Antihemophilic Factor/von Willebrand Factor (Human) (AN-tee-hee-moe-FIL-ik FAK-tor/von WILL-a-brand FAK-tor) Brand Name: Humate-PAntihemophilic Factor/von Willebrand Factor (Human) is used for:Preventing and controlling bleeding in adult patients with hemophilia A. It is also used more...

Azelex Azelex
Generic Name: azelaic acid Dosage Form: Cream For Dermatologic Use Only Not for Ophthalmic Use Azelex Description Azelex® (azelaic acid cream) 20% contains azelaic acid, a naturally occurring saturated dicarboxylic acid. Structural Formula: HOOC-(CH2)7-COOH. Chemical Name: 1,7-heptanedicarbo more...

Crysticillin 300 A.S. Crysticillin 300 A.S.
Some commonly used brand names are: In the U.S.— Amoxil 1 Bactocill 11 Beepen-VK 13 Betapen-VK 13 Bicillin L-A 12 Cloxapen 5 Crysticillin 300 A.S. 12 Dynapen 6 Dycill 6 Geocillin 4 Geopen 4 Ledercillin VK 13 Mezlin 9 Nafcil 10 Nallpen 10 Omnipen 2 Omnipen-N 2 Pathocil 6 Pentids 12 Pen Vee more...

Danazol Danazol
Some commonly used brand names are: In the U.S.— Danocrine In Canada— Cyclomen Generic name product may be available in the U.S. Category Angioedema, hereditary, prophylactic Gonadotropin inhibitor Description Danazol (DA-na-zole) may be used for a number of different med more...

Iressa Iressa
Generic Name: gefitinib (geh FIH tih nib) Brand Names: Iressa What is gefitinib? Gefitinib is a cancer chemotherapy medication. Gefitinib interferes with the growth of cancer cells and slows their growth and spread in the body. Gefitinib is used in the treatment of non-small cell lung ca more...

Migergot Suppositories Migergot Suppositories
Generic Name: Caffeine/Ergotamine Suppositories (ka-FEEN/er-GOT-a-meen) Brand Name: Examples include Cafergot and MigergotSerious and sometimes life-threatening decreases in the blood supply to the extremities (eg, hands, feet) or brain may occur if Migergot Suppositories is taken with certain o more...

Polocaine-MPF Parenteral-Local Polocaine-MPF Parenteral-Local
Some commonly used brand names are: In the U.S.— Carbocaine 7 Carbocaine with Neo-Cobefrin 7 Chirocaine 5 Citanest Forte 8 Citanest Plain 8 Dalcaine 6 Dilocaine 6 Duranest 4 Duranest-MPF 4 Isocaine 7 L-Caine 6 Lidoject-1 6 Lidoject-2 6 Marcaine 2 Marcaine Spinal 2 Nesacaine 3 Nesacaine-MP more...