For Intravenous or Intramuscular Use

INVANZ

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

(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 span 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.

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

Table 1 Plasma Concentrations of Ertapenem in Adults After Single Dose Administration

	Average Plasma Concentrations (mcg/mL)
Dose/Route	0.5 hr	1 hr	2 hr	4 hr	6 hr	8 hr	12 hr	18 hr	24 hr
1 g IVInfused at a constant rate over 30 minutes	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 IVInfused at a constant rate over 30 minutes Dose Administration

Age Group	Dose	Average Plasma Concentrations (mcg/mL)
		0.5 hr	1 hr	2 hr	4 hr	6 hr	8 hr	12 hr	24 hr
3 to 23 months	15 mg/kgup to a maximum dose of 1 g/day	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/kgup to a maximum dose of 2 g/day	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 gBased on three patients receiving 1 g ertapenem who volunteered for pharmacokinetic assessment in one of the two safety and efficacy studies	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

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):

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.

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.

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.

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.)

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.

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.

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.

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

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

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

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

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

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

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

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.

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

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

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

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

INVANZ is not recommended in the treatment of meningitis in the pediatric population due to lack of sufficient CSF penetration.

Of the 1,835 patients in Phase IIb/III studies treated with INVANZ, approximately 26 percent were 65 and over, while approximately 12 percent were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See DOSAGE AND ADMINISTRATION.)

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

In repeat-dose studies in rats, treatment-related neutropenia occurred at every dose-level tested, including the lowest dose of 2 mg/kg (approximately 2% of the human dose on a body surface area basis).

Studies in rabbits and Rhesus monkeys were inconclusive with regard to the effect on neutrophil counts.

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

Table 6 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥1.0% of Adult Patients Treated With INVANZ in Clinical Studies

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

In patients treated for complicated intra-abdominal infections, death occurred in 4.7% (15/316) of patients receiving ertapenem and 2.6% (8/307) of patients receiving comparator drug. These deaths occurred in patients with significant co-morbidity and/or severe baseline infections. Deaths were considered unrelated to study drugs by investigators.

In clinical studies, seizure was reported during study therapy plus 14-day follow-up period in 0.5% of patients treated with ertapenem, 0.3% of patients treated with piperacillin/tazobactam and 0% of patients treated with ceftriaxone. (See PRECAUTIONS.)

Additional adverse experiences that were reported with INVANZ with an incidence >0.1% within each body system are uled below:

Body as a whole: abdominal distention, pain, chills, septicemia, septic shock, dehydration, gout, malaise, necrosis, candidiasis, weight loss, facial edema, injection site induration, injection site pain, flank pain, and syncope;

Cardiovascular System: heart failure, hematoma, cardiac arrest, bradycardia, arrhythmia, atrial fibrillation, heart murmur, ventricular tachycardia, asystole, and subdural hemorrhage;

Digestive System: gastrointestinal hemorrhage, anorexia, flatulence, C. difficile associated diarrhea, stomatitis, dysphagia, hemorrhoids, ileus, cholelithiasis, duodenitis, esophagitis, gastritis, jaundice, mouth ulcer, pancreatitis, and pyloric stenosis;

Nervous System & Psychiatric: nervousness, seizure (see WARNINGS and PRECAUTIONS), tremor, depression, hypesthesia, spasm, paresthesia, aggressive behavior, and vertigo;

Respiratory System: pleural effusion, hypoxemia, bronchoconstriction, pharyngeal discomfort, epistaxis, pleuritic pain, asthma, hemoptysis, hiccups, and voice disturbance;

Skin & Skin Appendage: sweating, dermatitis, desquamation, flushing, and urticaria;

Special Senses: taste perversion;

Urogenital System: renal insufficiency, oliguria/anuria, vaginal pruritus, hematuria, urinary retention, bladder dysfunction, vaginal candidiasis, and vulvovaginitis.

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

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

Table 7 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥1.0% of Adult Patients Treated With INVANZ for Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery

Adverse Events	INVANZ 1 g (N= 476)	Cefotetan 2 g (N= 476)
Anemia	5.7	6.9
Small intestinal obstruction	2.1	1.9
Cellulitis	1.5	1.5
C. difficile infection or colitis	1.7	0.6
Pneumonia	2.1	4.0
Postoperative infection	2.3	4.0
Urinary tract infection	3.8	5.5
Wound infection	6.5	12.4
Anastomotic leak	1.5	1.3
Seroma	1.3	1.9
Wound complication	2.9	2.3
Wound dehiscence	1.3	1.5
Wound secretion	1.9	2.1
Dysuria	1.1	1.3
Atelectasis	3.4	1.9

Additional adverse experiences that were reported in this prophylaxis study with INVANZ, regardless of causality, with an incidence <1.0% and >0.5% within each body system are uled below:

Gastrointestinal Disorders: dry mouth, hematochezia;

General Disorders and Administration Site Condition: crepitations;

Infections and Infestations: abdominal abscess, fungal rash, pelvic abscess;

Injury, Poisoning and Procedural Complications: incision site complication, incision site hemorrhage, intestinal stoma complication;

Musculoskeletal and Connective Tissue Disorders: muscle spasms;

Nervous System Disorders: cerebrovascular accident;

Renal and Urinary Disorders: pollakiuria;

Respiratory, Thoracic and Mediastinal Disorders: crackles lung, lung infiltration, pulmonary congestion, pulmonary embolism, wheezing.

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

Table 8 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥1.0% of Pediatric Patients Treated With INVANZ in Clinical Studies

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

Additional adverse experiences that were reported with INVANZ with an incidence <1.0% and >0.5% within each body system are uled below:

General Disorders and Administration Site Condition: chest pain, infusion site pruritus;

Infections and Infestations: candidiasis, ear infection, oral candidiasis;

Metabolism and Nutrition Disorders: decreased appetite;

Musculoskeletal and Connective Tissue Disorders: arthralgia;

Nervous System Disorders: somnolence;

Psychiatric Disorders: insomnia;

Reproductive System and Breast Disorders: genital rash;

Respiratory, Thoracic and Mediastinal Disorders: pleural effusion, rhinitis, rhinorrhea;

Skin and Subcutaneous Tissue Disorders: dermatitis atopic, rash erythematous, skin lesion;

Vascular Disorders: phlebitis.

The following post-marketing adverse experiences have been reported:

Immune System: anaphylaxis including anaphylactoid reactions

Nervous System & Psychiatric: hallucinations

No specific information is available on the treatment of overdosage with INVANZ. Intentional overdosing of INVANZ is unlikely. Intravenous administration of INVANZ at a dose of 2 g over 30 min or 3 g over 1-2h in healthy adult volunteers resulted in an increased incidence of nausea. In clinical studies in adults, inadvertent administration of three 1 g doses of INVANZ in a 24 hour period resulted in diarrhea and transient dizziness in one patient. In pediatric clinical studies, a single IV dose of 40 mg/kg up to a maximum of 2 g did not result in toxicity.

In the event of an overdose, INVANZ should be discontinued and general supportive treatment given until renal elimination takes place.

INVANZ can be removed by hemodialysis; the plasma clearance of the total fraction of ertapenem was increased 30% in subjects with end-stage renal insufficiency when hemodialysis (4 hour session) was performed immediately following administration. However, no information is available on the use of hemodialysis to treat overdosage.

The dose of INVANZ in patients 13 years of age and older is 1 gram (g) given once a day. The dose of INVANZ in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1 g/day). INVANZ may be administered by intravenous infusion for up to 14 days or intramuscular injection for up to 7 days. When administered intravenously, INVANZ should be infused over a period of 30 minutes.

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

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

Table 11 presents treatment guidelines for INVANZ.

Table 11 Treatment Guidelines for Adults and Pediatric Patients With Normal Renal Functiondefined as creatinine clearance >90 mL/min/1.73 m² and Body Weight

Infectiondue to the designated pathogens (see INDICATIONS AND USAGE)	Daily Dose (IV or IM) Adults and Pediatric Patients 13 years of age and older	Daily Dose (IV or IM) Pediatric Patients 3 months to 12 years of age	Recommended Duration of Total Antimicrobial Treatment
Complicated intra-abdominal infections	1 g	15 mg/kg twice dailynot to exceed 1 g/day	5 to 14 days
Complicated skin and skin structure infections, including diabetic foot infectionsINVANZ has not been studied in diabetic foot infections with concomitant osteomyelitis (See CLINICAL STUDIES).	1 g	15 mg/kg twice daily	7 to 14 daysadult patients with diabetic foot infections received up to 28 days of treatment (parenteral or parenteral plus oral switch therapy)
Community acquired pneumonia	1 g	15 mg/kg twice daily	10 to 14 daysduration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated.
Complicated urinary tract infections, including pyelonephritis	1 g	15 mg/kg twice daily	10 to 14 days
Acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecologic infections	1 g	15 mg/kg twice daily	3 to 10 days

Table 12 presents prophylaxis guidelines for INVANZ.

Table 12 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 surgical incision

Patients with RenalInsufficiency: INVANZ 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, no dosage adjustment is necessary. Adult patients with advanced renal insufficiency (creatinine clearance ≤30 mL/min/1.73 m²) and end-stage renal insufficiency (creatinine clearance ≤10 mL/min/1.73 m²) should receive 500 mg daily. There are no data in pediatric patients with renal insufficiency.

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

When only the serum creatinine is available, the following formula

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

may be used to estimate creatinine clearance. 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)

Patients with Hepatic Insufficiency: No dose adjustment recommendations can be made in patients with impaired hepatic function. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency and PRECAUTIONS.)

No dosage adjustment is recommended based on age (13 years of age and older) or gender. (SeeCLINICAL PHARMACOLOGY, Special Populations.)

Do not store lyophilized powder above 25°C (77°F).

The reconstituted solution, immediately diluted in 0.9% Sodium Chloride Injection (see DOSAGE AND ADMINISTRATION, PREPARATION OF SOLUTION) 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 INVANZ should not be frozen.

INVANZ is supplied as a sterile lyophilized powder in single dose vials containing ertapenem for intravenous infusion or for intramuscular injection as follows:

No. 3843—1 g ertapenem equivalent

NDC 0006-3843-71 in trays of 10 vials

No. 3843—1 g ertapenem equivalent

NDC 0006-3843-45 in trays of 25 vials.

Ertapenem was evaluated in pediatric patients 3 months to 17 years of age in two randomized, multicenter clinical trials. The first study enrolled 404 patients and compared ertapenem (15 mg/kg IV every 12 hours in patients 3 months to 12 years of age, and 1 g IV once a day in patients 13 to 17 years of age) to ceftriaxone (50 mg/kg/day IV in two divided doses in patients 3 months to 12 years of age and 50 mg/kg/day IV as a single daily dose in patients 13 to 17 years of age) for the treatment of complicated urinary tract infection (UTI), skin and soft tissue infection (SSTI), or community-acquired pneumonia (CAP). Both regimens allowed the option to switch to oral amoxicillin/clavulanate for a total of up to 14 days of treatment (parenteral and oral). The microbiological success rates in the evaluable per protocol (EPP) analysis in patients treated for UTI were 87.0% (40/46) for ertapenem and 90.0% (18/20) for ceftriaxone. The clinical success rates in the EPP analysis in patients treated for SSTI were 95.5% (64/67) for ertapenem and 100% (26/26) for ceftriaxone, and in patients treated for CAP were 96.1% (74/77) for ertapenem and 96.4% (27/28) for ceftriaxone.

The second study enrolled 112 patients and compared ertapenem (15 mg/kg IV every 12 hours in patients 3 months to 12 years of age, and 1 g IV once a day in patients 13 to 17 years of age) to ticarcillin/clavulanate (50 mg/kg for patients<60 kg or 3.0 g for patients >60 kg, 4 or 6 times a day) up to 14 days for the treatment of complicated intra-abdominal infections (IAI) and acute pelvic infections (API). In patients treated for IAI (primarily patients with perforated or complicated appendicitis) the clinical success rates were 83.7% (36/43) for ertapenem and 63.6% (7/11) for ticarcillin/clavulanate in the EPP analysis. In patients treated for API (post-operative or spontaneous obstetrical endomyometritis, or septic abortion) the clinical success rates were 100% (23/23) for ertapenem and 100% (4/4) for ticarcillin/clavulanate in the EPP analysis.

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Seventh Edition; Approved Standard, CLSI Document M7-A7. Clinical and Laboratory Standards Institute, Wayne, PA, January 2006.
• Clinical And Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing– Sixteenth Informational Supplement. Approved Standard, CLSI Document M100-S16. Clinical and Laboratory Standards Institute, Wayne, PA, January 2006.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests. Ninth Edition; Approved Standard, CLSI Document M2-A9. Clinical and Laboratory Standards Institute, Wayne, PA, January 2006.
• Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria– Sixth Edition; Approved Standard, CLSI Document M11-A6. Clinical and Laboratory Standards Institute, Wayne, PA, January 2004.

Manuf for: Merck & Co., Inc., Whitehouse Station, NJ 08889, USA

By: Laboratories Merck Sharp& Dohme-Chibret

63963 Clermont-Ferrand Cedex 9, France

US Patent Nos.: 5,478,820; 5,952,323; 5,652,233

Issued August 2006