Indications and Usage

Treatment

INVANZ is indicated for the treatment of patients with the following moderate to severe infections caused by susceptible isolates of the designated microorganisms:

• 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/skin structure infections, including diabetic foot infections without osteomyelitis, due to Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes, E coli, Klebsiella pneumoniae, Proteus mirabilis, B fragilis, Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotella bivia. INVANZ has not been studied in diabetic foot infections with concomitant osteomyelitis.
• Community-acquired pneumonia due to S 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 E coli, including cases with concurrent bacteremia, or K pneumoniae.
• Acute pelvic infections, including postpartum endomyometritis, septic abortion, and postsurgical gynecologic infections, due to
  S agalactiae, E coli, B fragilis, P 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 INVANZ. Therapy with INVANZ 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. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE, OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION.

Seizures and other central nervous system (CNS) adverse experiences have been reported during treatment with INVANZ.

Co-administration of carbapenems, including INVANZ, to patients receiving valproic acid or divalproex sodium results in a reduction of valproic acid concentrations, which may drop below the therapeutic range and increase the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient. Concomitant use of INVANZ and valproic acid/divalproex sodium is generally not recommended. Consider other anti-bacterials in patients whose seizures are well controlled on valproic acid or divalproex sodium. If INVANZ is necessary, consider supplemental anticonvulsant therapy.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including INVANZ, and may range in severity from mild diarrhea to fatal colitis. CDAD must be considered in all patients who present with diarrhea following antibiotic use. CDAD has been reported to occur over 2 months after administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C difficile may need to be discontinued.

Lidocaine HCI is the diluent for intramuscular administration of INVANZ. Refer to the prescribing information for lidocaine HCI.

Precautions

General

During clinical investigations in adult patients treated with INVANZ (1 g once a day), seizures, irrespective of drug relationship,occured in 0.5% of patients during study therapy plus 14-day follow-up period. These experiences have occurred most commonly in patients with CNS disorders (eg, 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.

As with other antibiotics, prolonged use of INVANZ may result in overgrowth of nonsusceptible 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.

Drug Interactions

When INVANZ is coadministered with probenecid (500 mg by mouth every 6 hours), probenecid competes for active tubular secretion and reduces the renal clearance of INVANZ.

The potential for drug-drug interactions via the cytochrome P450 pathway is limited.

Pediatric Use

Safety and effectiveness of INVANZ in pediatric patients aged 3 months to 17 years 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 aged 3 months to 17 years for the treatment of the following^a:

• Complicated intra-abdominal infections
• Complicated skin/skin structure infections
• Community-acquired pneumonia
• Complicated urinary tract infections
• Acute pelvic infections

^aDue to the designated pathogens.

INVANZ is not recommended in infants younger than 3 months, as no data are available.

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

Adverse Reactions

Adults

During clinical trials, the most common drug-related adverse experiences in adult 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%).

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

Pediatric Patients

The overall adverse experience profile in pediatric patients is comparable to that in adult patients.

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%), and vomiting (2.1%).

Adverse Laboratory Experiences:Adults

In clinical studies, drug-related laboratory adverse experiences that were reported during therapy in >1.0% of adult patients treated with INVANZ, including those who were switched to therapy with an oral antimicrobial, were increased alanine transaminase (6.0%), increased aspartate transaminase (5.2%), increased serum alkaline phosphatase (3.4%), increased platelet count (2.8%), and increased eosinophils (1.1%), INVANZ was discontinued due to laboratory adverse experiences in 0.3% of patients.

Dosage and Administration

The dose of INVANZ in patients aged 13 years and older is 1 gram (g) given once daily. The dose of INVANZ in patients aged 3 months to 12 years 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.

DO NOT MIX OR CO-INFUSE INVANZ WITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE). INVANZ MUST BE RECONSTITUTED AND THEN DILUTED PRIOR TO INTRAVENOUS ADMINISTRATION.

INVANZ is approved for use in 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)—simply halve the dosage to 500 mg daily. There are no data in pediatric patients with renal insufficiency.

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. No data are available in patients undergoing peritoneal dialysis or hemofiltration. No data are available in pediatric patients on hemodialysis.

No dosage adjustment recommendations can be made in patients with impaired hepatic function.

Before prescribing INVANZ, please read the accompanying Prescribing Information.

For additional copies of the Prescribing Information, please call 1-800-672-6372, visit invanz.com, or contact your merck representative.