Invanz (Ertapenem Sodium) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

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.

A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics and may result in loss of seizure control. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that carbapenem antibiotics may inhibit valproic acid glucuronide hydrolysis. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop below the therapeutic range or a seizure occurs. (See WARNINGS, Seizure Potential.)

OVERDOSAGE

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.

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.)

REFERENCES

1. 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.
2. 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.
3. 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.
4. 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 February 2008

9709706

123A-02/08 515016Z

INSTRUCTIONS FOR USE OF INVANZ® [Registered trademark of MERCK & CO., Inc. COPYRIGHT © 2006 MERCK & CO., Inc. All rights reserved]

(Ertapenem for Injection)
IN ADD-Vantage® VIALS
For I.V. Use Only.

INSTRUCTIONS FOR USE

To Open Diluent Container:

Peel overwrap from the corner and remove container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container:

(Use Aseptic Technique)

1. Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:
   To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening. (SEE FIGURE 1.) Pull the ring approximately half way around the cap and then pull straight up to remove the cap. (SEE FIGURE 2.) NOTE: DO NOT ACCESS VIAL WITH SYRINGE.
   1. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover. (SEE FIGURE 3.)
2. Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately ½ turn (180°) after the first audible click. (SEE FIGURE 4.) The clicking sound does not assure a seal; the vial must be turned as far as it will go. NOTE: Once vial is seated, do not attempt to remove. (SEE FIGURE 4.)
3. Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.
4. Label appropriately.

To Prepare Admixture:

1. Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.
2. With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container. (SEE FIGURE 5.)
3. Pull the inner cap from the drug vial. (SEE FIGURE 6.) Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.
4. Mix container contents thoroughly and use within the specified time.

Preparation for Administration:

(Use Aseptic Technique)

1. Confirm the activation and admixture of vial contents.
2. Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
3. Close flow control clamp of administration set.
4. Remove cover from outlet port at bottom of container.
5. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.
6. Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.
7. Squeeze and release drip chamber to establish proper fluid level in chamber.
8. Open flow control clamp and clear air from set. Close clamp.
9. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
10. Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

Storage

INVANZ (Ertapenem for Injection) 1 g single dose ADD-Vantage® vials should be prepared with ADD-Vantage® diluent containers containing 50 mL or 100 mL of 0.9% Sodium Chloride Injection. When prepared with this diluent, INVANZ (Ertapenem for Injection) maintains satisfactory potency for 6 hours at room temperature (25°C) or for 24 hours under refrigeration (5°C) and used within 4 hours after removal from refrigeration. Solutions of INVANZ should not be frozen.

Before administering, see accompanying package circular for INVANZ (Ertapenem for Injection).

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 February 2008

9709706

123A-02/08 515016Z