IMIPENEM AND CILASTATIN Powder for solution for injection Ref.[10466] Active ingredients: Imipenem and Cilastatin

2.1 Dosage in Adults

For Intravenous Injection Only:

• The dosage of Imipenem and Cilastatin for Injection (I.V.) in adult patients should be based on suspected or confirmed pathogen susceptibility as shown in Table 1 below. The dosage recommendations for Imipenem and Cilastatin for Injection (I.V.) represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution.
• These doses should be used for patients with creatinine clearance of greater than or equal to 90 mL/min. A reduction in dose must be made for patients with creatinine clearance less than 90 mL/min as shown in Table 3 [see Dosage and Administration (2.3)].
• Recommend that the maximum total daily dosage not exceed 4 g/day.
• Administer 500 mg by intravenous infusion over 20 to 30 minutes.
• Administer 1,000 mg by intravenous infusion over 40 to 60 minutes.
• In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Table 1. Dosage of Imipenem and Cilastatin for Injection (I.V.) in Adult Patients with Creatinine Clearance Greater than or Equal to 90 mL/min:

2.2 Dosage in Pediatric Patients

Imipenem and Cilastatin for Injection (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures [see Use in Specific Populations (8.4)].

Imipenem and Cilastatin for Injection (I.V.) is not recommended in pediatric patients <30 kg with renal impairment, as no data are available [see Use in Specific Populations (8.4)].

Based on studies in adults, the maximum total daily dose in pediatric patients should not exceed 4 g/day [see Dosage and Administration (2.1)].

The recommended dosage for pediatric patients with non-CNS infections is shown in Table 2 below:

Table 2. Recommended Imipenem and Cilastatin for Injection (I.V.) Dosage in Pediatric Patients for Non-CNS Infections:

^* Doses less than or equal to 500 mg should be given by intravenous infusion over 20 to 30 minutes
^† Doses greater than 500 mg should be given by intravenous infusion over 40 to 60 minutes

Recommend that the maximum total daily dosage not exceed 4 g/day

2.3 Dosage in Adult Patients with Renal Impairment

Patients with creatinine clearance less than 90 mL/min require dosage reduction of Imipenem and Cilastatin for Injection (I.V.) as indicated in Table 3. The serum creatinine should represent a steady state of renal function. Use the Cockroft-Gault method described below to calculate the creatinine clearance:

Males: (weight in kg) x (140-age in years) / (72) x serum creatinine (mg/100 mL)

Females: (weight in kg) x (140-age in years) / (0.85) x (value calculated for males)

Table 3. Dosage of Imipenem and Cilastatin for Injection (I.V.) for Adult Patients in Various Renal Function Groups Based on Estimated Creatinine Clearance (CLcr):

^* Administer doses less than or equal to 500 mg by intravenous infusion over 20 to 30 minutes.
^† Administer doses greater than 500 mg by intravenous infusion over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

In patients with creatinine clearances of less than 30 to greater than or equal to 15 mL/min, there may be an increased risk of seizures [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]. Patients with creatinine clearance less than 15 mL/min should not receive Imipenem and Cilastatin for Injection (I.V.) unless hemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of Imipenem and Cilastatin for Injection (I.V.) for patients undergoing peritoneal dialysis.

2.4 Dosage in Hemodialysis Patients

When treating patients with creatinine clearances of less than 15 mL/min who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of less than 30 to greater than or equal to 15 mL/min in Table 3 above [see Dosage and Administration (2.3)]. Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive Imipenem and Cilastatin for Injection (I.V.) after hemodialysis and at intervals timed from the end of that hemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, Imipenem and Cilastatin for Injection (I.V.) is recommended only when the benefit outweighs the potential risk of seizures [see Warnings and Precautions (5.2)].

2.5 Reconstitution and Preparation of Imipenem and Cilastatin for Injection (I.V.) Solution for Intravenous Administration

Imipenem and Cilastatin for Injection (I.V.) Vials:

• Do not use diluents containing benzyl alcohol to reconstitute Imipenem and Cilastatin for Injection (I.V.) for administration to neonates because it has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity.
• Contents of the vials must be reconstituted by adding approximately 10 mL of the appropriate diluent to the vial. List of appropriate diluents are as follows:
  • 0.9% Sodium Chloride Injection
  • 5% Dextrose Injection
  • 5% Dextrose and 0.9% Sodium Chloride Injection
  • 5% Dextrose Injection with 0.225% or 0.45% saline solution
• Reconstituted Solutions of Imipenem and Cilastatin for Injection (I.V.) range from colorless to yellow. Variations of color within this range do not affect the potency of the product.
• The reconstituted suspension must not be administered by direct Intravenous Infusion.
• After reconstitution, shake vial well and transfer the resulting suspension to 100 mL of an appropriate infusion solution before administering by intravenous infusion.
• Repeat transfer of the resulting suspension with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution. Agitate the resulting mixture until clear.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• Discard unused portion.

2.6 Storage of Reconstituted Solutions

Vials (After Reconstitution):

• Imipenem and Cilastatin for Injection (I.V.), as supplied in single dose vials and reconstituted with the appropriate diluents [see Dosage and Administration (2.5)], maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (5°C). Do not freeze solutions of Imipenem and Cilastatin for Injection (I.V.).

2.7 Incompatibility and Compatibility of Imipenem and Cilastatin for Injection (I.V.) with other Antibacterial Drugs

• Do not mix Imipenem and Cilastatin for Injection (I.V.) with, or physically add to, other antibacterial drugs
• Imipenem and Cilastatin for Injection (I.V.) may be administered concomitantly with other antibacterial drugs, such as aminoglycosides.

In the case of overdosage, discontinue Imipenem and Cilastatin for Injection (I.V.), treat symptomatically, and institute supportive measures as required. Imipenem and Cilastatin for Injection (I.V.) is hemodialyzable.

Before Reconstitution:

Imipenem and Cilastatin for Injection, USP (I.V.) sterile powder should be stored at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].