ASHP INJECTABLE DRUG INFORMATION Imipenem–Cilastatin Sodium 875

Imipenem–Cilastatin Sodium
AHFS 8:12.07.08

Products Administration
Imipenem–cilastatin sodium for intravenous use is available as a Imipenem–cilastatin sodium for intravenous use is adminis-
fixed combination of equal quantities of both drugs. The combi- tered by intermittent intravenous infusion at a concentration
nation is provided in vials and infusion bottles containing 250 not exceeding 5 mg/mL. Infusion periods vary from 20 to 60
or 500 mg of each drug with sodium bicarbonate 10 or 20 mg, minutes, depending on the dose. The intramuscular formu-
respectively.1(8/06) lation should be injected deeply into a large muscle mass.
The contents of a vial should be reconstituted with about Suspensions of either formulation should not be given intrave-
10 mL of a compatible diluent from a 100-mL infusion container nously.1(8/06) 4
and shaken well to form a suspension. Diluents containing
benzyl alcohol should not be used to reconstitute the drug for Stability
use in neonates and small pediatric patients. The suspension The product should be stored below 25°C.1(8/06) 4
must be transferred to the remaining solution in the infusion Reconstituted as directed, intravenous solutions are colorless
container for dilution. The suspension is not for direct injection. to yellow but may become a deeper yellow over time. Intramus-
The procedure is then repeated: a 10-mL aliquot from the admix- cular suspensions are white to light tan. The manufacturer indi-
ture is added to the vial and, once again, returned to the infusion cates that stability is not affected by color variations within this
admixture. This procedure ensures that all of the vial contents range,1(8/06) but the solutions should be discarded if they darken
are transferred. The admixture should be agitated until it is clear to brown.4 Intramuscular suspensions prepared with lidocaine
to yield either a 2.5- or 5-mg/mL concentration, depending on hydrochloride (without epinephrine) should be used within 1
the vial content. The admixture should not be heated to aid hour.1(8/06) 4
dissolution.1(8/06) 4
In solution, imipenem is substantially less stable than cilas-
ADD-Vantage vials of imipenem–cilastatin sodium should be tatin and is the determining factor in the overall stability of the
prepared with 100 mL of dextrose 5% or sodium chloride 0.9% combination product. Reconstitution results in solutions that
in ADD-Vantage diluent bags.1(8/06) 4 are stable for 4 hours at room temperature or 24 hours under
The 250- and 500-mg piggyback infusion bottles should be refrigeration at 4°C.1(8/06)
reconstituted with 100 mL of compatible diluent and shaken Imipenem degradation kinetics were determined for a
until clear to yield 2.5- and 5-mg/mL concentrations, respec- 2.5-mg/mL solution in sodium chloride 0.9%. The degradation
tively.1(8/06) 4 rates were temperature dependent, with a half-life of over 44
Imipenem–cilastatin sodium for intramuscular use is avail- hours at 2°C dropping to 6 hours at 25°C and to 2 hours at 37°C.
able in vials containing 500 or 750 mg of each component. The The decomposition was consistent with hydrolysis, and the
vials should be reconstituted with 2 or 3 mL, respectively, of loss of antimicrobial activity suggests cleavage of the β-lactam
lidocaine hydrochloride 1% (without epinephrine) and agitated ring.1272
to form a suspension. This intramuscular formulation is not for
intravenous use.1(8/06) 4 Concentration Effects
In one study, solutions of imipenem–cilastatin in sterile water
pH for injection at concentrations exceeding 8 g/L (not specified
The intravenous product is buffered to pH 6.5 to 8.5.1(8/06) whether concentration refers to single component or combined
components) resulted in precipitation.3105
Osmolarity
When reconstituted and diluted as directed by the manufac- pH Effects
turer, the osmolarity of the intravenous admixture approxi- Imipenem is inactivated at acidic or alkaline pH but is more
mates that of the diluent.4 stable at neutral pH.4 The pH range of maximum stability
appears to be 6.5 to 7.5, with increasing rates of decomposition
Sodium Content occurring as the pH moves away from this range.1273 At a pH of
The 250- and 500-mg intravenous vials contain 0.8 mEq (18.8 about 4, the half-life of imipenem is about 35 minutes.2166
mg) and 1.6 mEq (37.5 mg) of sodium, respectively. The 500-
and 750-mg intramuscular vials contain 1.4 mEq (32 mg) and Freezing Solutions
2.1 mEq (48 mg) of sodium, respectively.1(8/06) 4 The manufacturer recommends that imipenem–cilastatin solutions
not be frozen.1(8/06) At concentrations of 250 and 500 mg/100 mL
Trade Name(s) in sodium chloride 0.9%, imipenem losses of around 15% occurred
Primaxin I.V., Primaxin I.M. in 1 week when frozen at −20 and −10°C.1141 Freezing solutions at

DOI: 10.37573/9781585286850.206
876 Imipenem–Cilastatin Sodium ASHP INJECTABLE DRUG INFORMATION

temperatures above −70°C offers no stability advantage over potential to natural rubber elastomeric reservoirs (Baxter). Less
refrigerated storage1141 and results in decomposition of imipenem than 1% binding was found after storage for 2 weeks at 35°C
in a manner similar to ampicillin.4 with gentle agitation.2014
Effects of Solution Components Central Venous Catheter
Dextrose exerts an adverse effect on the stability of imipenem. Imipenem–cilastatin (MSD) 2 mg/mL in sodium chloride 0.9%
Dextrose 5 and 10% reduced the time to 10% decomposition was found to be compatible with the ARROWg+ard Blue Plus
by about one-half compared to sterile water. Sodium chlo- (Arrow International) chlorhexidine-bearing triple-lumen central
ride content increases imipenem stability because of a posi- catheter. Essentially complete delivery of the drug was found
tive kinetic salt effect similar to other β-lactam antibiotics. Both with little or no drug loss occurring. Furthermore, chlorhexidine
lactate and bicarbonate anions attack the β-lactam ring and delivered from the catheter remained at trace amounts with no
decrease imipenem stability.1141 substantial increase due to the delivery of the drug through the
catheter.2335
Elastomeric Reservoir Pumps
Imipenem–cilastatin sodium (Merck) 5 mg/mL in both dextrose
5% and sodium chloride 0.9% was evaluated for binding

Compatibility Information
Solution Compatibility
Imipenem–cilastatin sodium
Test Soln Name Mfr Mfr Conc/L or % Remarks Ref C/I

Dextrose 5% in Ringer’s ABa MSD 2.5d g 8% imipenem loss in 3 hr, 15% in 6 hr at 25°C. 9% loss in 24 hr, 1141 I
injection, lactated 15% in 48 hr at 4°C

Dextrose 5% in Ringer’s ABa MSD 5d g 14% imipenem loss in 3 hr at 25°C and 13% in 24 hr at 4°C 1141 I
injection, lactated

Dextrose 5% in sodium ABa MSD 2.5d g 8% imipenem loss in 6 hr and 12% in 9 hr at 25°C. 10% loss in 1141 Ib
chloride 0.225% 48 hr at 4°C

Dextrose 5% in sodium ABa MSD 5d g 5% imipenem loss in 3 hr, 13% in 6 hr at 25°C. 7% loss in 24 hr, 1141 Ib
chloride 0.225% 13% in 48 hr at 4°C

Dextrose 5% in sodium ABa MSD 2.5d g 8% imipenem loss in 6 hr, 11% in 9 hr at 25°C. 9% loss in 48 hr, 1141 Ib
chloride 0.45% 13% in 72 hr at 4°C

Dextrose 5% in sodium ABa MSD 5d g 5% imipenem loss in 3 hr, 11% in 6 hr at 25°C. 6% loss in 24 hr, 1141 Ib
chloride 0.45% 13% in 48 hr at 4°C

Dextrose 5% in sodium ABa MSD 2.5d g 6% imipenem loss in 6 hr, 10% in 9 hr at 25°C. 6% loss in 24 hr, 1141 Ib
chloride 0.9% 11% in 48 hr at 4°C

Dextrose 5% in sodium ABa MSD 5d g 6% imipenem loss in 3 hr, 11% in 6 hr at 25°C. 6% loss in 24 hr, 1141 Ib
chloride 0.9% 13% in 48 hr at 4°C

Dextrose 5% ABa MSD 2.5d g 5% imipenem loss in 3 hr, 10% in 6 hr at 25°C. 8% loss in 24 hr, 1141 Ib
14% in 48 hr at 4°C

Dextrose 5% ABa MSD 5d g 6% imipenem loss in 3 hr, 15% in 6 hr at 25°C. 8% loss in 24 hr, 1141 Ib
14% in 48 hr at 4°C

Dextrose 5% BA MSD 5d g Visually compatible. 10% imipenem loss in about 6 hr at 23°C 2166 Ib
and in 48 hr at 4°C

Dextrose 10% ABa MSD 2.5d g 6% imipenem loss in 3 hr, 10% in 6 hr at 25°C. 8% loss in 24 hr, 1141 Ib
13% in 48 hr at 4°C

Dextrose 10% ABa MSD 5d g 8% imipenem loss in 3 hr and 13% in 6 hr at 25°C. 10% loss in 1141 Ib
24 hr at 4°C

Normosol M in dextrose 5% ABa MSD 2.5d g 7% imipenem loss in 3 hr, 11% in 6 hr at 25°C. 9% loss in 24 hr, 1141 Ib
19% in 48 hr at 4°C