Cefazolin sodium is available as a powder in vials containing the equivalent of 500 mg or 1 g of cefazolin as the sodium salt and pharmacy bulk packages containing 10 or 20 g of cefazolin as the sodium salt.3899; 3902 Each 500-mg or 1-g vial should be reconstituted with 2 or 2.5 mL of sterile water for injection to yield a solution containing cefazolin 225 or 330 mg/mL, respectively.3899 Vials should be shaken well until dissolved.3899
For direct intravenous injection, further dilute the reconstituted solution with approximately 5 mL of sterile water for injection.3899 For intravenous infusion, the reconstituted solution should be diluted in 50 to 100 mL of compatible infusion solution.3899
Pharmacy bulk packages may be reconstituted with sterile water for injection, bacteriostatic water for injection, or sodium chloride for injection.3902 The 10-g pharmacy bulk vial should be reconstituted with 45 or 96 mL to yield a concentration of 1 g/5 mL or 1 g/10 mL, respectively.3902 The 20-g pharmacy bulk vial should be reconstituted with 87 mL to yield a concentration of 1 g/5 mL.3902 Vials should be shaken well until dissolved.3902 The reconstituted solution should be diluted in 50 to 100 mL of a compatible solution for intravenous infusion.3902
Cefazolin sodium also is available in single-dose dual-chamber flexible containers containing the equivalent of 1 or 2 g of cefazolin as a lyophilized powder.3900 The diluent chamber for the 1- or 2-g dose contains approximately 50 mL of dextrose 4 or 3%, respectively, to yield an iso-osmotic solution upon reconstitution.3900
Cefazolin sodium also is available as a frozen premixed infusion solution in single-dose Galaxy plastic containers containing the equivalent of 1 or 2 g of cefazolin in 50- or 100-mL, respectively, and dextrose 4% in water.3901 Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH.3901
pH
Reconstituted solutions have a pH of 4 to 6.3902
Osmolality
The osmolality of a 225-mg/mL solution in sterile water for injection was determined to be 636 mOsm/kg by freezing-point depression.1071
The osmolality of cefazolin sodium 1 and 2 g was calculated for the following dilutions:1054
| Osmolality (mOsm/kg) | ||
|---|---|---|
| Cefazolin in Diluent | 50 mL | 100 mL |
| 1 g in Dextrose 5% | 321 | 291 |
| 1 g in Sodium chloride 0.9% | 344 | 317 |
| 2 g in Dextrose 5% | 379 | 324 |
| 2 g in Sodium chloride 0.9% | 406 | 351 |
Cefazolin sodium in dual-chamber flexible containers has an osmolality of 290 mOsm/kg when reconstituted (activated) with the dextrose diluent.3900
The frozen premixed solutions have an osmolality of approximately 290 mOsm/kg.3901
The following maximum cefazolin sodium concentrations were recommended to achieve osmolalities suitable for peripheral infusion in fluid-restricted patients:1180
| Diluent | Maximum Concentration (mg/mL) | Osmolality (mOsm/kg) |
|---|---|---|
| Dextrose 5% | 77 | 507 |
| Sodium chloride 0.9% | 69 | 494 |
| Sterile water for injection | 138 | 404 |
Sodium Content
Each gram of cefazolin sodium contains 48 mg of sodium.3899; 3900; 3901
Cefazolin sodium is administered by intramuscular or direct intravenous injection or by continuous or intermittent intravenous infusion following dilution in 50 to 100 mL of a compatible infusion solution.3899 For direct intravenous injection, the reconstituted solution should be diluted with approximately 5 mL of sterile water for injection and administered slowly over 3 to 5 minutes directly into the vein or tubing of a running infusion solution.3899
Cefazolin sodium in activated dual-chamber flexible containers and frozen premixed infusion solutions are intended for intravenous infusion over approximately 30 minutes.3900; 3901
Solutions prepared from bulk pharmacy containers are intended only for intravenous infusion after dilution in a compatible solution.3902
Cefazolin sodium is a white to off-white powder that forms a pale yellow to yellow solution upon reconstitution.3899 Intact containers should be stored at controlled room temperature and protected from light.3899; 3902 Reconstituted solutions are stated to be stable for 24 hours at room temperature or 10 days under refrigeration.3899 The storage recommendations are intended to reduce the potential for the growth of microorganisms and to minimize an increase in color and a change in pH.276 A test of cefazolin sodium 250 mg/mL in water for injection showed that the drug lost less than 3% in 14 days at 5°C. A loss of 8 to 10% was noted in 4 days at 25°C.276
Solutions diluted in a manufacturer-recommended solution for infusion are stable for 24 hours at room temperature or 10 days under refrigeration.3899
Reconstituted solutions prepared from pharmacy bulk packages should be further diluted for infusion within 4 hours after initial entry into the vial.3902 Unused portions of pharmacy bulk packages should be discarded after 4 hours of initial entry.3902 Solutions further diluted in a manufacturer-recommended solution for infusion are stable for 24 hours at room temperature or 10 days under refrigeration.3902
Unactivated dual-chamber flexible plastic containers should be stored at controlled room temperature and not frozen.3900 Once the foil strip has been removed from the drug chamber, the product must be protected from light and used within 7 days, but not beyond the labeled expiration date.3900 Once reconstituted (activated), the drug should be used within 24 hours if stored at room temperature or 7 days if stored under refrigeration.3900 Do not freeze reconstituted solution.3900 If the reconstituted solution has been refrigerated, allow the container to equilibrate to room temperature prior to administration.3900 Reconstituted solutions range in color from pale yellow to amber.3900
Crystallization
Crystal formation has also been observed in reconstituted cefazolin sodium 330 mg/mL stored at room temperature after complete dissolution when sodium chloride 0.9% is the diluent. The crystals formed initially are fine and may be easily overlooked. At 330 mg/mL, cefazolin sodium is near its saturation point, and the room temperature and ionic content of the diluent are important for maintaining the drug in solution. In an evaluation of cefazolin sodium reconstituted with 2.5 mL of either sodium chloride 0.9% or sterile water for injection and stored at 24 or 26°C, none of the vials reconstituted with sterile water for injection formed crystals within 24 hours. However, when sodium chloride 0.9% was the diluent, all vials had crystals. Consequently, sterile water for injection was recommended as the diluent when possible.875 The crystals of cefazolin sodium can be redissolved by hand-warming the vials or by immersion in a 35°C water bath for 2 minutes. The clear solution will then be suitable for use.1075
pH Effects
Cefazolin sodium solutions are relatively stable at pH 4.5 to 8.5. Above pH 8.5, rapid hydrolysis of the drug occurs. Below pH 4.5, precipitation of the insoluble free acid may occur.4; 284
Cefazolin sodium in solutions containing dextrose, fructose, sucrose, dextran 40 or 70, mannitol, sorbitol, or glycerol in concentrations up to 15% was most stable at pH 5 to 6.5. At neutral and alkaline pH, the rate of degradation was accelerated by the carbohydrates and alcohols.820
Cefazolin sodium 3.33 mg/mL was evaluated in several aqueous buffer solutions. The drug was most stable in pH 4.5 acetate buffer, exhibiting 10% decomposition in 3 days at 35°C and in 5 days at 25°C. In pH 5.7 acetate buffer, a 13% loss occurred in 3 days at 35°C and a 10% loss occurred in 5 days at 25°C. No loss occurred in either acetate buffer in 7 days at 4°C.1147
In pH 7.5 phosphate buffer, a yellow color and particulate matter developed after 3 to 4 days at 35°C. This change was accompanied by a 6% cefazolin loss in 1 day and an 18% loss in 3 days. At 25 and 4°C, 10 and 5% cefazolin losses occurred, respectively, in 5 days.1147
Freezing Solutions
Frozen premixed infusion solution in single-dose Galaxy plastic containers should be stored at -20°C.3901 Solutions should be thawed at room temperature or under refrigeration; the manufacturer states that solutions should not be force thawed by immersion in water baths or by microwave radiation.3901 Thawed solutions are stable for 48 hours at room temperature or 30 days refrigerated.3901 Thawed solutions should not be refrozen.3901 The manufacturer states that precipitation may occur in the frozen solution which will dissolve with little or no agitation upon reaching room temperature.3901 The container should be agitated after reaching room temperature.3901 Discard the solution if it is cloudy or precipitate is present.3901
When reconstituted with water for injection, dextrose 5%, or sodium chloride 0.9% in concentrations of 1 g/2.5 mL, 500 mg/100 mL, and 10 g/45 mL, cefazolin sodium retained more than 90% potency for up to 26 weeks when frozen within 1 hour after reconstitution at -10 and -20°C. In a concentration of 500 mg/100 mL in dextrose 5% in Ringer’s injection, lactated, Ionosol B in dextrose 5%, Normosol M in dextrose 5%, Plasma-Lyte in dextrose 5%, or Ringer’s injection, lactated, cefazolin sodium was stable for up to 4 weeks when frozen within 1 hour after reconstitution at -10°C.277
In another study, cefazolin sodium (SKF) 1 g/50 mL of dextrose 5% and also sodium chloride 0.9% in PVC containers was frozen at -20°C for 30 days. The results indicate that potency was retained for the duration of the study.299
Cefazolin sodium (Lilly) 1 g/100 mL in dextrose 5% in PVC bags was frozen at -20°C for 30 days and then thawed by exposure to ambient temperature or microwave radiation. The solutions showed no evidence of precipitation or color change and showed no loss of potency as determined microbiologically. Subsequent storage of the admixture at room temperature for 24 hours also yielded a physically compatible solution which exhibited a 3 to 6% loss of potency.554
In an additional study, cefazolin sodium (Lilly and SKF) 10 mg/mL in 50, 100, and 250 mL of dextrose 5% and sodium chloride 0.9% in PVC bags was frozen at -20°C for 48 hours. Thawing was then performed by exposure to microwave radiation carefully applied so that the solution temperature did not exceed 20°C and so that a small amount of ice remained at the endpoint. This procedure avoids accelerated decomposition due to inadvertent excessive temperature increases. The solutions were stored for 4 hours at room temperature. Both brands of cefazolin sodium retained at least 90% of the initial activity as determined by microbiological assay. In addition, the solutions did not exhibit color changes or significant pH changes.627
An approximate fourfold increase in particles of 2 to 60 µm was produced by freezing and thawing cefazolin sodium (Lilly) 2 g/100 mL of dextrose 5% (Travenol). The reconstituted drug was filtered through a 0.45-µm filter into PVC bags of solution and frozen for 7 days at -20°C. Thawing was performed at room temperature (29°C) for 12 hours. Although the total number of particles increased significantly, no particles greater than 60 µm were observed; the solution complied with USP standards for particle sizes and numbers in large volume parenteral solutions.822
No loss of cefazolin sodium (SKF) was reported from a solution containing 73.2 mg/mL in sterile water for injection in PVC and glass containers after 30 days at -20°C. Subsequent thawing and storage for 4 days at 5°C, followed by 24 hours at 37°C to simulate the use of a portable infusion pump, also did not result in a cefazolin loss.1391
The manufacturer warns against continued heating of a completely thawed solution, which can result in accelerated drug decomposition and possibly dangerous pressure increases in the container.627
Syringes
Cefazolin sodium (SKF) 1 and 2 g/10 mL in sterile water for injection, packaged in plastic syringes (Monoject), exhibited a 10% cefazolin loss in 13 days at 24°C. At 4°C, the drug exhibited less than a 10% loss during the 28-day study period. Frozen at -15°C, less than 10% drug loss occurred in 3 months.1178
Cefazolin sodium (Apothecon) 50 mg/mL in sodium chloride 0.9% was packaged in 5-mL polypropylene syringes (Becton Dickinson) and stored at 23 and 5°C. About 10% loss was found after 12 days of storage at 23°C. About 3% loss was found after 22 days of refrigerated storage.2474
Cefazolin sodium (Apotex) 100 and 200 mg/mL in sterile water for injection was packaged in polypropylene syringes and stored at 5°C protected from light.2986 A slight increase in yellow discoloration of the solution occurred with less than 10% loss in 30 days at 5°C with light protection followed by 72 hours at 21 to 25°C with light exposure.2986
Filtration
Cefazolin sodium (SKF) 10 g/L in dextrose 5% and also in sodium chloride 0.9% was filtered through 0.45- and 0.22-µm Millipore membrane filters at time zero and at 4, 8, and 24 hours after mixing. No significant difference in concentration occurred between any of the filtered samples compared to unfiltered solutions at these time intervals. It was concluded that filtration of cefazolin sodium solutions through these membrane filters could be performed without adversely affecting the drug concentration.375
Central Venous Catheter
Cefazolin sodium (SmithKline Beecham) 5 mg/mL in dextrose 5% was found to be compatible with the ARROWg+ard Blue Plus (Arrow International) chlorhexidine-bearing triple-lumen central catheter. Essentially complete delivery of the drug was found with little or no drug loss occurring. Furthermore, chlorhexidine delivered from the catheter remained at trace amounts with no substantial increase due to the delivery of the drug through the catheter.2335
Cefazolin sodium 10 mg/mL with heparin sodium 5000 units/mL as an antibiotic lock in polyurethane central hemodialysis catheters lost about 50% of the antibiotic over 72 hours at 37°C. The loss was attributed to sorption to the catheters. Nevertheless, the reduced antibiotic concentration (about 5 mg/mL) remained effective against common microorganisms in catheter-related bacteremia in hemodialysis patients.2515; 2516
Drugs in Syringe Compatibility
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Peritoneal Dialysis Solutions
The stability of cefazolin sodium 75 and 150 mg/L, alone and with gentamicin sulfate 8 mg/L, was evaluated in a peritoneal dialysis solution of dextrose 1.5% with heparin sodium 1000 units/L. Cefazolin activity was retained for 48 hours at both 4 and 26°C at both concentrations, alone and with gentamicin. Gentamicin activity also was retained over the study period. At 37°C, however, cefazolin losses were greater, with about a 10 to 12% loss occurring in 48 hours. Gentamicin losses ranged from 4 to 8% in this time period.1029
Gentamicin 4 mcg/mL in Dianeal PDS with dextrose 1.5 and 4.25% (Travenol) was evaluated with cefazolin sodium 125 mcg/mL, heparin 500 units, and albumin 80 mg in 2-L bags. The gentamicin content was retained for 72 hours.1413
The stability of cefazolin sodium (Lilly) 0.5 mg/mL in Dianeal PD-1 with dextrose 1.5 and 4.25% (Travenol) was studied. The drug was stable, exhibiting losses of 10.5% or less in 14 days at 4°C, 8 days at 25°C, and 24 hours at 37°C. However, losses of 11.7 and 14.6% occurred in the solutions containing dextrose 1.5% and dextrose 4.25%, respectively, in 11 days at 25°C.1480
Cefazolin sodium (Lilly) 125 mcg/mL combined separately with the aminoglycosides amikacin sulfate (Bristol), gentamicin sulfate (Schering), and tobramycin sulfate (Lilly) at a concentration of 25 mcg/mL in peritoneal dialysis solution (Dianeal 1.5%) exhibited enhanced rates of lethality to Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa compared to any of the drugs alone.1623
Cefazolin sodium (Fujisawa) 0.333 mg/mL in PD-2 with dextrose 1.5% (Baxter) peritoneal dialysis solution with and without heparin sodium 1000 units/1.5 L was stored at 4, 25, and 37°C. No visible changes occurred, and less than 10% loss of cefazolin occurred in 20 days at 4°C, 11 days at 25°C, and 24 hours at 37°C.2388
Cefazolin sodium (Fujisawa) 0.5 mg/mL in Extraneal PD (Baxter) containing 7.5% icodextrin was physically compatible and chemically stable for 30 days at 4°C with about 7% cefazolin loss and for 7 days at room temperature with about 9% loss. At 37°C, 8% cefazolin loss occurred in 24 hours.2480
Cefazolin sodium 125 and 500 mg/mL (Apothecon) was evaluated for stability at 38°C in Dianeal PD-2 with dextrose 1.5, 2.5, and 4.25% and in Extraneal 7.5% with and without added heparin. Less than 10% loss occurred in 48 hours and 10 to 14% loss in 60 hours.2655
Cefazolin sodium (Hospira) 500 mg/L in Extraneal with icodextrin 7.5% (Baxter) peritoneal dialysis solution bags exhibited less than 10% loss in 14 days at 4°C, 7 days at 25°C, and 6 hours at 37°C.3537 Cefazolin sodium (Hospira) 500 mg/L with gentamicin sulfate (Pfizer) 20 mg/L in Extraneal with icodextrin 7.5% (Baxter) peritoneal dialysis solution bags exhibited less than 10% loss of either drug in 14 days at 4°C, 7% loss of cefazolin and no loss of gentamicin in 4 days at 25°C, and 5% loss of cefazolin and 1% loss of gentamicin in 1 day at 37°C.3537 Cefazolin sodium (Hospira) 500 mg/L with ceftazidime (Sandoz) 500 mg/L in Extraneal with icodextrin 7.5% (Baxter) peritoneal dialysis solution bags exhibited less than 10% loss of either drug in 14 days at 4°C, 2% loss of cefazolin and 6% loss of ceftazidime in 2 days at 25°C, and 2% loss of cefazolin and no loss of ceftazidime in 6 hours at 37°C.3537
For a list of references cited in the text of this monograph, search the monograph titled References.