Cefazolin for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Cefazolin for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Bacterial Infection, Bone infection (Osteomyelitis), Endocarditis, Joint Infection, Respiratory Tract Infection, Upper (Upper Respiratory Tract Infection), Septicemia, Skin and Structure Infection, Urinary Tract Infection
Class: First generation cephalosporins
Form: Intramuscular (IM), Intravenous (IV), Powder
Ingredients: cefazolin

Pharmaceutical Information

Drug Substance

Proper Name:Cefazolin Sodium
Chemical Name:Sodium (6R,7R)-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-7-[2-(1H-tetrazol-1-yl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
Structural Formula:
Molecular Formula:C14H13N8NaO4S3
Molecular Weight: 476.5
Description:Cefazolin sodium is a white, odorless crystalline powder. It is easily soluble in water, slightly soluble in methanol and ethanol, and practically insoluble in benzene, acetone and chloroform. The pH of the constituted solution ranges from 4.5 to 6.0.

Composition

Cefazolin for Injection, USP contains 500 mg, 1 g, 10 g, or 20 g cefazolin in each vial, or 100 g in each SmartPak bag, present as cefazolin sodium. Each gram of cefazolin sodium contains 48 mg of sodium. Contains no preservative.

Stability and Storage Recommendations

Cefazolin for Injection, USP (unconstituted product) in vials should be stored between 15°C and 30°C and protected from light.

Cefazolin for Injection, USP in SmartPak bag: Prior to constitution, store dry powder between 15°C and 25°C. PROTECT FROM LIGHT. THE INNER BAG SHOULD BE RETAINED IN THE OUTER BAG UNTIL TIME OF USE.

Constitution

When constituted, the vial should be SHAKEN WELL and inspected visually for particulate matter prior to administration. The drug solution should be discarded if particulate matter is evident in constituted fluids.

Constituted Cefazolin for Injection, USP is stable for 24 hours at controlled room temperature not exceeding 25°C, or for 72 hours under refrigeration (2°C to 8°C) protected from light, from the time of initial puncture of the stopper.

For Intramuscular Injection

Single-dose Vials

Constitute according to the Single-dose Vial Constitution Table below.

SHAKE WELL.

For Intravenous Direct (Bolus) Injection

Single-dose Vials

Constitute according to the Single- dose Vial Constitution Table below. SHAKE WELL. For further dilution of the constituted solution, a minimum of 10 mL of Sterile Water for Injection should be used.

Pharmacy Bulk Vial

Add, according to the Pharmacy Bulk Vial Dilution Table below, 45 mL or 96 mL Sterile Water for Injection, or Sodium Chloride Injection 0.9%. One of the solutions listed below under For Intermittent or Continuous Intravenous Infusion may be used to further dilute aliquots. SHAKE WELL. The Pharmacy Bulk Vial is intended for multiple dispensing and i.v. use only employing a single puncture. Any unused stock solution remaining after a period of 8 hours should be discarded. THE USE OF PHARMACY BULK VIALS IS RESTRICTED TO HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM.

For Intermittent or Continuous Intravenous Infusion

Single-dose Vials

Constitute according to the Single-dose Vial Constitution Table below. SHAKE WELL. Further dilute the constituted cefazolin sodium in 50 to 100 mL of Sterile Water for Injection or one of the following solutions:

Sodium Chloride Injection 0.9%

Dextrose Injection 5% or 10%

Single-dose Vial Constitution Table
Vial Size
(mg)
DiluentVolume to
be Added
to Vial (mL)
Approx.
Available
Volume (mL)
Nominal
Concentration
(mg/mL)
5000.9% Sodium Chloride Injection2.02.2225
500Sterile Water for Injection3.84.0125
1000Sterile Water for Injection2.53.0334
Pharmacy Bulk Vial Dilution Table
Vial Size
(g)
Volume to be Added to Vial
(mL)
Approx. Available Volume
(mL)
Nominal Concentration
(mg/mL)
104550200
96100100
2087100200

Extended use of IV Admixtures

Although i.v. admixtures may often be physically and chemically stable for longer periods, due to microbiological considerations, they are usually recommended for use within 24 hours at room temperature or 72 hours when refrigerated (2°C to 8°C), from the time of initial puncture of the stopper.

DIRECTIONS FOR PROPER USE OF SMARTPAK PHARMACY BULK PACKAGE

Not for direct infusion. The Pharmacy Bulk Package is for use in the hospital pharmacy admixture service only in a suitable work area, such as a laminar flow hood. Using aseptic technique, the container closure may be penetrated only one time using a suitable sterile dispensing set or transfer device that allows measured dispensing of the contents. Use of a

syringe and needle is not recommended as it may cause leakage. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 8 HOURS from initial port closure entries is permitted to complete fluid transfer operations. This time limit should begin with the introduction of the solvent or diluent into the Pharmacy Bulk Package.

Instructions for Constitution

Visually examine outer (natural foil) bag for damage. IF THE SEAL IS BROKEN OR DAMAGE IS OBSERVED, DO NOT OPEN THE OUTER BAG.

STERILITY OF THE INNER BAG SURFACE MAY BE COMPROMISED. DISCARD BOTH BAGS IMMEDIATELY. DO NOT USE THE INNER BAG IF PARTICULATE OR FOREIGN MATTER IS PRESENT, IF THE DRY POWDER IS DARK YELLOW OR BROWN, IF THE SEALS ARE NOT INTACT, OR IF THERE IS ANY OTHER DAMAGE TO THE BAG. IN SUCH CASES, DISCARD THE BAG IMMEDIATELY. Remove the translucent unthreaded cap from the constitution (smaller) port and discard it. Follow the above “DIRECTIONS FOR PROPER USE OF SMARTPAKPHARMACY BULK PACKAGE” and proceed to constitute the powder through the constitution (smaller) port, using Sterile Water for Injection. Mix gently by picking up the bag and gently moving from side to side until dissolution is complete. Once the powder is completely dissolved, approximately 15 minutes for 100 grams, hang the bag from the eyelets support.

If a pump is used, the following general procedure is recommended:

  1. Attach a sterile spike to the outlet (unspiked) end of a new sterile transfer tube set, and insert spike into spike port of the bag of Sterile Water for Injection to be used to constitute the SmartPak Pharmacy Bulk Package.
  2. Attach the inlet (attached spike) end of the tube set to the Transfer Port of the SmartPak Pharmacy Bulk Package.
  3. Reverse the pump to transfer Sterile Water for Injection into the SmartPak Pharmacy Bulk Package.
  4. After completing the transfer of Sterile Water for Injection, remove the spike from the bag of Sterile Water for Injection, and disconnect the spike from this end of the tube set.
  5. Replace this spike with a transfer needle, and insert this needle into the Constitution Port of the SmartPak Pharmacy Bulk Package.
  6. Using the pump, circulate the constituted drug through the tube set and SmartPak Pharmacy Bulk Package to thoroughly mix (about 15 minutes for the 100-gram container).
  7. After solution is complete, remove the transfer needle from the Constitution Port of the SmartPak Pharmacy Bulk Package, and replace it with a syringe-filling adaptor.
  8. Hang the bag from the eyelets support. Constituted solution can now be transferred using a pump from the SmartPak Pharmacy Bulk Package, through the tube set in the Transfer Port, into syringes via the syringe-filling adaptor.

It should be noted that the spike placed into the SmartPak Pharmacy Bulk Package in Step 2 is NEVER removed during this procedure and that the Constitution Port is self-sealing.

Solutions should be allowed to stand after dissolution to allow any foaming to dissipate in order to permit visual inspection for completed solubilization. CAUTION: TO AVOID POSSIBLE LEAKAGE CAUSED BY THE HEAVY WEIGHT OF THE ADDED WATER, DO NOT SHAKE VIGOROUSLY OR PULL STRONGLY ON THE BAG.

SmartPak Pharmacy Bulk Package Dilution Table
SmartPak Bag Size
(g)
Amount of Sterile Water for
Injection
(mL)
Nominal Concentration
(mg/mL)
100 9960 mL100 mg/mL (1 g/10 mL)

Dispensing Constituted Cefazolin/Instructions for Filling Empty Syringes

Unscrew the clear threaded cap from the Transfer (larger) Port and discard it. Using this Transfer Port, fill sterile empty syringes, using a new transfer device. Syringes may be filled using aseptic technique following the usual practice of the institution. Such practices may range from the use of a three-way stopcock to the use of a calibrated peristaltic pump. If constituted to 100 mg/mL: transfer 5 mL in syringe for 500 mg or 10 mL for 1 g. For pediatric dosages, see PEDIATRIC DOSAGE GUIDE.

Stability of Filled Syringes

In those situations in which the drug has been constituted with water and transferred to empty syringes, but not immediately administered to the patient, the syringes may be stored under the following conditions:

  1. 24 hours at room temperature
  2. 72 hours under refrigeration, 2°C to 8°C (36 °F to 46 °F), if immediately refrigerated after transfer.

AFTER INITIAL ENTRY, USE ENTIRE CONTENTS OF THE PHARMACY BULK PACKAGE PROMPTLY; ANY UNUSED PORTION MUST BE DISCARDED WITHIN 8 HOURS.

Prior to administration, parenteral drug products should be inspected visually for particulate matter and discolouration whenever solution and container permit.

If, after visual inspection, the solution is cloudy, contains particulate matter or leaks are detected, discard the syringe as sterility may be impaired.

Special Instructions

PROPER PROCEDURE FOR CONSTITUTION AND DISPENSING OF THE SMARTPAK PHARMACY BULK PACKAGE

Entire procedure to be performed under Laminar Flow Hood using Aseptic Technique

CONSTITUTION PHASEMMIXING PHASEDISPENSING PHASE
1. Remove translucent Constitution Port cap by pulling.
2. Insert new transfer device for constitution.
3. Add appropriate volume of Sterile Water for Injection.
4. Disconnect transfer device from Sterile Water for
Injection container, and replace the spike or needle
with appropriate new transfer adaptor.
5. See Package Insert for further details.
1. Mix gently: either recirculate via a tubing loop or by picking up the bag and gently moving it from side to side until dissolution is completed (15 to 25 minutes) and foam, if any, dissipates.
2. Check for particulate matter, leaks and discolouration (dark yellow or brown).
3. If any of the above are found, discard bag immediately.
4. If satisfactory, hang bag using the eyelets.
5. See Package Insert for further details.
1. Unscrew clear Transfer Port cap.
2. Insert new transfer device.
3. Transfer dose into sterile empty syringe.
4. Properly label syringes.
5. See Package Insert for further details.

Warning

As with all parenteral products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

AVAILABILITY OF DOSAGE FORMS

Cefazolin for Injection, USP is supplied in:

PF32002015 mL vials containing cefazolin sodium equivalent to 500 mg of cefazolin, packaged 25 vials per carton.
PF32002115 mL vials containing cefazolin sodium equivalent to 1 g of cefazolin, packaged 25 vials or 10 vials per carton.
C236R1100 mL vials containing cefazolin sodium equivalent to 500 mg of cefazolin, packaged 10 vials per carton.
C237R1100 mL vials containing cefazolin sodium equivalent to 1 g of cefazolin, packaged 10 vials per carton.
PF320022100 mL “Pharmacy Bulk Package” vials containing cefazolin sodium equivalent to 10 grams of cefazolin, packaged 10 vials per carton.
C446B1100 mL “Pharmacy Bulk Vials” containing cefazolin sodium equivalent to 20 grams of cefazolin, packaged 10 vials per carton.
CP1455B1100 grams SmartPak “Pharmacy Bulk Package” containing cefazolin sodium equivalent to 100 grams of cefazolin.

CEFAZOLIN FOR INJECTION, USP DOES NOT CONTAIN PRESERVATIVE.

Microbiology

Activity of Cefazolin Against Clinical Isolates
Type of
Organism
No. of
Strains
Cumulative Percentage Susceptible to Indicated Concentration (μg/mL)
  < 0.05< 0.1-0.781.56-3.136.25-12.525-50100> 100
S. aureus7000.1459.190.6 - 92.4*97.399.799.9100
S. pyogenes8 100     
S. faecalis14   2857+  
S. pneumoniae23 100     
E. coli46  869296100# 
P. mirabilis30  5086.79090100
K. pneumoniae56 308498   
Enterobacter18    34♦100# 
H. influenzae15 6666 100  
N. gonorrhoeae55 22§98‡    
Shigella spp.2 505050100  
Salmonella spp.9 8989‡100†   
Staphylococci
(coagulase
negative)
295 66829093100 
§ Reported as 0.8 µg/mL
* Reported as 3.13-6.25 µg/mL
‡ Reported as 3.1 µg/mL
† Reported as 6.2 µg/mL
+ Reported as 25 µg/mL
♦ Reported as 50 µg/mL
# Reported as > 50 µg/mL

Disc Susceptibility Tests

The following criteria should be employed to interpret susceptibility tests using a standardized 30 µg cephalosporin-class disc:

Interpretive standards for organisms other than Haemophilus and Streptococcus spp.

Zones of ≥ 18 mm indicate that the tested organisms are susceptible and are likely to respond to therapy.

Zones of 15 to 17 mm indicate organisms of intermediate susceptibility that may be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic levels can be attained.

Zones of ≤ 14 mm are produced by resistant organisms.

A gram-positive isolate having a zone of 18 mm indicates a cefazolin-susceptible organism when tested with the cephalosporin-class disc (30 μg cephalothin) or the cefazolin disc.

Since cefazolin has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found resistant when tested with the cephalothin disc, gram-negative organisms should be tested with the cefazolin disc.

Gram-negative organisms having zones around the cephalothin disc of less than 18 mm may be susceptible to cefazolin.

The cefazolin disc should not be used for testing susceptibility to other cephalosporins.

Zone diameter limits for individual tests on Mueller-Hinton medium without blood or other supplements for cefazolin:

    E. coli ATCC 25922: 23 - 29 mm

    S. aureus ATCC 25923: 29 - 35 mm

Dilution Techniques

For organisms other than Hemophilus and Streptococcus spp., if the equivalent minimal inhibitory concentration breakpoint (MIC) for cefazolin is ≤ 8 μg/mL, then a bacterial isolate

may be considered susceptible. If the equivalent MIC breakpoint is ≥ 32 μg/mL organisms are considered to be resistant.

The MIC ranges for cefazolin for the control strains are:

    E. coli ATCC 25922: 1.0 - 4.0 μg/mL

    S. aureus ATCC 29213: 0.25 - 1.0 μg/mL

Pharmacology

Animal

The subcutaneous administration of cefazolin to experimentally infected mice demonstrated its effectiveness. In the presence of 25% and 50% serum, only a slight reduction of in vitro activity was detected.

Peak blood levels were attained in 5 minutes (i.v.) or in 15 - 30 minutes (s.c. and i.m.) in rats, rabbits, and dogs. Bioassay showed that 80% of cefazolin was recovered from urine, 24 hours post-dosing when administered intramuscularly to rats, rabbits and dogs; an indication that it was well absorbed and excreted in the urine. Following intravenous, intramuscular and subcutaneous administration of 20 mg/kg of cefazolin to rats and rabbits, significant tissue penetration was observed. Cefazolin was highly bound to human, rabbit and rat serum while only minimally bound to dog serum.

Cefazolin was administered by various parenteral routes in single doses of 20 mg/kg. In 24 hours, 0.5 to 3.3% of the dose was excreted in the bile of dogs and rabbits and 17 to 23% was excreted in the bile of rats; cefazolin was excreted in bile to a greater extent than cephaloridine or cephalothin after parenteral administration. Only one biologically active component equivalent to cefazolin was present in the urine of dogs after intramuscular administration, as revealed by bioautography. Rats received intramuscular injections of l4C-labelled cefazolin in order to perform radioactive tracer studies. Most of the parent compound was recovered unchanged in the urine or bile. Biologically inactive metabolites were recovered, comprising only a few percent or less of the given dose. At doses of 64 and 250 mg/kg in cats, there was a transient pressor response and slightly increased heart rate. In dogs at doses higher than 64 mg/kg, the femoral blood flow increased.

In various antigenicity tests, cefazolin showed a sensitizing activity and cross-reacted minimally with benzylpenicillin, ampicillin and cephaloridine.

Human

The blood levels of cefazolin listed on the following tables was determined following intramuscular and intravenous administration to healthy volunteers.

SERUM CONCENTRATION (µg/mL) FOLLOWING INTRAVENOUS ADMINISTRATION
Time After IV Injection
MinutesHours
51530124
Cefazolin1 g188.4135.8106.873.745.616.5
SERUM CONCENTRATION (µg/mL) FOLLOWING INTRAMUSCULAR ADMINISTRATION
Time After IM Injection (hours)
½1246810
Cefazolinnbsp;nbsp;1 g65.868.360.629.311.26.5< 4.2
500 mg36.236.837.915.56.33.02.2
250 mg15.517.013.05.12.5< 1.5< 1.5

The serum half-life for cefazolin is approximately 1.8 hours following intravenous administration and 2.0 hours following intramuscular administration.

In clinical pharmacology studies with hospitalized patients, the mean peak serum levels of cefazolin are approximately equivalent to those seen in normal volunteers.

Normal volunteers received a continuous intravenous infusion of 3.5 mg/kg for 1 hour (approximately 250 mg) followed by 1.5 mg/kg hourly for the next two hours (approximately 100 mg). In the third hour a steady serum level of 28 µg/mL was attained.

Similar levels of cefazolin were found in synovial fluid and serum four hours after drug administration. Cefazolin levels in cord blood were equivalent to 40% of those found in maternal blood.

Bile levels can exceed serum levels of cefazolin by 2 to 5 fold after 4 doses in patients without obstructive biliary disease. However, bile levels of cefazolin were considerably lower than serum levels in patients with obstructive biliary disease.

Cefazolin also reached therapeutic levels in various body tissues (e.g., heart, bone, gall bladder, and skeletal muscle) and in body fluids (e.g., surgical wound fluid, pleural fluid and urine).

Cefazolin is excreted unchanged in the urine, with approximately 60% of the drug excreted in the first six hours. 70% to 80% is excreted within 24 hours. Peak urine concentrations of approximately 2400 µg/mL and 4000 µg/mL were achieved following intramuscular doses of 500 mg and 1 gram, respectively.

Toxicology

Acute Toxicology

Both parenteral and oral cefazolin demonstrated a low order of toxicity in all species tested in acute toxicity studies. In mice, the intravenous LD50 was 3.8 g/kg or greater. The intravenous LD50 was 2.2 g/kg in dogs, and 4.5 g/kg in rats. The subcutaneous LD50 was 7.6 g/kg in mice and > 10 g/kg in rats. The intraperitoneal LD50 was 6.2 g/kg and 7.4 g/kg or more in mice and rats, respectively, while the oral LD50 in both these species was greater than 11.0 g/kg.

Subacute and Chronic Toxicity

Rats were treated for 3 and 6 months subcutaneously and for one month intra-peritoneally in subacute and chronic toxicity studies. The highest doses used were 2000 mg/kg per day in the 6 month study to 4000 mg/kg per day in the 1 and 3 month studies. Anemia was the only significant abnormality attributable to s.c. drug administration. In all studies there was a definite dose-related depression of ALT levels. Leukocytosis and hypererythropoiesis accompanies the anemia, which was probably related to injection site hemorrhage. The extent of the depression of the ALT values was dependent upon both the dose and the duration of treatment. The depression was not statistically significant at the low doses and was reversible upon withdrawal of the drug.

Similar results were found in chronic toxicity studies in dogs. At the higher doses there was marked depression of the ALT values and frank anemia resulted from high subcutaneous doses. Dogs treated intravenously did not develop the anemia indicating that it was probably associated with site of injection hemorrhage.

In all studies, the dose-related ALT decrease was not accompanied by histologic lesion in the liver. The effect on ALT was reversible upon drug withdrawal in both rats and dogs.

Reproduction and Teratology

Rabbits and mice received 240 mg/kg/day and 2400 mg/kg/day of cefazolin respectively. No teratologic effects were observed. No adverse effects on mating, fertility, gestation, delivery and lactation were observed in rats administered 2000 mg/kg/day. Baby rats, whose mothers were injected with 1200 mg/kg/day of cefazolin prior to delivery and throughout lactation, were observed and no effect of cefazolin administration on the birth, peri- and post-natal development was found.

Nephrotoxicity Study

The mean nephrotoxic intravenous dose in rabbits was between 300 and 400 mg/kg/day. No evidence of renal damage was produced when cefazolin was injected subcutaneously into mice at a dose of 8 g/kg/day for up to 3 days and into rats at a dose of 4 g/kg/day for up to 7 days.