Product Monograph - Cefazolin for Injection USP (Sandoz Canada)
RECENT MAJOR LABEL CHANGES
| 7 Warnings and Precautions, Skin | 11/2020 |
| 7 Warnings and Precautions, Renal | 09/2022 |
TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGES ................................................................................................. 2
TABLE OF CONTENTS ................................................................................................................... 2
PART I: HEALTH PROFESSIONAL INFORMATION ........................................................................... 3
1 INDICATIONS ....................................................................................................................... 4
1.1 Pediatrics ................................................................................................................... 5
1.2 Geriatrics .................................................................................................................... 5
2 CONTRAINDICATIONS .......................................................................................................... 5
4 DOSAGE AND ADMINISTRATION .......................................................................................... 5
4.2 Recommended Dose and Dosage Adjustment ............................................................. 5
4.3 Reconstitutions .......................................................................................................... 8
4.4 Administration ........................................................................................................... 9
5 OVERDOSAGE .................................................................................................................... 10
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ....... ERROR! BOOKMARK NOT DEFINED.
7 WARNINGS AND PRECAUTIONS ......................................................................................... 10
7.1 Special Populations .................................................................................................. 12
7.1.1 Pregnant Women .................................................................................................. 12
7.1.2 Breast-feeding ............................................................................................................... 12
7.1.3 Pediatrics ...................................................................................................................... 12
8 ADVERSE REACTIONS ......................................................................................................... 12
9 DRUG INTERACTIONS ......................................................................................................... 13
10 CLINICAL PHARMACOLOGY ................................................................................................ 13
10.1 Mechanism of Action .............................................................................................. 13
10.3 Pharmacokinetics ................................................................................................... 13
11 STORAGE, STABILITY AND DISPOSAL .................................................................................. 14
12 SPECIAL HANDLING INSTRUCTIONS .................................................................................... 14
PART II: SCIENTIFIC INFORMATION ............................................................................................ 15
13 PHARMACEUTICAL INFORMATION ..................................................................................... 15
14 CLINICAL TRIALS ................................................................................................................. 15
15 MICROBIOLOGY ................................................................................................................. 16
16 NON-CLINICAL TOXICOLOGY .............................................................................................. 17
17 SUPPORTING PRODUCT MONOGRAPHS ............................................................................. 18
PATIENT MEDICATION INFORMATION ....................................................................................... 19
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
Cefazolin for Injection USP (Cefazolin for Injection) is indicated for the treatment of the following infections when caused by susceptible strains of the listed organisms:
RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniæ, Klebsiella pneumoniæ, Hemophilus influenzæ, Staphylococcus aureus (penicillin-sensitive and penicillin- resistant) and group A beta-hemolytic streptococci.
URINARY TRACT INFECTIONS caused by Escherichia coli, Proteus mirabilis. Klebsiella pneumoniæ and some strains of enterobacter, and enterococci. See NOTE below.
SKIN AND SOFT TISSUE INFECTIONS caused by Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), group A beta-hemolytic streptococci and other strains of streptococci.
BONE AND JOINT INFECTIONS caused by Staphylococcus aureus.
SEPTICEMIA caused by Streptococcus pneumoniæ, Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), Proteus mirabilis, Escherichia coli and Klebsiella pneumoniæ. See NOTE below.
ENDOCARDITIS caused by Staphylococcus aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.
Determine susceptibility of the causative organism to cefazolin sodium by performing appropriate culture and susceptibility studies should be performed. (See MICROBIOLOGY for disc susceptibility tests and dilution techniques).
NOTE: Most strains of Enterococci, indole positive Proteus (P. vulgaris), Enterobacter cloacæ, Morganella morganii, Providencia rettgeri and methicillin-resistant staphylococci are resistant. Serratia, Pseudomonas, and Acinetobacter calcoaceticus (formerly Mima and Herellea species) are almost uniformly resistant to cefazolin. (See MICROBIOLOGY).
Perioperative Prophylaxis: In patients undergoing potentially contaminated surgical procedures, and in patients in whom infection would pose a serious risk (e.g. during open-heart surgery and prosthetic arthroplasty), the preoperative, intraoperative and postoperative administration of Cefazolin for Injection USP may reduce the incidence of certain postoperative infections.
Identification of the causative organisms should be made by culture should signs of infection occur so that appropriate therapy may be instituted.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin for Injection USP and other antibacterial drugs, Cefazolin for Injection USP should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
1.1 Pediatrics
Pediatrics (< 1 month): The use of cefazolin in prematures and infants under one month of age has not been established.
1.2 Geriatrics
Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.
2 CONTRAINDICATIONS
- Cefazolin for Injection USP is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
4 DOSAGE AND ADMINISTRATION
4.2 Recommended Dose and Dosage Adjustment
After reconstitution Cefazolin for Injection USP may be administered either intramuscularly or intravenously. In both cases total daily dosages are the same.
Adults
Adult Dosage Guide
| Type of Infection | Dose | Frequency |
| Mild infections caused by susceptible Gram- positive cocci | 250 mg to 500 mg | Every 8 hours |
| Acute, uncomplicated urinary tract infections* | 1 g | Every 12 hours |
| Moderate to severe infections | 500 mg to 1 g | Every 6 to 8 hours |
*This dosage recommendation applies to intramuscular use. The efficacy of cefazolin sodium when administered intravenously at 12 hour intervals has not been established.
Cefazolin sodium has been administered in dosages of 6 g per day in serious infections such as endocarditis.
Treatment should be continued for at least 10 days in beta-hemolytic streptococcal infections to minimize possible complications associated with the disease.
Dosage in Patients with Reduced Renal Function
After an initial loading dose appropriate to the severity of the infection, the following reduced dosage schedule is recommended:
Dosage Guide for Patients with Renal Impairment
| Creatinine Clearance (mL/s) | Serum Creatinine (mMol/L) | Dosage |
|---|---|---|
| ≤0.91 | ≥ 140 | 250 mg to 1 g every 6-12 hours |
| 0.58-0.9 | 141-273 | 250 mg to 1 g every 8-12 hours |
| 0.18-0.57 | 274-406 | 125 mg to 500 mg every 12 hours |
| ≤0.17 | ≥407 | 125 mg to 500 mg every 18 hours |
Perioperative Prophylactic Use
The recommended dosage regimen to prevent postoperative infection in contaminated or potentially contaminated surgery is:
- a. One gram intravenously or intramuscularly administered ½ hour to 1 hour prior to the start of surgery so that at the time of the initial surgical incision adequate antibiotic levels are present in the serum and tissues.
- b. For lengthy operative procedures (e.g. 2 hours or more) 0.5 g -1 g administered intravenously or intramuscularly during surgery. (Administration should be modified according to the duration of the operative procedure and the time of greatest exposure to infective organisms.)
- c. Postoperatively, 0.5 gram -1 gram intravenously or intramuscularly every 6 to 8 hours for 24 hours postoperatively. The prophylactic administration of Cefazolin for Injection USP may be continued for 3 to 5 days following the completion of surgery in which the occurrence of infection may be particularly devastating (e.g. open-heart surgery and prosthetic arthroplasty).
Pediatric Use:
A total daily dosage of 25 mg to 50 mg per kg (approximately 10 mg to 20 mg per pound) of body weight, divided into three or four equal doses, is effective for most mild to moderately severe infections in children.
For severe infections total daily dosage may be increased to 100 mg per kg (45 mg per pound) of body weight. The use of cefazolin in prematures and in infants under one month of age is not recommended since the safety for use in these patients has not been established.
Pediatric Dosage Guide – 25 mg/kg/day
| Weight | 25 mg/kg/day Divided Into 3 Doses | 25 mg/kg/day Divided Into 4 Doses | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| lb | kg | Approximate Single Dose mg/q8h | Volume Needed of 125 mg/mL* Solution | Approximate Single Dose mg/q6h | Volume Needed of 125 mg/mL* Solution | ||||||||
| 10 | 4.5 | 40 mg | 0.35 mL | 30 mg | 0.25 mL | ||||||||
| 20 | 9 | 75 mg | 0.6 mL | 55 mg | 0.45 mL | ||||||||
| 30 | 13.6 | 115 mg | 0.9 mL | 85 mg | 0.7 mL | ||||||||
| 40 | 18.1 | 150 mg | 1.2 mL | 115 mg | 0.9 mL | ||||||||
| 50 | 22.7 | 190 mg | 1.5 mL | 140 mg | 1.1 mL | ||||||||
- * 125 mg/mL concentration may be obtained by reconstituting the 500 mg vial with 3.8 mL of diluent.
Pediatric Dosage Guide – 50 mg/kg/day
| Weight 50 mg/kg/day 50 mg/kg/day | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Divided Into 3 Doses | Divided Into 4 Doses | ||||||||||||
| lb | kg | Approximate Single Dose mg/q8h | Volume Needed of 225 mg/mL* Solution | Approximate Single Dose mg/q6h | Volume Needed of 225 mg/mL* Solution | ||||||||
| 10 | 4.5 | 75 mg | 0.35 mL | 55 mg | 0.25 mL | ||||||||
| 20 | 9 | 150 mg | 0.7 mL | 110 mg | 0.5 mL | ||||||||
| 30 | 13.6 | 225 mg | 1 mL | 170 mg | 0.75 mL | ||||||||
| 40 | 18.1 | 300 mg | 1.35 mL | 225 mg | 1 mL | ||||||||
| 50 | 22.7 | 375 mg | 1.7 mL | 285 mg | 1.25 mL | ||||||||
*225 mg/mL concentration may be obtained by reconstituting the 500 mg vial with 2 mL of diluent.
Treatment with 60 percent of the normal daily dose may be administered in divided doses every 12 hours to children with mild to moderate renal impairment (Ccr 0.67-1.17 mL/s). Children with moderate to severe renal impairment (Ccr 0.33-0.87 mL/s) should be given 25 percent of the normal daily dose in equally divided doses every 12 hours, and children with severe renal impairment (Ccr 0.08-0.33 mL/s) should receive 10 percent of the normal daily dose every 24 hours.
All dosage recommendations apply after an initial loading dose.
4.3 Reconstitutions
Reconstituted Solutions
Parenteral drug products should be SHAKEN TO DISSOLVE ALL POWDER when reconstituted and inspected visually for particulate matter prior to administration. The drug solutions should be discarded if particulate matter is evident in reconstituted fluids.
Reconstituted solutions may range in colour from pale yellow to yellow without a change in potency.
(1) For Intramuscular Injection:
Single Dose Vials:
Reconstitute according to the table which follows. SHAKE TO DISSOLVE ALL POWDER.
Single Dose Vial Reconstitution Table
| Strength | Diluent | Volume to be Added to Vial (rnL) | Approximate Available Volume (mL) | Nominal Concentration (mg/mL) |
| 500 | Sodium Chloride Injection OR Sterile Water for Injection | 2 3.8 | 2.2 4 | 225 125 |
| 1000 | Sterile Water for Injection | 2.5 | 3 | 334 |
(2) For Direct Intravenous (Bolus) Injection:
Single Dose Vial:
Reconstitute as directed above. SHAKE TO DISSOLVE ALL POWDER. A minimum of 10 mL of Sterile Water for Injection should be used to dilute the reconstituted solution.
Pharmacy Bulk Vial:
Pharmacy Bulk Vials should be used for intravenous use only. Add, according to the table below, Sterile Water for injection, or Sodium Chloride injection. SHAKE TO DISSOLVE ALL POWDER.
Pharmacy Bulk Vial Reconstitution Table
| Strength | Amount of Diluent | Approximate Available Volume | Approximate Concentration |
| 10 grams | 45 mL 96 mL | 50 mL 100 mL | 200 mg/mL 100 mg/mL |
The vial is intended for single puncture and multiple dispensing, and the vial contents should be used within 8 hours.
(3) For intermittent or continuous intravenous infusion, reconstituted Cefazolin for Injection USP may be further diluted as follows:
Single Dose Vials:
Reconstitute according to the Single Dose Vial Reconstitution Table above. SHAKE TO DISSOLVE ALL POWDER. Further dilute the reconstituted Cefazolin for Injection USP to 50 mL to 100 mL in one of the following solutions:
Sodium Chloride Injection 0.9%
Dextrose Injection 5% or 10%
Dextrose 5% in Lactated Ringer’s Injection
Dextrose 5% and Sodium Chloride Injection 0.9% (also may be used with Dextrose 5% and Sodium Chloride Injection 0.45% or 0.2%)
Lactated Ringer’s Injection
Ringer’s Injection
Sodium Bicarbonate 5% in Sterile Water for Injection
Pharmacy Bulk Vial:
Reconstitute according to the Pharmacy Bulk Vial Reconstitution Table. SHAKE TO DISSOLVE ALL POWDER. Further dilute aliquots in 50 mL to 100 mL of Sterile Water for Injection or one of the solutions listed above.
The further diluted solutions above should be used within 24 hours at room temperature or 72 hours under refrigeration from the time of initial puncture.
4.4 Administration
NOTE: See 13 PHARMACEUTICAL INFORMATION for reconstitution and dilution directions.
Intramuscular Administration:
Inject the reconstituted solution into a large muscle mass. Pain on injection of Cefazolin for Injection USP occurs infrequently.
Intravenous Administration:
Direct (bolus) injection: Inject the appropriately diluted reconstituted solution slowly over 3 to 5 minutes directly into a vein or through tubing for patients receiving parenteral fluids. (See list of solutions for intravenous infusion in 13 PHARMACEUTICAL INFORMATION).
Intermittent or Continuous Infusion: The reconstituted solution can be administered along with primary intravenous fluid management programs in a volume control set or in a separate secondary IV bottle. (See list of solutions for intravenous infusion in 13 PHARMACEUTICAL INFORMATION).
5 OVERDOSAGE
There is a lack of experience with acute CEFAZOLIN FOR INJECTION overdosage. Supportive therapy should be instituted according to symptoms in cases of suspected overdosage.
| For management of a suspected drug overdose, contact your regional poison control centre. |
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table 1 – Dosage Forms, Strengths, Composition and Packaging
Cefazolin for Injection USP (sterile cefazolin sodium) is supplied as a powder in 15 mL, glass vials, with rubber stoppers and flip-off caps, equivalent to 500 mg or 1 g of cefazolin ,supplied in boxes of
10 vials.
Cefazolin for Injection USP is also available as a pharmacy bulk in a 100 mL infusion bottle, closed with hollow rubber stoppers and flip-off caps, equivalent to 10 g of cefazolin, supplied in boxes of 1 bottle.
THE AVAILABILITY OF THE PHARMACY BULK VIAL IS INTENDED FOR HOSPITALS WITH A RECOGNIZED IV ADMIXTURE PROGRAM.
Stopper is not made with natural rubber latex.
7 WARNINGS AND PRECAUTIONS
General
Cefazolin for Injection USP should be used with caution in penicillin-allergic patients. There is clinical evidence of partial cross-allergenicity of the penicillins and the cephalosporins. There are instances of patients who have had reactions to both penicillins and cephalosporins (including fatal anaphylaxis after parenteral use). Clinical and laboratory evidence of partial cross- allergenicity of
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
Intravenous Intramuscular | Powder for Solution 500 mg, 1 g, 10 g Powder for Solution 500 mg, 1 g | None. None. |
the two drug classes exists.
Cefazolin for Injection USP should be administered cautiously and then only when absolutely necessary to any patient who has demonstrated allergy, particularly to drugs. Immediate emergency treatment with epinephrine is indicated for serious anaphylactoid reactions. As indicated, oxygen, intravenous steroids, and airway management, including intubation, should also be employed.
In beta-hemolytic streptococcal infections, treatment should be continued for at least 10 days, to minimize possible complications associated with the disease
The overgrowth of non-susceptible organisms may result from the prolonged use of Cefazolin for Injection USP. It is essential that the patient be carefully observed. In patients with a history of lower gastrointestinal disease, particularly colitis, Cefazolin for Injection USP should be prescribed with caution.
Susceptibility/Resistance
Development of Drug Resistant Bacteria
Prescribing Cefazolin for Injection USP in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug- resistant bacteria.
Skin
Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions (SCAR) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported in association with beta-lactam treatment, When SCAR is suspected, Cefazolin for Injection USP should be discontinued and appropriate therapy and/or measures should be taken.
Monitoring and Laboratory Tests
Clinitest® tablets solution, but not enzyme-based tests such as Clinistix® and Tes-Tape® may falsely indicate glucose in the urine of patients on cefazolin.
Positive direct and indirect Coombs’ tests have been reported during treatment with cefazolin. These may also occur in neonates whose mothers received cephalosporins before delivery. The clinical significance of this effect has not been established.
Renal
Caution should be exercised in treating patients with pre-existing renal damage although cefazolin has not shown evidence of nephrotoxicity.
Patients with low urinary output due to impaired renal function should be administered reduced daily dosages of cefazolin. (See 4 DOSAGE AND ADMINISTRATION, Dosage in Patients with Reduced
Renal Function). Blood levels of cefazolin in dialysis patients remain fairly high and should be monitored.
Probenecid may decrease renal tubular secretion of cefazolin when used concurrently with cefazolin sodium, resulting in increased and prolonged cefazolin blood levels.
Seizures may occur with the administration of Cefazolin for Injection USP, particularly in patients with renal impairment when the dosage is not reduced appropriately. Discontinue Cefazolin for Injection USP if seizures occur or make appropriate dosage adjustments in patients with renal impairment. Anticonvulsant therapy should be continued in patients with known Seizure disorders.
7.1 Special Populations
7.1.1 Pregnant Women
The safety of the use of cefazolin sodium during pregnancy has not been established.
7.1.2 Breast-feeding
Very low concentrations of cefazolin are found in the milk of nursing mothers. Cefazolin for Injection USP should be administered with caution to a nursing woman.
7.1.3 Pediatrics
The safety of the use of cefazolin sodium in prematures and infants under one month of age has not been established.
8 ADVERSE REACTIONS
The following reactions have been reported:
Gastrointestinal: Diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach cramps and anorexia. During antibiotic treatment symptoms of pseudo membranous colitis can appear.
There have been rare reports of nausea and vomiting. There have been reports of pseudo membranous colitis with the use of cephalosporins. It is therefore important to consider its diagnosis in patients who develop diarrhea in association with antibiotic use.
Allergic: Allergic reactions occur infrequently and include: anaphylaxis, eosinophilia, itching, drug fever, skin rash.
Hematologic: Neutropenia, anemia, leukopenia, thrombocythemia, positive direct and indirect antiglobulin (Coombs’) tests.
Hepatic and Renal: Without clinical evidence of renal or hepatic impairment transient increases in AST (SGOT), ALT (SGPT), BUN and alkaline phosphatase levels have been observed.
Transient hepatitis and cholestatic jaundice have been reported rarely, as with some penicillins and some other cephalosporins.
Local Reactions: Phlebitis at the site of injection has occurred rarely. Infrequently there is pain at the site of injection following intramuscular injection. Some induration has been reported.
Other Reactions: Vulvar pruritus, genital moniliasis, vaginitis and anal pruritus.
9 DRUG INTERACTIONS
The renal tubular secretion of cefazolin may be decreased when probenecid is used concurrently, resulting in increased and prolonged cefazolin blood levels.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
Cefazolin is a cephalosporin antibiotic for parenteral administration. Cefazolin exerts its bactericidal effect by inhibiting bacterial cell wall synthesis.
10.3 Pharmacokinetics
Cefazolin is about 85% bound to serum protein. The peak level in serum is approximately 32-42 mg/mL after an intramuscular (IM) injection of 500 mg. Over 80% of injected cefazolin is excreted in the urine during the first 24 hours after IM injection; most is excreted during the first 4-6 hours.
The blood levels of cefazolin listed on the following tables were determined following intramuscular and intravenous administration.
Serum Concentration (mg/mL) Following Administration:
(Time After Intravenous Injection in Minutes)
| 5 | 15 | 30 | 60 | 120 | 240 | |
| Cefazolin 1g | 188.4 | 135.8 | 106.8 | 73.7 | 45.6 | 16.5 |
(Time After Intramuscular Injection in Hours)
| Cefazolin | 1/2 | 1 | 2 | 4 | 6 | 8 |
| 1g | 65.8 | 68.3 | 60.6 | 29.3 | 11.2 | 6.5 |
| 500 mg | 36.2 | 36.8 | 37.9 | 15.5 | 6.3 | 3 |
| 250 mg | 15.5 | 17 | 13 | 5.1 | 2.5 | <1.5 |
The serum half-life is approximately 1.8 hours following intravenous administration and 2.0 hours after intramuscular administration.
The mean peak serum levels of cefazolin in hospitalized patients are approximately equivalent to those seen in normal volunteers.
Healthy volunteers received a continuous intravenous infusion of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg hourly for the next two hours (approximately 100 mg). A steady serum level of 28 mg/mL was attained at the third hour.
Cefazolin levels in synovial fluid and serum are similar four hours after drug administration. Levels in cord blood are equivalent to 40% of those found in maternal blood.
In patients without obstructive biliary disease, serum levels of cefazolin can be up to five times lower than bile levels of cefazolin. However, bile levels of cefazolin are considerably lower than serum levels in patients with obstructive biliary disease.
Cefazolin is excreted unchanged in the urine. Approximately 60% of the drug is excreted in the first six hours, and this increases to 70%-80% within 24 hours. Peak urine concentrations of approximately 2400 mcg/mL and 4000 mcg/mL are achieved following intramuscular doses of 500 mg and 1 gram, respectively.
11 STORAGE, STABILITY AND DISPOSAL
Cefazolin for Injection USP should be stored between 15°C and 25°C, protected from light.
Reconstituted Cefazolin for Injection USP may be stored for 24 hours at controlled room temperature (between 15°C and 25°C) or for 72 hours under refrigeration (2 to 8°C), protected from light.
Cefazolin for Injection USP solution reconstituted with bacteriostatic diluent and used for intramuscular administration as multiple-dose containers should be used within 7 days when stored under refrigeration.
The Pharmacy Bulk Vial is intended for multiple dispensing for intravenous use only, employing a single puncture. Following reconstitution, the solution should be dispensed and diluted for use within eight hours. Any unused reconstituted solution should be discarded after eight hours.
12 SPECIAL HANDLING INSTRUCTIONS
None.
PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper Name: Cefazolin sodium
Chemical Name: 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-[[(5- methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-7-[[(1H-tetrazol- 1-yl)acetyl] amino]-, monosodium salt (6R-trans).
Monosodium (6R, 7R)-3{[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl}-8- oxo-7-[2-(1H-tetrazol-l-yl)acetamido}-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylate.
Structural Formula:
N N
N N O
H H
H N
- N S S
O
O ONa N N
CH3
Molecular Formula and Molecular Mass: C14H13N8NaO4S3 476.50 g/mol
Description: Cefazolin sodium is a white to off-white, practically odourless solid. The drug is freely soluble in water and very slightly soluble in alcohol. It is practically insoluble in chloroform and ether. The pH is between 4.5 and 6.0, in an aqueous solution containing 100 mg of cefazolin per millilitre.
14 CLINICAL TRIALS
Clinical Trial information is not available.
S
15 MICROBIOLOGY
Cefazolin Activity Against Clinical Isolates
| No. of Strains | Cumulative Percentage Susceptible to Strains Indicated Concentration (mcg/mL) | ||||||||||||||||||||
| <0.05 | <0.1- 0.78 | 1.56-3.13 | 6.25- 12.5 | 25-50 | 100 | ||||||||||||||||
| S. aureus | 700 | 0.14 | 59.1 | 90.6 – 92.4* | 97.3 | 99.7 | 99.9 | ||||||||||||||
| S. pyogenes | 5 | 80+ | 100 | ||||||||||||||||||
| S. fæcalis | 2 | 50 | 100 | ||||||||||||||||||
| S. pneumoniæ | 6 | 100+ | |||||||||||||||||||
| E. coli | 484 | 8.7 | 67.9 | 92.1 | 95.9 | 97.7 | |||||||||||||||
| P. mirabilis | 30 | 50 | 86.7 | 90 | 90 | ||||||||||||||||
| K. pneumoniæ | 138 | 2.9 | 53.6 | 73.2 | 91.3 | 93.5 | |||||||||||||||
| Enterobacter | 31 | 6.5 | 29 | 64.5 | 77.4 | ||||||||||||||||
| H. influenzæ | 30 | 13.3 | 70 | 100 | |||||||||||||||||
| N. gonorrhoeæ | 13 | 38.5 | 100 | ||||||||||||||||||
| Shigella SPP | 2 | 50 | 50 | 100 | |||||||||||||||||
| Salmonella SPP | 8 | 100 | |||||||||||||||||||
Staphylococci (coagulase - negative) | 295 | 66 | 82 | 90 | 93 | 100 | |||||||||||||||
- * Reported as 3.13-6.25 mcg/mL
+ Reported as ≤0.1 mcg/mL
Disc Susceptibility Tests
The following criteria should be used to interpret tests using a standardized 30 mcg cephalosporin-class disc:
Zones of 18 mm or greater 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 which 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 are attained. Zones of 14 mm or less are produced by resistant organisms.
The cephalothin disc should not be used for testing susceptibility to other cephalosporins.
Dilution Techniques: If the minimal inhibitory concentration (MIC) for cefazolin is not more than 16 mg/mL, then a bacterial isolate may be considered susceptible. If the MIC is equal to or greater than 64 mg/mL, organisms are considered to be resistant.
The ranges of MIC for the control strains were:
E. coli ATCC 25922 1-4 mg/mL
S. aureus ATCC 25923 0.25-1 mg/mL
16 NON-CLINICAL TOXICOLOGY
General Toxicology:
Acute Toxicity
Parenteral and oral cefazolin demonstrated low toxicity in rodents, canines and rabbits tested in acute toxicity studies.
| Species | Route of Administration | LD50 (g/kg) |
| intravenous | ≥3.9 | |
| Mice | Intraperitoneal subcutaneous | ≥4 7.6 |
| oral | >11 | |
| intravenous | ≥3 | |
| Rats | Intraperitoneal subcutaneous | 7.4 >10 |
| oral | >11 | |
| Rabbits | intravenous | >2 |
| Dogs | intravenous | >2 |
Subacute and Chronic Toxicity
Rats and dogs were studied in subacute and chronic parenteral toxicity of cefazolin. Rats were treated for 3 and 6 months subcutaneously and for one month intraperitoneally. The highest doses ranged from 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 SC drug administration. In all experiments there was a definite dose-related depression of SGPT levels. Leukocytosis and hypererythropoiesis accompanied the anemia, which was probably related to hemorrhaging at the injection site.
The lowering of the SGPT was dependent upon both the dose and the duration of treatment. This was not statistically significant at the low doses and was reversible upon withdrawal of the drug. Equivalent chronic studies in dogs produced similar results: at the higher doses there was a fall in SGPT and frank anemia resulted from high subcutaneous doses. Dogs treated intravenously did not develop the anemia indicating that it was probably associated with hemorrhaging at the site of injection.
Reproductive and Developmental Toxicology:
Rabbits and mice were administered cefazolin in doses of 240 mg/kg/day and 2 400 mg/kg/day. No teratologic effects were observed. No adverse effects on mating, fertility, gestation, delivery and lactation were observed in rats administered 2000 mg/kg per day. Baby rats whose mothers were injected with 1200 mg/kg/day of cefazolin prior to delivery and throughout lactation were observed and there was no effect on the birth, or peri- and postnatal development.
Special Toxicology:
Nephrotoxicity
The nephrotoxicity of cefazolin was studied following intravenous injections of rabbits and subcutaneous injections of mice and rats. 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.
17 SUPPORTING PRODUCT MONOGRAPHS
Cefazolin for Injection, 500 mg, 1.0 g and 10.0 g, Submission Control #254395, Product Monograph, Teva Canada Limited, Date of Revision: February 4, 2022.