Product Monograph - Cefazolin for Injection, USP (Fresenius Kabi Canada, 500 mg, ..., 100 G)
RECENT MAJOR LABEL CHANGES
| 7 WARNINGS AND PRECAUTIONS, Skin | 09/2022 |
|---|---|
| 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 ....................................................................... 4
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 Reconstitution ......................................................................................................... 8
4.4 Administration ....................................................................................................... 10
5 OVERDOSAGE ............................................................................................................. 12
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 13
7 WARNINGS AND PRECAUTIONS ................................................................................. 13
7.1 Special Populations ................................................................................................ 15
7.1.1 Pregnant Women .............................................................................................. 15
7.1.2 Breast-feeding ................................................................................................... 15
7.1.3 Pediatrics........................................................................................................... 15
8 ADVERSE REACTIONS ................................................................................................. 15
9 DRUG INTERACTIONS ................................................................................................. 15
10 CLINICAL PHARMACOLOGY ........................................................................................ 16
10.1 Mechanism of Action ............................................................................................. 16
10.3 Pharmacokinetics ................................................................................................... 16
11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 17
12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 17
PART II: SCIENTIFIC INFORMATION ........................................................................................ 18
13 PHARMACEUTICAL INFORMATION ............................................................................. 18
14 CLINICAL TRIALS ......................................................................................................... 18
15 MICROBIOLOGY ......................................................................................................... 18
16 NON-CLINICAL TOXICOLOGY ...................................................................................... 20
17 SUPPORTING PRODUCT MONOGRAPHS ..................................................................... 21
PATIENT MEDICATION INFORMATION ................................................................................... 22
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
Cefazolin for Injection, USP (cefazolin for injection) is indicated in the treatment of the following infections when caused by susceptible strains of the listed organisms:
RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Klebsiella pneumoniae, Hemophilus influenzae, Staphylococcus aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.
URINARY TRACT INFECTIONS caused by Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae 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 pneumoniae, Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), Proteus mirabilis, Escherichia coli and Klebsiella pneumoniae.
ENDOCARDITIS caused by Staphylococcus aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.
Determine the susceptibility of the causative organism to cefazolin sodium by performing appropriate culture and susceptibility studies. (See 15 MICROBIOLOGY for disc susceptibility tests and dilution techniques).
NOTE: Most strains of enterococci, indole positive Proteus (P. vulgaris), Enterobacter cloacae, 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 15 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 safety of 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 |
| Pneumococcal pneumonia | 500 mg | Every 12 hours |
| 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 grams per day in serious infections such as endocarditis.
Treatment should be continued in beta-hemolytic streptococcal infections for at least 10 days 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 to 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, the 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 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 Divided into 3 Doses | 50 mg/kg/day 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 Reconstitution
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 (mL) | Approximate Available Volume (mL) | Nominal Concentration (mg/mL) | |||||||
| 500 mg | 0.9% Sodium Chloride Injection OR Sterile Water for Injection | 2 | 2.2 | 225 | |||||||
| 3.8 | 4 | 125 | |||||||||
| 1000 mg | Sterile Water for Injection | 2.5 | 3 | 334 | |||||||
(2) For Direct Intravenous (Bolus) Injection:
Single Dose Vials:
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 0.9%. SHAKE TO DISSOLVE ALL POWDER.
Pharmacy Bulk Vial Reconstitution Table
| Strength | Amount of Diluent | Approximate Available Volume | Approximate Concentration | |||
| 10 grams | 45 mL | 50 mL | 200 mg/mL | |||
| 96 mL | 100 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 to 100 mL in Sterile Water for Injection or one of the following solutions:
Sodium Chloride Injection 0.9%
Dextrose Injection 5% or 10%
Pharmacy Bulk Vial:
Reconstitute according to the Pharmacy Bulk Vial Reconstitution Table. SHAKE TO DISSOLVE ALL POWDER. Further dilute aliquots in 50 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.
PROPER PROCEDURE FOR RECONSTITUTION AND DISPENSING OF THE SMARTPAK® PHARMACY BULK PACKAGE
Entire procedure to be performed under Laminar Flow Hood using Aseptic Technique.
| RECONSTITUTION PHASE | MIXING PHASE | DISPENSING PHASE |
|---|---|---|
|
|
|
Warning
As with all parenteral products, intravenous 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.
4.4 Administration
NOTE: See 4.3 Reconstitution section 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 vein or through tubing for patients receiving parenteral fluids. (See list of solutions for intravenous infusion in 4.3 Reconstitution).
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 intravenous bottle. (See list of solutions for intravenous infusion in 4.3 Reconstitution). Cefazolin for Injection, USP SmartPak® Pharmacy Bulk Packages are for intravenous use only following reconstitution and transfer into syringes.
After transfer of the contents from the SmartPak® Pharmacy Bulk Packages into syringes, Cefazolin for Injection, USP can be administered in intermittent or continuous infusion via a syringe pump.
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 Reconstitution:
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 reconstitution (smaller) port and discard it. Follow the above “DIRECTIONS FOR PROPER USE OF SMARTPAK® PHARMACY BULK PACKAGE” and proceed to reconstitute the powder through the reconstitution (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 reconstitute 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 Reconstitution Port of the SmartPak® Pharmacy Bulk Package.
- 6. Using the pump, circulate the reconstituted 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 Reconstitution Port of the SmartPak® Pharmacy Bulk Package, and replace it with a syringe-filling adaptor.
- 8. Hang the bag from the eyelets support. Reconstituted 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 Reconstitution 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 | Amount of Sterile Water for Injection | Approximate Concentration |
| 100 grams | 960 mL | 100 mg/mL (1 g/10 mL) |
Dispensing Reconstituted Cefazolin/Instructions for Filling Empty Syringes:
Remove the 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 reconstituted 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.
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.
5 OVERDOSAGE
There is a lack of experience with acute Cefazolin for Injection, USP 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
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
|---|---|---|
| Intravenous | Sterile Powder for Solution, 500 mg, 1 g, and 10 g cefazolin (as cefazolin sodium) per vial | None. |
| Sterile Powder for Solution, 100 g cefazolin (as cefazolin sodium) per SmartPak® bag | None. | |
| Intramuscular | Sterile Powder for Solution, 500 mg and 1 g cefazolin (as cefazolin sodium) per vial | None. |
Cefazolin for Injection, USP is supplied in:
- 15 mL vials containing cefazolin sodium equivalent to 500 mg of cefazolin, packaged 25 vials per carton.
- 15 mL vials containing cefazolin sodium equivalent to 1 g of cefazolin, packaged 10 vials or 25 vials per carton.
- 100 mL “Pharmacy Bulk Package” vials containing cefazolin sodium equivalent to 10 grams of cefazolin, packaged 10 vials per carton.
- 100 grams SmartPak® “Pharmacy Bulk Package” containing cefazolin sodium equivalent to 100 grams of cefazolin.
Each gram of cefazolin sodium contains 48 mg of sodium.
CEFAZOLIN FOR INJECTION, USP DOES NOT CONTAIN PRESERVATIVES.
THE AVAILABILITY OF THE PHARMACY BULK PACKAGES IS INTENDED FOR HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM.
The SmartPak® bag 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 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-haemolytic 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
ClinitestR tablets solution, but not enzyme-based tests such as ClinistixR and Tes-TapeR, 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 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, anorexia. During antibiotic treatment, symptoms of pseudomembranous colitis can appear. There have been rare reports of nausea and vomiting. There have been reports of pseudomembranous 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, and skin rash.
Haematologic: 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 injection of 500 mg. Over 80% of injected cefazolin is excreted in the urine during the first 24 hours after intramuscular 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 1 g | 188.4 | 135.8 | 106.8 | 73.7 | 45.6 | 16.5 |
| (Time After Intramuscular Injection in Hours) | ||||||
| Cefazolin | ½ | 1 | 2 | 4 | 6 | 8 |
| 1 g | 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 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 excreted in the first six hours, and this increases to 70% to 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 (unreconstituted 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 reconstitution, 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.
Reconstituted 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.
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 8 hours. Any unused reconstituted solution should be discarded after 8 hours.
Extended Use of Intravenous Admixtures
Although intravenous 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.
Stability of Filled Syringes
In those situations in which the drug has been reconstituted 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.
12 SPECIAL HANDLING INSTRUCTIONS
Not applicable.
PART II: SCIENTIFIC INFORMATION
13 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 |
| Molecular formula and molecular mass: | C14H13N8NaO4S3 , 476.5 g / mol |
| Structural formula: | |
| Physicochemical properties: | Cefazolin sodium is a white, odourless 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 reconstituted solution ranges from 4.5 to 6. |
14 CLINICAL TRIALS
Clinical trial information is not available.
15 MICROBIOLOGY
CEFAZOLIN ACTIVITY AGAINST CLINICAL ISOLATES
| Type of Organism | 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. faecalis | 2 | 50 | 100 | ||||
 |
| Type of Organism | 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. pneumoniae | 6 | 100+ | |||||
| E. coli | 484 | 8.7 | 67.9 | 92.1 | 95.9 | 97.7 | |
| P. mirabilis | 30 | 50 | 86.7 | 90 | 90 | ||
| K. pneumoniae | 138 | 2.9 | 53.6 | 73.2 | 91.3 | 93.5 | |
| Enterobacter | 31 | 6.5 | 29 | 64.5 | 77.4 | ||
| H. influenzae | 30 | 13.3 | 70 | 100 | |||
| N. gonorrhoeae | 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 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 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 29213: 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.
ACUTE TOXICITY
| SPECIES | ROUTE OF ADMINISTRATION | LD50 LD (g/kg) | ||||||
|---|---|---|---|---|---|---|---|---|
| mice | intravenous | ≥ 3.9 | ||||||
| intraperitoneal | ≥ 4 | |||||||
| subcutaneous | 7.6 | |||||||
| oral | > 11 | |||||||
| rats | intravenous | ≥ 3 | ||||||
| intraperitoneal | 7.4 | |||||||
| subcutaneous | > 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 subcutaneous 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 2400 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/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
- 1. PrCEFAZOLIN FOR INJECTION (powder for solution, 500 mg, 1 g, and 10 g), Submission Control 254395, Product Monograph, Teva Canada Limited. FEB 04, 2022