PRECAUTIONS

The overgrowth of non-susceptible organisms may result from the prolonged use of Cefazolin for Injection, USP. It is essential that careful clinical observation be maintained. Appropriate measures should be taken if superinfection occurs during therapy. In patients with a history of lower gastrointestinal disease, and in particular, colitis, cefazolin should be prescribed with caution. Caution should be used in treating patients with pre-existing renal damage even though cefazolin has not shown evidence of nephrotoxicity. In patients with low urinary output due to impaired renal function, cefazolin is not readily excreted and these patients should be administered reduced daily dosages of cefazolin (see DOSAGE AND ADMINISTRATION, Adult Dosage, Dosage in Patients with Reduced Renal Function). Blood levels of cefazolin in dialysis patients remain fairly high and should be monitored. There have been reports during treatment with cefazolin of positive direct and indirect Coombs tests. These may also occur in neonates whose mothers received cephalosporins before delivery. The clinical significance of this effect has not been established. False positive indications of urinary glucose may occur in cefazolin-treated patients where Clinitest* tablets solution are used, but not enzyme-based tests such as Clinistix* and Tes-Tape**. Drug Interactions The renal tubular secretions of cefazolin may be decreased when probenecid is used concurrently, resulting in increased and prolonged cefazolin blood levels. Pregnancy The safety of cefazolin sodium for use during pregnancy has not been established. Infants The safety of cefazolin sodium for use in premature infants and in infants under one month of age has not been established. Nursing Mothers Very low concentrations of cefazolin sodium are found in the milk of nursing mothers. Caution should be used when cefazolin sodium is administered to a nursing woman.

NO820381

July 2008

Cefazolin

for Injection, USP

500 mg/15 mL Vial 1 g/15 mL Vial 10 g/100 mL Pharmacy Bulk Package Vial 20 g/100 mL Pharmacy Bulk Package Vial

Antibiotic

THERAPEUTIC CLASSIFICATION
Antibiotic

ACTION AND CLINICAL PHARMACOLOGY

Cefazolin sodium is a cephalosporin antibiotic for parenteral administration. It exerts its bacterial effect by inhibiting bacterial cell wall synthesis.

INDICATIONS AND CLINICAL USES

Cefazolin for Injection, USP may be 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. SKIN AND SOFT TISSUE INFECTIONS caused by Staphylococcus aureus (penicillinsensitive 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. In order to determine the susceptibility of the causative organism to cefazolin sodium, appropriate culture and susceptibility studies should be performed. 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. 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 sodium may reduce the incidence of certain postoperative infections. Should signs of infection occur, identification of the causative organisms should be made by culture in order that appropriate therapy may be instituted.

ADVERSE REACTIONS
The following reactions have been reported. Allergic Anaphylaxis, eosinophilia, itching, drug fever, and skin rash. Gastrointestinal Diarrhea, oral candidiasis (oral thrush), cheilitis, vomiting, nausea, stomach cramps, anorexia. During antibiotic treatment, symptoms of pseudomembranous colitis can appear. Nausea and vomiting have been reported rarely. Hematologic Neutropenia, anemia, leukopenia, thrombocythemia, positive direct and indirect antiglobulin (Coombs) tests. Hepatic and Renal Transient increases in AST (SGOT), ALT (SGPT), BUN and alkaline phosphatase levels have been observed without clinical evidence of hepatic or renal impairment. 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 rarely occurred, infrequently there may be pain and induration at the site of injection following intramuscular injection. Other Reactions Genital moniliasis, vaginitis, vulvar and anal pruritus.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Supportive therapy should be instituted according to symptoms in cases of suspected overdosage. There is presently a lack of experience with acute cefazolin overdosage.

CONTRAINDICATIONS
In patients with known allergy or hypersensitivity to the cephalosporin group of antibiotics, Cefazolin for Injection, USP is contraindicated.

DOSAGE AND ADMINISTRATION

Cefazolin for Injection, USP may be administered either intramuscularly or intravenously after constitution. In both cases, total daily dosages are the same. Treatment should be continued in beta-hemolytic streptococcal infections for at least 10 days to minimize possible complications associated with the disease. Adult Dosage Type of Infection Pneumoccoccal pneumonia Mild infections caused by susceptible Gram + cocci Acute, uncomplicated urinary tract infections* Moderate to severe infections ADULT DOSAGE GUIDE Dose 500 mg 250 to 500 mg 1g 500 mg to 1 g Frequency Every 12 hours Every 8 hours Every 12 hours Every 6 to 8 hours

WARNINGS
CEPHALOSPORIN DERIVATIVES SHOULD BE USED WITH CAUTION IN PENICILLINALLERGIC PATIENTS. 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 CROSSALLERGENICITY FOR THESE TWO DRUG CLASSES EXISTS. FOR ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS, CEFAZOLIN FOR INJECTION, USP SHOULD BE ADMINISTERED CAUTIOUSLY AND THEN ONLY WHEN ABSOLUTELY NECESSARY. IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE IS REQUIRED FOR SERIOUS ANAPHYLACTOID REACTIONS. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT INCLUDING INTUBATION, SHOULD ALSO BE EMPLOYED, AS NECESSARY. 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.

*This dosage recommendation applies to intramuscular use. The efficacy of cefazolin sodium when administered intravenously at 12-hour intervals has not been established. page 1 of 3
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Cefazolin sodium has been administered in dosages of 6 grams per day in serious infections such as endocarditis. Dosage in Patients with Reduced Renal Function: After an initial loading dose appropriate to the severity of the infections, the following reduced dosage schedule is recommended: DOSAGE GUIDE FOR RENALLY IMPAIRED PATIENTS Creatinine Serum Clearance Creatinine (mL/s) ( mol/ L) Dosage 0.91 140 250 mg to 1 g every 6 - 12 hours 0.58 - 0.90 141 - 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 following dosage regimens are recommended to prevent postoperative infection in contaminated or potentially contaminated surgery: a) 1 gram i.v. or i.m. administered 1 2 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) 0.5 to 1 gram administered i.v. or i.m. during surgery for lengthy operative procedures (e.g., 2 hours or more). (Administration should be modified according to the duration of the operative procedure and the time of greatest exposure to infective organisms.) c) 0.5 gram to 1 gram i.v. or i.m. every 6 to 8 hours for 24 hours postoperatively. Following the completion of surgery in which the occurrence of infection may be particularly devastating (e.g., open heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin sodium may be continued for 3 to 5 days. Pediatric Dosage A total daily dosage of 25 to 50 mg per kg of body weight, divided into three or four equal doses, is effective for most mild to moderately severe infections in children. Duration of therapy in most cases should be 5 to 10 days. Treatment should be continued in beta-hemolytic streptococcal infections for at least 10 days to minimize possible complications associated with the disease. For severe infections, the total daily dosage may be increased to 100 mg per kg of body weight. Cefazolin administration to premature infants and in infants under one month is not recommended since the safety of cefazolin use in these patients has not been established. Administration of 60 percent of the normal daily dose in divided doses every 12 hours may be used for children with mild to moderate renal impairment (CCr 0.67 - 1.17 mL/s). Children with moderate 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. An initial loading dose precedes all recommended doses. PEDIATRIC DOSAGE GUIDE 25 mg/kg/day 25 mg/kg/day 25 mg/kg/day Divided into 3 doses Divided into 4 doses Approx. Volume Needed Approx. Volume Needed Single Dose of 125 mg/mL* Single Dose of 125 mg/mL* mg/q8h Solution mg/q6h Solution 40 mg 0.35 mL 30 mg 0.25 mL 75 mg 0.60 mL 55 mg 0.45 mL 115 mg 0.90 mL 85 mg 0.70 mL 150 mg 1.20 mL 115 mg 0.90 mL 190 mg 1.50 mL 140 mg 1.10 mL

For Intramuscular Use: Inject the constituted solution into a large muscle mass. Pain on injection with cefazolin is infrequent. For Intravenous Use: The intravenous route is preferred for patients with septicemia, peritonitis, or other severe life threatening infections. Direct Intravenous (bolus) Injection: Inject the appropriately diluted constituted 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 PHARMACEUTICAL INFORMATION.) Intermittent or Continuous Intravenous Infusion: The constituted solution can be administered along with primary intravenous fluid management programs in a volume control set or in a separate secondary i.v. bottle. (See list of solutions for intravenous infusion in PHARMACEUTICAL INFORMATION.) It is desirable to discontinue the administration of other solutions during the infusion of cefazolin.

PHARMACEUTICAL INFORMATION
Drug Substance Proper Name: Chemical Name: Cefazolin Sodium 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
N COONa O N N NCH2COHN N N H H S CH2S S CH3 N

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, present as cefazolin sodium. Each gram of cefazolin sodium contains 48 mg of sodium. Contains no preservative.

STABILITY AND STORAGE RECOMMENDATION

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

Weight (kg) 4.5 9.0 13.6 18.1 22.7

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 25C, or for 72 hours under refrigeration (2 - 8C) 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. 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% page 2 of 3
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*125 mg/mL concentration may be obtained by constituting the 500 mg vial with 3.8 mL of diluent. PEDIATRIC DOSAGE GUIDE 50 mg/kg/day 50 mg/kg/day 50 mg/kg/day Divided into 3 doses Divided into 4 doses Approx. Volume Needed Approx. Volume Needed Single Dose of 225 mg/mL* Single Dose of 225 mg/mL* mg/q8h Solution mg/q6h Solution 75 mg 0.35 mL 55 mg 0.25 mL 150 mg 0.70 mL 110 mg 0.50 mL 225 mg 1.00 mL 170 mg 0.75 mL 300 mg 1.35 mL 225 mg 1.00 mL 375 mg 1.70 mL 285 mg 1.25 mL

Weight (kg) 4.5 9.0 13.6 18.1 22.7

*225 mg/mL concentration may be obtained by constituting the 500 mg vial with 2.0 mL of diluent. Administration NOTE: See section under PHARMACEUTICAL INFORMATION for constitution and dilution directions.

Vial Size (mg) 500 500 1000

SINGLE-DOSE VIAL CONSTITUTION TABLE Volume Approx. to be Added Available Diluent to Vial (mL) Volume (mL) 0.9% Sodium 2.0 2.2 Chloride Injection Sterile Water 3.8 4.0 for Injection Sterile Water 2.5 3.0 for Injection

Nominal Concentration (mg/mL) 225 125 334

Vial Size (g) 10 20

PHARMACY BULK VIAL DILUTION TABLE Volume to be Approx. Available Nominal Concentration Added to Vial (mL) Volume (mL) (mg/mL) 45 50 200 96 100 100 87 100 200

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 to 8C), from the time of initial puncture of the stopper.

SPECIAL INSTRUCTIONS
THE USE OF PHARMACY BULK VIALS IS RESTRICTED TO HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM. 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: PF320020 15 mL vials containing cefazolin sodium equivalent to 500 mg of cefazolin, packaged 25 vials per carton. PF320021 15 mL vials containing cefazolin sodium equivalent to 1 g of cefazolin, packaged 25 vials per carton. PF320022 100 mL Pharmacy Bulk Package vials containing cefazolin sodium equivalent to 10 grams of cefazolin, packaged 10 vials per carton. C446B1 100 mL Pharmacy Bulk Package vials containing cefazolin sodium equivalent to 20 grams of cefazolin, packaged 10 vials per carton. CEFAZOLIN FOR INJECTION, USP DOES NOT CONTAIN ANY PRESERVATIVE.

* Registered trademark of Miles Laboratories, Inc. ** Registered trademark of Eli Lilly Canada, Inc.

PHARMACEUTICAL PARTNERS OF CANADA INC. Richmond Hill, ON L4B 3P6 ? 1-877-821-7724

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