Human Pharmacology:

Studies have shown that following intravenous administration of cefazolin to normal volunteers, mean serum concentrations peaked at approximately 185 mcg/mL and were approximately 4 mcg/mL at 8 hours for a 1 gram dose.

The serum half-life for cefazolin is approximately 1.8 hours following IV administration. In a study (using normal volunteers) of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg). Cefazolin produced a steady serum level at the third hour of approximately 28 mcg/mL.

Studies in patients hospitalized with infections indicate that cefazolin produces mean peak serum levels approximately equivalent to those seen in normal volunteers.

Bile levels in patients without obstructive biliary disease can reach or exceed serum levels by up to five times; however, in patients with obstructive biliary disease, bile levels of cefazolin for are considerably lower than serum levels (<1.0 mcg/mL).

In synovial fluid, the level of cefazolin becomes comparable to that reached in serum at about 4 hours after drug administration. Studies of cord blood show prompt transfer of cefazolin across the placenta. Cefazolin is present in very low concentrations in the milk of nursing mothers.

Cefazolin is excreted unchanged in the urine. In the first 6 hours approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours.

In patients undergoing peritoneal dialysis (2 L/hr.), cefazolin produced mean serum levels of approximately 10 and 30 mcg/mL after 24 hours' instillation of a dialyzing solution containing 50 mg/L and 150 mg/L, respectively. Mean peak levels were 29 mcg/mL (range 13 to 44 mcg/mL) with 50 mg/L (three patients), and 72 mcg/mL (range 26 to 142 mcg/mL) with 150 mg/L (six patients). Intraperitoneal administration of cefazolin is usually well tolerated.

Controlled studies on adult normal volunteers, receiving 1 gram 4 times a day for 10 days, monitoring CBC, SGOT, SGPT, bilirubin, alkaline phosphatase, BUN, creatinine, and urinalysis, indicated no clinically significant changes attributed to cefazolin.

Microbiology:

In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell wall synthesis. Cefazolin is active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic Gram-positive microorganisms:

 

Staphylococcus aureus (including penicillinase-producing strains)

 

Staphylococcus epidermidis

 

Streptococcus pneumoniae

 

Streptococcus pyogenes and other strains of Streptococci

Note: Methicillin-resistant staphylococci are uniformly resistant to cefazolin.

Group A beta-hemolytic streptococci and other strains of streptococci (many strains of enterococci are resistant)

 

Escherichia coil

 

Haemophilus influenzae

 

Klebsiella species

 

Proteus mirabilis

Note: Most strains of indole- positive Proteus (Proteus vulgaris), Enterobacter cloacae, Morganella morganii, and Providencia rettgeri are resistant. Serratia,

Pseudomonas, Mima, Herellea are almost uniformly resistant to cefazolin.

Disk Susceptibility Tests:

General:

Prolonged use of cefazolin may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential.

When cefazolin is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required (see DOSAGE AND ADMINISTRATION).

As with other beta-lactam antibiotics, seizures may occur if inappropriately high doses are administered to patients with impaired renal function (see DOSAGE AND ADMINISTRATION).

Cefazolin, as with all cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated

Prescribing cefazolin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Drug Interactions:

Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood levels.

Drug/Laboratory Test Interactions:

A false positive reaction for glucose in the urine may occur with Benedict's solution, Fehling's solution or with Clinitest® tablets, but not with enzyme-based tests such as Clinistix® and Tes-Tape®

Positive direct and indirect antiglobulin (Coombs) tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery.

Information for Patients:

Patients should be counseled that antibacterial drugs including cefazolin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefazolin is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping dosesor not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefazolin or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Carcinogenesis/Mutagenesis:

Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of cefazolin have not been performed.

Pregnancy:

Teratogenic Effects-Pregnancy Category B. Reproduction studies have been performed in rats, mice, and rabbits at doses up to 25 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefazolin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery:

When cefazolin has been administered prior to caesarean section, drug levels in cord blood have been approximately one quarter to one third of maternal drug levels. The drug appears to have no adverse effect on the fetus.

Nursing Mothers:

Cefazolin is present in very low concentrations in the milk of nursing mothers. Caution should be exercised when cefazolin is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness for use in premature infants and neonates have not been established. See DOSAGE AND ADMINISTRATION for recommended dosage in pediatric patients over 1 month old.

Geriatric Use:

Of the 920 subjects who received cefazolin in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).

Perioperative Prophylactic Use:

To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are:

1. 1 gram IV administered one half to 1 hour prior to the start of surgery.
2. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV during surgery (administration modified depending on the duration of the operative procedure).
3. 500 mg to 1 gram IV every 6 to 8 hours for 24 hours postoperatively.

It is important that (1) the preoperative dose be given just (one half to 1 hour) prior to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision and (2) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

Directions for Proper Use of Pharmacy Bulk Package:

Not for direct infusion. This Pharmacy Bulk Package is for use in a 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 4 HOURS from the initial closure entry 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. DISCARD ANY UNUSED PORTION AFTER 4 HOURS. THIS PHARMACY BULK PACKAGE IS NOT INTENDED TO BE DISPENSED AS A UNIT.

Dosage Adjustment for Patients With Reduced Renal Function:

Cefazolin may be used in patients with reduced renal function with the following dosage adjustments. Patients with a creatinine clearance of 55 mL/min or greater or a serum creatinine of 1.5 mg% or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min or serum creatinine of 1.6 to 3 mg% can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min or serum creatinine of 3.1 to 4.5 mg% should be given half the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min or less or serum creatinine of 4.6 mg% or greater should be given one half the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis, see CLINICAL PHARMACOLOGY (Human Pharmacology).

Pediatric Dosage:

In pediatric patients, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg/lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min.), 60% of the normal daily dosage given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min), 25% of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min.) may be given 10% of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

Preparation of Parenteral Solution:

Parenteral drug products should be SHAKEN WELL when reconstituted and inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solutions should be discarded.

Reconstituted solutions may range in color from pale yellow to yellow without change in potency.

When reconstituted or diluted according to the instructions below, cefazolin is stable for 24 hours at room temperature or for 10 days if stored under refrigeration (5˚C or 41˚F). Reconstituted solutions may range in color from pale yellow to yellow without a change in potency.

Pharmacy Bulk Packages:

Add Sterile Water for Injection, Bacteriostatic Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection according to the table below. SHAKE WELL. Use promptly. Discard vial within 4 hours after initial entry.

Intravenous Administration:

Intermittent or continuous infusion - Dilute reconstituted cefazolin in 50 to 100 mL of one of the following solutions:

 

Sodium Chloride Injection, USP

 

5% or 10% Dextrose Injection, USP

 

5% Dextrose in Lactated Ringer's Injection, USP

 

5% Dextrose and 0.9% Sodium Chloride Injection, USP

 

5% Dextrose and 0.45% Sodium Chloride Injection, USP

 

5% Dextrose and 0.2% Sodium Chloride Injection, USP

 

Lactated Ringer's Injection, USP

 

Invert Sugar 5% or 10% in Sterile Water for Injection

 

Ringer's Injection, USP

 

5% Sodium Bicarbonate Injection, USP

When diluted according to the instructions above, cefazolin is stable for 24 hours at room temperature or for 10 days if stored under refrigeration (5°C or 41°F).

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

Storage Conditions

Before reconstitution, store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

LATEX-FREE

Sterile, Nonpyrogenic, Preservative-free.