Cefazolin

General Injectables & Vaccines, Inc

Cefazolin 1 gm Injection, USP Vial

FULL PRESCRIBING INFORMATION: CONTENTS*

• Description
• Clinical Pharmacology
• Cefazolin Indications and Usage
• Contraindications
• Warnings
• Precautions
• Side Effects
• Dosage and Administration
• How Supplied
• References
• Sample Package Label

FULL PRESCRIBING INFORMATION

Description

Rx only
SAGENT™
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 or prevent infections that are proven or strongly suspected to be caused by bacteria.

Cefazolin for injection USP is a semi-synthetic cephalosporin for parenteral administration. It is the sodium salt of 3-{[(5-ethyl-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-carboxylic acid.
Cefazolin sodium USP has the following structural formula:

Cefazolin for injection USP is a white to off-white, practically odorless, crystalline powder.
Cefazolin for injection USP is supplied in 500 mg or 1 g vials. Each vial contains, cefazolin sodium equivalent to 500 mg or 1 g of cefazolin. The sodium content is approximately 24 mg (1 mEq sodium ion) per 500 mg or 48 mg (2.1 mEq sodium ion) per 1 g of cefazolin sodium. The 500 mg and 1 g vials are to be administered by intramuscular or intravenous routes.

Clinical Pharmacology

After intramuscular administration of cefazolin to normal volunteers, the mean serum concentrations were 37 mcg/mL at 1 hour and 3 mcg/mL at 8 hours following a 500 mg dose, and 64 mcg/mL at 1 hour and 7 mcg/mL at 8 hours following a 1 gram dose. 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 and approximately 2 hours following IM 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 are considerably lower than serum levels (less than 1 mcg/mL). In synovial fluid, the cefazolin level 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 levels 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. Cefazolin achieves peak urine concentrations of approximately 2,400 mcg/mL and 4,000 mcg/mL respectively following 500 mg and 1 gram intramuscular doses. 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 has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS AND USAGE.

Gram-Positive Aerobes
Staphylococcus aureus (including beta-lactamase-producing strains)
Staphylococcus epidermidis
Streptococcus pyogenes, Streptococcus agalactiae, and other strains of streptococci
Streptococcus pneumoniae
Methicillin-resistant staphylococci are uniformly resistant to cefazolin, and many strains of enterococci are resistant.

Gram-Negative Aerobes
Escherichia coli
Proteus mirabilis
Most strains of indole positive Proteus (Proteus vulgaris), Enterobacter spp.,
Morganella morganii, Providencia rettgeri, Serratia spp., and Pseudomonas spp. are resistant to cefazolin.

Susceptibility Tests
Diffusion Techniques
Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure1 that has been recommended for use with disks to test the susceptibility of microorganisms to cefazolin uses the 30 mcg cefazolin disk. Results of the standardized single-disk susceptibility test1 with a 30 mcg cefazolin disk should be interpreted according to the following criteria:

Cefazolin Indications and Usage

Cefazolin for injection USP is indicated in the treatment of the following infections due to susceptible organisms:
Respiratory Tract Infections: Due to S. pneumoniae, S. aureus (including beta-lactamase-producing strains) and S. pyogenes. Injectable benzathine penicillin is considered to be the drug of choice in treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefazolin is effective in the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of cefazolin in the subsequent prevention of rheumatic fever are not available.
Urinary Tract Infections: Due to E. coli, P. mirabilis.
Skin And Skin Structure Infections: Due to S. aureus (including beta-lactamase-producing strains), S. pyogenes, and other strains of streptococci.
Biliary Tract Infections: Due to E. coli, various strains of streptococci, P. mirabilis, and S. aureus.
Bone And Joint Infections: Due to S. aureus.
Genital Infections: (i.e., prostatitis, epididymitis) due to E. coli, P. mirabilis.
Septicemia: Due to S. pneumoniae, S. aureus (including beta-lactamase-producing strains), P. mirabilis, E. coli.
Endocarditis: Due to S. aureus (including beta-lactamase-producing strains) and S. pyogenes.
Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to cefazolin.

Perioperative Prophylaxis
The prophylactic administration of cefazolin preoperatively, intraoperatively, and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures which are classified as contaminated or potentially contaminated (e.g., vaginal hysterectomy, and cholecystectomy in high-risk patients such as those older than 70 years, with acute cholecystitis, obstructive jaundice, or common duct bile stones). The perioperative use of cefazolin may also be effective in surgical patients in whom infection at the operative site would present a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty). The prophylactic administration of cefazolin should usually be discontinued within a 24- hour period after the surgical procedure. 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.  If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism so that  appropriate therapy may be instituted.(See DOSAGE AND ADMINISTRATION.) 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 or prevent 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.

Contraindications

CEFAZOLIN FOR INJECTION USP IS CONTRAINDICATED IN PATIENTS WITH KNOWN ALLERGY TO THE CEPHALOSPORIN GROUP OF ANTIBIOTICS.

Warnings

BEFORE THERAPY WITH CEFAZOLIN FOR INJECTION USP IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFAZOLIN, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFAZOLIN FOR INJECTION USP OCCURS, DISCONTINUE TREATMENT WITH THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefazolin for injection USP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate
fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Precautions

General
Prolonged use of cefazolin for injection USP may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential. When cefazolin for injection USP 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 for injection USP, 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 for injection USP 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®.
Positive direct and indirect antiglobulin (Coombs) tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery.

Information for Patients
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. Patients should be counseled that antibacterial drugs including cefazolin for injection USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefazolin for injection USP is prescribed to treat a 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 doses or not completing the full course of therapy may (1) decrease the effectiveness oft the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefazolin for injection USP or other antibacterial drugs in the future.

Carcinogenesis/Mutagenesis
Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of cefazolin for injection USP 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 for injection USP 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 older than 1 month.

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, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).

Side Effects

The following reactions have been reported:
Gastrointestinal: Diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach cramps, anorexia and pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS). Nausea and vomiting have been reported rarely.
Allergic: Anaphylaxis, eosinophilia, itching, drug fever, skin rash, Stevens-Johnson syndrome.
Hematologic: Neutropenia, leukopenia, thrombocytopenia, thrombocythemia.
Hepatic: Transient rise in SGOT, SGPT, and alkaline phosphatase levels has been observed. As with other cephalosporins, reports of hepatitis have been received.
Renal: As with other cephalosporins, reports of increased BUN and creatinine levels, as well as renal failure, have been received.
Local Reactions: Rare instances of phlebitis have been reported at site of injection. Pain at the site of injection after intramuscular administration has occurred infrequently. Some induration has occurred.
Other Reactions: Genital and anal pruritus (including vulvar pruritus, genital moniliasis, and vaginitis).

Dosage and Administration

How Supplied

Cefazolin for Injection, USP is white to off-white crystalline powder and supplied as follows:

References

1. National Committee for Clinical Laboratory Standards (NCCLS). January 2003. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Eighth Edition.             NCCLS Document M2-A8 and Disk Diffusion Supplemental Tables M100-S13. NCCLS, Wayne, PA, USA.

2. National Committee for Clinical Laboratory Standards (NCCLS). January 2003. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved                 Standard-Sixth Edition. NCCLS Document M7-A6 and MIC Testing Supplemental Tables, M100-S13. NCCLS, Wayne, PA, USA.

Clinitest is a registered trademark of Miles, Inc.
Clinistix is a registered trademark of Bayer Corporation.
SAGENT™
Mfd. for SAGENT Pharmaceuticals
Schaumburg, IL 60195 (USA)
Made in India
©2009 Sagent Pharmaceuticals, Inc.
Revised: October 2009

Sample Package Label