Cefazolin

General Injectables & Vaccines, Inc

Cefazolin Sodium Injection USP 500mg

FULL PRESCRIBING INFORMATION: CONTENTS*

• CEFAZOLIN DESCRIPTION
• CLINICAL PHARMACOLOGY
• INDICATIONS & USAGE
• CEFAZOLIN CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• CEFAZOLIN ADVERSE REACTIONS
• DOSAGE & ADMINISTRATION
• HOW SUPPLIED
• PACKAGE LABEL

FULL PRESCRIBING INFORMATION

CEFAZOLIN DESCRIPTION

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin for Injection and other antibacterial drugs, Cefazolin for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
   DESCRIPTION

Cefazolin for Injection is a semi-synthetic cephalosporin for parenteral administration. It is the sodium salt of 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-carboxylic acid.

Structural Formula:

The sodium content is 24 mg (1.05 mEq) per 500 mg of cefazolin sodium and 48 mg (2.1 mEq) per 1 gram of cefazolin sodium. Cefazolin for Injection is a sterile, white to yellowish powder.

Cefazolin for Injection is supplied in vials equivalent to 500 mg of cefazolin or to 1 gram of cefazolin.

CLINICAL PHARMACOLOGY

After intramuscular administration of Cefazolin for Injection 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 for Injection 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 one 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 injection are considerably lower than serum levels (less than 1 mcg/mL).

In synovial fluid, the level of Cefazolin for injection becomes comparable to that reached in serum at about 4 hours after drug administration.

Studies of cord blood show prompt transfer of cefazolin for injection across the placenta. Cefazolin for injection is present in very low concentrations in the milk of nursing mothers.

Cefazolin for injection 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.

In patients undergoing peritoneal dialysis (2L/hr.), Cefazolin for Injection 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 (3 patients), and 72 mcg/mL (range 26 to 142 mcg/mL) with 150 mg/L (6 patients). Intraperitoneal administration of Cefazolin for Injection 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 for injection.
  

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 the  INDICATIONS AND USAGE section:

Aerobic Gram-positive microorganisms:
Staphylococcus aureus (including pencillinase-producing strains)
Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus pyogenes,and other strains of streptococci



Note: Methicillin-resistant staphylococci are uniformly resistant to cefazolin. Many Enterococcus strains are resistant to cefazolin.

Aerobic Gram-negative microorganisms:

Escherichia coli

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 cloacae. Morganelia morganii, and Providencia rettgeri are resistant. Serratia, Pseudomonas. Mirna and Herellea species are almost uniformly resistant to cefazolin.

Susceptibility Testing

Dilution Techniques:
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs probide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth) or equivalent with standardized inoculum concentrations and standardized concentrations of cefazolin powder.

The MIC values should be interpreted according to the following criteria:

For Enterobacteriaceae and Staphylococcus spp.

INDICATIONS & USAGE

Cefazolin for Injection is indicated in the treatment of the following serious infections due to susceptible organisms:

Respiratory Tract Infections: Due to S. pneumoniae, Klebsiella species, H. influenzae,  S. aureus (penicillin-sensitive and penicillin-resistant). and group A beta-hemolytic streptococci.

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 for injection 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 at present.

Urinary Tract Infections: Due to E. coli, P. mirabilis, Klebsiella species, and some strains of enterobacter and enterococci.

Skin and Skin Structure Infections: Due to S. aureus (penicillin-sensitive and penicilin-resistant), group A beta-hemolytic streptococci, and other strains of streptococci.

Biliary Tract Infections: Due to E. coli, various strains of streptococci, P. mirabilis, Klebsiella species and S. aureus.

Bone and Joint Infections: Due to S. aureus.

Genital Infections: (i.e., prostatitis, epididymitis) due to E. coli, P. mirabilis, Klebsiella species, and some strains of enterococci.

Septicemia: Due to S. pneumoniae, S. aureus (penicillin-sensitive and penicillin-resistant), P. mirabilis, E. coli, and Klebsiella species.

Endocarditis: Due to S. aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.

Perioperative Prophylaxis: The prophylactic administration of cefazolin for injection 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 cefazolinfor injection 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 for injection 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 for injection 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 and other antibacterial drugs, Cefazolin for Injection 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.

CEFAZOLIN CONTRAINDICATIONS

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

WARNINGS

BEFORE THERAPY WITH CEFAZOLIN FOR INJECTION 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 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 may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential.

When Cefazolin for Injection 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 β-lactam antibiotics, seizures may occur if inappropriately high doses are administered to patients with impaired renal function (see  DOSAGE AND ADMINISTRATION ).

Cefazolin for Injection, 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 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 Clinitest tablets, but not with enzyme-based test 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
Patients should be counseled that antibacterial drugs including Cefazolin for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefazolin for Injection 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 of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefazolin for Injection 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 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 for Injection. 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 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).

CEFAZOLIN ADVERSE REACTIONS

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).
   Cephalosporin-class Adverse Reactions

In addition to the adverse reactions listed above that have been observed in patients treated with cefazolin, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:

Adverse Reactions: Allergic reactions, urticaria, serum sickness-like reaction, erythema multiforme, toxic epidermal necrolysis, colitis, renal dysfunction, toxic nephropathy, abdominal pain, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and superinfection.

Altered Laboratory Tests: Prolonged prothrombin time, positive direct Coomb’s test, false-positive test for urinary glucose, elevated bilirubin, elevated LDH, increased creatinine, pancytopenia, and agranulocytosis.

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (See  DOSAGE AND ADMINISTRATION ). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

DOSAGE & ADMINISTRATION

HOW SUPPLIED

Each vial contains cefazolin sodium equivalent to 500 mg or 1 gram cefazolin.

NDC 0781-3450-95, 500 mg, packaged in 10s

NDC 0781-3451-96, 1 gram, package in 25s

As with other cephalosporins, Cefazolin for Injection tends to darken depending on storage conditions; within the stated recommendations, however product potency is not adversely affected.
 

Before reconstitution protect from light and store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].
   REFERENCE

   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. January 2000.
   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. January 2000.

 

Clinitest® is a registered trademark of Miles, Inc.

Clinistix® is a registered trademark of Bayer Corporation.

06-2009



Manufactured in Austria by

Sandoz GmbH for

Sandoz Inc., Princeton, NJ 08540

  

PACKAGE LABEL