CEFAZOLIN: Package Insert and Label Information

CEFAZOLIN- cefazolin sodium injection, powder, lyophilized, for solution
GlaxoSmithKline

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefazolin and other antibacterial drugs, cefazolin 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 sterile, semi-synthetic cephalosporin for intravenous or intramuscular 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:

Image from Drug Label Content

Its molecular formula is C14 H13 N8 NaO4 S3 and the molecular weight is 476.50.

Each vial contains 48 mg of sodium/1 gram of cefazolin sodium.

Cefazolin for injection is supplied as a lyophilized form.

Each ADD-Vantage® vial of cefazolin for injection is equivalent to 1 gram cefazolin.

CLINICAL PHARMACOLOGY

Human Pharmacology

After intramuscular administration of cefazolin to normal volunteers, the mean serum concentrations were 37 mcg/mL at one hour and

3 mcg/mL at eight hours following a 500 mg dose, and 64 mcg/mL at one hour and

7 mcg/mL at eight 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 eight hours for a 1 gram dose.

The serum half-life for cefazolin is approximately 1.8 hours following I.V. administration and approximately 2.0 hours following I.M. 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 two 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 (< 1.0 mcg/mL).

In synovial fluid, the cefazolin level becomes comparable to that reached in serum at about four 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 six hours approximately 60% of the drug is excreted in the urine and this increases to 70%-80% within 24 hours. Cefazolin achieves peak urine concentrations of approximately 2400 mcg/mL and 4000 mcg/mL respectively following 500 mg and 1 gram intramuscular doses.

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 13-44 mcg/mL) with 50 mg/L (three patients), and 72 mcg/mL (range 26-142 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 the following organisms in vitro and in clinical infections:

Staphylococcus aureus (including penicillinase-producing strains)

Staphylococcus epidermidis

Methicillin-resistant staphylococci are uniformly resistant to cefazolin

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

Streptococcus pneumoniae

Escherichia coli

Proteus mirabilis

Klebsiella species

Enterobacter aerogenes

Haemophilus influenzae

Most strains of indole positive Proteus (Proteus vulgaris) , Enterobacter cloacae , Morganella morganii and Providencia rettgeri are resistant. Serratia , Pseudomonas , Mima , Herellea species are almost uniformly resistant to cefazolin.

Disk Susceptibility Tests

Disk diffusion technique

— Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure1 has been recommended for use with disks to test susceptibility to cefazolin.

Reports from a laboratory using the standardized single-disk susceptibility test1 with a 30 mcg cefazolin disk should be interpreted according to the following criteria:

Susceptible organisms produce zones of 18 mm or greater, indicating that the tested organism is likely to respond to therapy.

Organisms of intermediate susceptibility produce zones 15 to 17 mm, indicating that the tested organism would 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 are attained.

Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected.

For gram-positive isolates, a zone of 18 mm is indicative of a cefazolin-susceptible organism when tested with either the cephalosporin-class disk (30 mcg cephalothin) or the cefazolin disk (30 mcg cefazolin).

Gram-negative organisms should be tested with the cefazolin disk (using the above criteria), since cefazolin has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found resistant when tested with the cephalothin disk. Gram-negative organisms having zones of less than 18 mm around the cephalothin disk may be susceptible to cefazolin.

Standardized procedures require use of control organisms. The 30 mcg cefazolin disk should give zone diameter between 23 and 29 mm for E. coli ATCC 25922 and between 29 and 35 mm for S. aureus ATCC 25923.

The cefazolin disk should not be used for testing susceptibility to other cephalosporins.

Dilution techniques

— A bacterial isolate may be considered susceptible if the minimal inhibitory concentration (MIC) for cefazolin is not more than 16 mcg per mL. Organisms are considered resistant if the MIC is equal to or greater than 64 mcg per mL.

The range of MIC’s for the control strains are as follows:

S. aureus ATCC 25923, 0.25 − 1.0 mcg/mL

E. coli ATCC 25922, 1.0 − 4.0 mcg/mL

CEFAZOLIN Indications and Usage

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

RESPIRATORY TRACT INFECTIONS due to Streptococcus pneumoniae , Klebsiella species, Haemophilus influenzae , Staphylococcus 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 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 Escherichia coli , Proteus mirabilis , Klebsiella species and some strains of enterobacter and enterococci.

SKIN AND SKIN STRUCTURE INFECTIONS due to Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), group A beta-hemolytic streptococci and other strains of streptococci.

BILIARY TRACT INFECTIONS due to Escherichia coli , various strains of streptococci, Proteus mirabilis , Klebsiella species and Staphylococcus aureus.

BONE AND JOINT INFECTIONS due to Staphylococcus aureus.

GENITAL INFECTIONS (i.e., prostatitis, epididymitis) due to Escherichia coli , Proteus mirabilis , Klebsiella species and some strains of enterococci.

SEPTICEMIA due to Streptococcus pneumoniae , Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), Proteus mirabilis , Escherichia coli and Klebsiella species.

ENDOCARDITIS due to Staphylococcus aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.

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 over 70 years of age, 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, and other antibacterial drugs, cefazolin 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 IS CONTRAINDICATED IN PATIENTS WITH KNOWN ALLERGY TO THE CEPHALOSPORIN GROUP OF ANTIBIOTICS.

WARNINGS

BEFORE THERAPY WITH CEFAZOLIN IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFTAZIDIME, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE 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 OCCURS, DISCONTINUE 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.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefazolin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of ‘‘antibiotic-associated colitis.’’

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis.

PRECAUTIONS

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®.

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 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 or other antibacterial drugs in the future.

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 one month.

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).

DOSAGE AND ADMINISTRATION

NOTE: Cefazolin for injection in the ADD-Vantage® Vial is not intended for direct intravenous or intramuscular injection.

Usual Adult Dosage

Type of Infection

Dose

Frequency

Moderate to severe infections

500 mg to 1 gram

every 6 to 8 hrs.

Mild infections caused by susceptible

gram + cocci

250 mg to 500 mg

every 8 hours

Acute, uncomplicated urinary

tract infections

1 gram

every 12 hours

Pneumococcal pneumonia

500 mg

every 12 hours

Severe, life-threatening infections

(e.g., endocarditis, septicemia)*

1 gram to 1.5 grams

every 6 hours

*In rare instances, doses of up to 12 grams of cefazolin per day have been used.

Perioperative Prophylactic Use

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

a. 1 gram I.V. or I.M. administered 1/2 hour to 1 hour prior to the start of surgery.

b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram I.V. or I.M. during surgery (administration modified depending on the duration of the operative procedure).

c. 500 mg to 1 gram I.V. or I.M. every 6 to 8 hours for 24 hours postoperatively.

It is important that 1) the preoperative dose be given just (1/2 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.

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