CEFAZOLIN FOR INJECTION, USP PHARMACY BULK PACKAGE -NOT FOR DIRECT INFUSION

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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 intravenous administration that has the following chemical name: 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.Cefazolin sodium has the following structural formula:

The sodium content is 48 mg per gram of cefazolin.

Cefazolin for injection, USP is supplied as a lyophilized form in Pharmacy Bulk Packages containing cefazolin sodium equivalent to 10 grams of cefazolin.

FURTHER DILUTION IS REQUIRED BEFORE USE. A Pharmacy Bulk Package is a container of a sterile preparation for intravenous use that contains many single doses. The contents are intended for use in a pharmacy admixture service and are restricted to the preparation of admixtures for intravenous infusion (see DOSAGE AND ADMINISTRATION, and DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE).

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 concentration at the third hour of approximately 28 mcg/mL.

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

Bile concentrations in patients without obstructive biliary disease can reach or exceed serum concentrations by up to five times; however, in patients with obstructive biliary disease, bile concentrations of cefazolin are considerably lower than serum concentrations (< 1 mcg/mL).

In synovial fluid, the cefazolin concentration 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 13-44 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, AST (SGOT), ALT (SGPT), bilirubin, alkaline phosphatase, BUN, creatinine and urialysis, indicated no clinically significant changes attributed to cefazolin.

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 penicillinase-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, Pseudomonas, Mima, Herellea species are almost uniformly resistant to cefazolin.

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide 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 method (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.

MIC (mcg/mL                Interpretation < 8                               Susceptible (S)   16                             Intermediate (I)> 32                             Resistant (R)

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefazolin powder should provide the following MIC values:

Microorganism                       MIC (mcg/mL) S. aureus ATCC 25923             0.25 to 1.0  E. coli ATCC 25922                      1 to 4

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-mcg cegfazolin to test the susceptibility of microorganisms to cefazolin. 

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg cefazolin disk should be interpreted according to the following criteria:

For Enterobacteriaceae using the 30-mcg cefazolin disk

Zone Diameter (mm)                    Interpretation     > 18                                         Susceptible (S)   15 to 17                                    Intermediate (I)    < 14                                         Resistant (R)

For Staphylococcus spp, using the 30-mcg cefazolin or the 30-mcg cephalothin disks

Zone Diameter (mm)                   Interpretation     > 18                                        Susceptible (S)   15 to 17                                   Intermediate (I)    < 14                                        Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefazolin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-mcg cefazolin disk should provide the following zone diameters in this laboratory test quality control strain:

Microorganism                            Zone diameter (mm) S. aureus   ATCC 25923                  29 to 35 E. coli          ATCC 25922                23 to 29

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

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.

Due to Escherichia coli, Proteus mirabilis, Klebsiella species and some strains of enterobacter and enterococci.

Due to Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), group A beta-hemolytic streptococci and other strains of streptococci.

Due to Escherichia coli, various strains of streptococci, Proteus mirabilis, Klebsiella species and Staphylococcus aureus.

Due to Staphylococcus aureus.

For example, prostatitis, epididymitis, due to Escherichia coli, Proteus mirabilis, Klebsiella species and some strains of enterococci.

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

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.

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 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 the 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.

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

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 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.

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 oral antibacterial drug clinically effective against C. difficile colitis.

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. 

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 of 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.

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

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.

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

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.

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

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.

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.

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 subject 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).

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 have been observed. As with other cephalosporins, reports of hepatitis have been received.

Renal: As with other cephalosporins, reports of increasesd 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. 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 cholestatis, aplastic anemia, hemolytic anemia, hemorrhage, and superinfection.

Altered Laboratory Tests: Prolonged prothrombin time, positive direct Coombs' 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.

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

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 concentrations 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 the surgery.

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 3.0 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 1/2 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 1/2 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.

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

In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60 percent of the normal daily dose 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 percent 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 percent of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

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.

Add Serile Water for Injection, Bacteriostatic Water for Injection or Sodium Chloride Injection according to the table below. SHAKE WELL. Use promptly. (Discard vial within 4 hours after initial entry).

                                                        DILUTION TABLE                                       

After reconstitution, transfer solution of cefazolin [i.e., 500 mg or 1 gram] into 50 mL or 100 mL of a secondary diluent or solution, [see list under ADMINISTRATION ]. These secondary diluents or solutions should be used within 24 hours after dilution if stored at room temperaturre or within 96 hours if stored under refrigeration 2º to 8ºC (36º to 46ºF).

NOTE: Administration of compounded admixtures should be as soon after preparation as is feasible.

The 10 gram Pharmacy Bulk should be penetrated ONLY ONE TIME utilizing a suitable tsterile transfer device or dispensing set, which allows measured distribution of the contents. Use of a syringe and needle is not recommended as it may cause leakage. Use of this product is restricted to a suitable work area such as a laminar flow hood, using aseptic technique. Reconstituted cefazolin solution may be further diluted for IV infusion with the secondary diluents or solutions listed under ADMINISTRATION. The reconstituted content of the 10 g Pharmacy Bulk Package should be withdrawn immediately. However, should this not be possible transfer fluid operation must be completed within four hours after reconstitution. Discard the reconstituted cefazolin solution 4 hours after initial closure entry.

RECONSTITUTION BULK SOLUTIONS SHOULD NOT BE USED FOR DIRECT INFUSION. FURTHER DILUTION IS REQUIRED.

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

Cefazolin for Injection, USP, in Pharmacy Bulk Packages is a dry powder supplied in bottles containing cefazolin sodium equivalent  to 10 grams cefazolin, as follows:10 g Cefazolin for Injection, USP, bottles in packages of 10 (NDC 0143-9983-03)

Also available as: 500 mg Cefazolin for Injection, USP vials in packages of 25 (NDC 0143-9923-90)1 g Cefazolin for Injection, USP vials in packages of 25 (NDC 0143-9924-90)

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° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

1. National Committee for Clinical Laboratory Standards, Method for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Fifth Edition. Approved Standard NCCLS Document M7-A4, Vol 20, no. 2, NCCLS, Wayne, PA, January 2000.2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January 2000.

Manufactured by:Hikma Farmaceutica (Portugal), S.A. Estrada do Rio da Mo, 8, 8A8BFervenca, 2705-906 Terrugem SNT, PORTUGAL

For: West-Ward Pharmaceutical Corp. EATONTOWN, NJ 07724USA

Rev. March 2010PIN089-WES/2

Cefazolin for Injection, USPPharmacy Bulk PackageNDC 0143-9983-91Manufacturer

West-ward Pharmaceutical Corp

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
• Last Updated: 2nd of March 2011