Label: CEFAZOLIN- cefazolin sodium injection, powder, for solution

  • NDC Code(s): 44567-706-25, 44567-707-25
  • Packager: WG Critical Care, LLC
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated 05/15

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use Cefazolin for Injection safely and effectively. See full prescribing information for Cefazolin for Injection.
    Cefazolin for Injection, USP for intramuscular or intravenous use.
    Initial U.S. Approval: 1973
    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.

    INDICATIONS AND USAGE

    Cefazolin for Injection is a cephalosporin antibacterial indicated in the treatment of the following infectionscaused by susceptibleisolates of the designated microorganisms: Respiratory tract infections (1.1); urinary tract infections (1.2); skin and skinstructure infections (1.3); biliary tract infections (1.4); bone and joint infections (1.5); genital infections (1.6); septicemia (1.7); endocarditis (1.8) and perioperative prophylaxis (1.9). (1)

    DOSAGE AND ADMINISTRATION

    For intramuscular or intravenous use only over approximately 30 minutes. (2) (2)

    Recommended Dosing Schedule in Adult Patients with CrCl Greater Than or Equal To 55 mL/min. (2.1) (2)

    Site and Type of Infection (2)

    Dose (2)

    Frequency (2)

    Moderate to severe infections (2)

    500 mg to (2)

    1 gram (2)

    every 6 to 8 hours (2)

    Mild infections caused by susceptible gram-positive cocci (2)

    250 mg to (2)

    500 mg (2)

    every 8 hours (2)

    Acute, uncomplicated urinary tract infections (2)

    1 gram (2)

    every 12 hours (2)

    Pneumococcal pneumonia (2)

    500 mg (2)

    every 12 hours (2)

    Severe, life-threatening infections (e.g., endocarditis, septicemia)* (2)

    1 gram to (2)

    1.5 grams (2)

    every 6 hours (2)

    Perioperative prophylaxis (2)

    1 gram to 2 grams (2)

    ½ to 1 hour prior to start of surgery (2)

    500 mg to 1 gram (2)

    during surgery for lengthy procedures (2)

    500 mg to 1 gram (2)

    every 6 to 8 hours for 24 hours postoperatively (2)

    * In rare instances, doses of up to 12 grams of cefazolin per day have been used. (2)

    DOSAGE FORMS AND STRENGTHS

    500 mg per vial and 1 gram per vial. (3)

    CONTRAINDICATIONS

    Hypersensitivity to cefazolin or other cephalosporin class antibacterial drugs, penicillins, or other beta-lactams (4.1)

    WARNINGS AND PRECAUTIONS

    Hypersensitivity reactions: Cross-hypersensitivity may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue the drug. (5.1)
    Use in patients with renal impairment: Dose adjustment required for patients with CrCl less than 55 mL/min. (5.2)
    Clostridium difficile-associated diarrhea: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. (5.3)

    ADVERSE REACTIONS

    Most common adverse reactions: gastrointestinal (nausea, vomiting, diarrhea), and allergic reactions (anaphylaxis, urticaria, skin rash). (6)

    To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. (6)

    DRUG INTERACTIONS

    Probenecid: may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood concentrations. (7)

    USE IN SPECIFIC POPULATIONS

    Pediatric use: Safety and effectiveness for use in premature infants and neonates have not been established. See Dosage and Administration (2.4) for recommended dosage in pediatric patients older than 1 month. (8.4)
    Renal impairment: Lower daily dosage of Cefazolin for Injection is required in patients with impaired renal function (creatinine clearance less than 55 mL/min.) (8.6)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 3/2015

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  • FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    1.1 Respiratory Tract Infections

    1.2 Urinary Tract Infections

    1.3 Skin and Skin Structure Infections

    1.4 Biliary Tract Infections

    1.5 Bone and Joint Infections

    1.6 Genital Infections

    1.7 Septicemia

    1.8 Endocarditis

    1.9 Perioperative Prophylaxis

    2 DOSAGE AND ADMINISTRATION

    2.1 Adult Population

    2.2 Perioperative Prophylactic Use

    2.3 Patients with Renal Impairment

    2.4 Pediatric Dosage

    2.5 Preparation for Use of Cefazolin for Injection

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    4.1 Hypersensitivity to Cefazolin or the Cephalosporin Class of Antibacterial Drugs, Penicillins, or Other Beta-lactams

    5 WARNINGS AND PRECAUTIONS

    5.1 Hypersensitivity Reactions to Cefazolin, Cephalosporins, Penicillins, or Other Beta-lactams

    5.2 Use In Patients with Renal Impairment

    5.3 Clostridium difficile-associated Diarrhea

    5.4 Risk of Development of Drug-resistant Bacteria

    5.5 Drug/Laboratory Test Interactions

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

    6.2 Cephalosporin-class Adverse Reactions

    7 DRUG INTERACTIONS

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Labor and Delivery

    8.3 Nursing Mothers

    8.4 Pediatric Use

    8.5 Geriatric Use

    8.6 Patients with Renal Impairment

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.2 Pharmacodynamics

    12.3 Pharmacokinetics

    12.4 Microbiology

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    15 REFERENCES

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
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  • 1 INDICATIONS AND USAGE

    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 indicated for the treatment of the following infections when caused by susceptible bacteria.

    1.1 Respiratory Tract Infections

    Respiratory tract infections due to Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus pyogenes.

    Injectable benzathine penicillin is considered 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.

    1.2 Urinary Tract Infections

    Urinary tract infections due to Escherichia coli, and Proteus mirabilis.

    1.3 Skin and Skin Structure Infections

    Skin and skin structure infections due to S. aureus, S. pyogenes, and Streptococcus agalactiae.

    1.4 Biliary Tract Infections

    Biliary infections due to E. coli, various isolates of streptococci, P. mirabilis, and S. aureus.

    1.5 Bone and Joint Infections

    Bone and joint infections due to S. aureus.

    1.6 Genital Infections

    Genital infections due to E. coli and P. mirabilis.

    1.7 Septicemia

    Septicemia due to S. pneumoniae, S. aureus, P. mirabilis and E. coli.

    1.8 Endocarditis

    Endocarditis  due to S. aureus and S. pyogenes.

    1.9 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).

    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.

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  • 2 DOSAGE AND ADMINISTRATION

    2.1 Adult Population

    The recommended adult dosages are outlined in Table 1. Cefazolin for Injection should be administered intramuscularly (IM) or intravenously (IV) over approximately 30 minutes.

    Table 1: Recommended Dosing Schedule in Adult Patients with CrCl Greater Than or Equal To 55 mL/min.

    Site and Type of Infection

    Dose

    Frequency

    Moderate to severe infections

    500 mg to

    1 gram

    every 6 to 8 hours

    Mild infections caused by susceptible gram-positive 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.

    2.2 Perioperative Prophylactic Use

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

    1 gram IV or IM administered ½ hour to 1 hour prior to the start of surgery.
    For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV or IM during surgery (administration modified depending on the duration of the operative procedure).
    500 mg to 1 gram IV or IM every 6 to 8 hours for 24 hours postoperatively.

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

    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.

    2.3 Patients with Renal Impairment

    Cefazolin may be used in patients with renal impairment with the dosage adjustments outlined in Table 2. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection.

    Table 2: Dosage Adjustment for Patients with Renal Impairment

    Creatinine Clearance

    Dose

    Frequency

    55 mL/min. or greater

    full dose

    normal frequency

    35 to 54 mL/min.

    full dose

    every 8 hours or longer

    11 to 34 mL/min.

    1/2 usual dose

    every 12 hours

    10 mL/min. or less

    1/2 usual dose

    every 18 to 24 hours

    2.4 Pediatric Dosage

    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 3 or 4 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 in these patients is not recommended.


    Table 3: Pediatric Dosage Guide

    Weight

    25 mg/kg/day

    Divided into 3 Doses

    25 mg/kg/day

    Divided into 4 Doses

    Lbs

    Kg

    Approximate Single Dose mg/q 8 h

    Vol. (mL) needed with dilution of

    125 mg/mL

    Approximate Single Dose mg/q 6 h

    Vol. (mL) needed with dilution of

    125 mg/mL

    10

    20

    30

    40

    50

    4.5

    9

    13.6

    18.1

    22.7

    40 mg

    75 mg

    115 mg

    150 mg

    190 mg

    0.35 mL

    0.6 mL

    0.9 mL

    1.2 mL

    1.5 mL

    30 mg

    55 mg

    85 mg

    115 mg

    140 mg

    0.25 mL

    0.45 mL

    0.7 mL

    0.9 mL

    1.1 mL

    Weight

    50 mg/kg/day

    Divided into 3 Doses

    50 mg/kg/day

    Divided into 4 Doses

    Lbs

    Kg

    Approximate Single Dose mg/q 8 h

    Vol. (mL) needed with dilution of

    225 mg/mL

    Approximate Single Dose mg/q 6 h

    Vol. (mL) needed with dilution of

    225 mg/mL

    10

    20

    30

    40

    50

    4.5

    9

    13.6

    18.1

    22.7

    75 mg

    150 mg

    225 mg

    300 mg

    375 mg

    0.35 mL

    0.7 mL

    1 mL

    1.35 mL

    1.7 mL

    55 mg

    110 mg

    170 mg

    225 mg

    285 mg

    0.25 mL

    0.5 mL

    0.75 mL

    1 mL

    1.25 mL

    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.

    2.5 Preparation for Use of Cefazolin for Injection

    Reconstitution

    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.

    When reconstituted or diluted according to the instructions below, Cefazolin for Injection 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.

    Single-Dose Vials

    For IM injection, IV direct (bolus) injection or IV infusion, reconstitute with Sterile Water for Injection according to the following table. SHAKE WELL.

    Table 4: Reconstitution Instructions

    Vial Size

    Amount of Diluent

    Approximate

    Concentration

    Approximate

    Available Volume

    500 mg

    2 mL

    225 mg/mL

    2.2 mL

    1 gram

    2.5 mL

    330 mg/mL

    3 mL

    Administration

    Intramuscular Administration

    Reconstitute vials with Sterile Water for Injection according to the dilution table above. Shake well until dissolved Cefazolin for Injection should be injected into a large muscle mass. Pain on injection is infrequent with Cefazolin for Injection.

    Intravenous Administration

    Direct (bolus) injection:Following reconstitution according to the above table, further dilute vials with approximately 5 mL Sterile Water for Injection. Inject the solution slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below).

    Intermittent or continuous infusion: Dilute reconstituted Cefazolin for Injection 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

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

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  • 3 DOSAGE FORMS AND STRENGTHS

    Cefazolin for Injection is supplied in 500 mg and 1 gram vials.

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  • 4 CONTRAINDICATIONS

    4.1 Hypersensitivity to Cefazolin or the Cephalosporin Class of Antibacterial Drugs, Penicillins, or Other Beta-lactams

    Cefazolin for Injection is contraindicated in patients who have a history of immediate hypersensitivity reactions (e.g., anaphylaxis, serious skin reactions) to cefazolin or the cephalosporin class of antibacterial drugs, penicillins, or other beta-lactams [see Warnings and Precautions (5.1)].

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypersensitivity Reactions to Cefazolin, Cephalosporins, Penicillins, or Other Beta-lactams

    Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with Cefazolin for Injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefazolin, cephalosporins, penicillins, or carbapenems. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterial drugs 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 the drug.

    5.2 Use In Patients with Renal Impairment

    As with other beta-lactam antibacterial drugs, seizures may occur if inappropriately high doses are administered to patients with impaired renal function (creatinine clearance less than 55 mL/min.) [see Dosage and Administration (2.3)].

    5.3 Clostridium difficile-associated Diarrhea

    Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefazolin, 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 isolates 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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

    5.4 Risk of Development of Drug-resistant Bacteria

    Prescribing Cefazolin for Injection in the absence of 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.

    As with other antimicrobials, prolonged use of Cefazolin for Injection may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

    5.5 Drug/Laboratory Test Interactions

    Urinary Glucose

    The administration of cefazolin may result in a false-positive reaction with glucose in the urine when using CLINITEST® tablets. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (e.g., CLINISTIX®) be used.

    Coombs’ Test

    Positive direct Coombs' tests have been reported during treatment with cefazolin. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' testing of newborns whose mothers have received cephalosporin antibacterial drugs before parturition, it should be recognized that a positive Coombs' test may be due to the drug.

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  • 6 ADVERSE REACTIONS

    The following serious adverse reactions to cefazolin are described below and elsewhere in the labeling:

    • Hypersensitivity reactions [see Warnings and Precautions (5.1)]

    • Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.3)]

    6.1 Clinical Trials Experience

    The following adverse reactions were reported from clinical trials:

    Gastrointestinal: Diarrhea, oral candidiasis (oral thrush), mouth ulcers, vomiting, nausea, stomach cramps, epigastric pain, heartburn, flatus, anorexia and pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.3)].

    Allergic: Anaphylaxis, eosinophilia, urticaria, 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: Instances of phlebitis have been reported at site of injection. Some induration has occurred.

    Other Reactions: Pruritus (including genital, vulvar and anal pruritus, genital moniliasis, and vaginitis). Dizziness, fainting, lightheadedness, confusion, weakness, tiredness, hypotension, somnolence and headache.

    6.2 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 antibacterials: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal impairment, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic impairment including cholestasis, and pancytopenia.

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  • 7 DRUG INTERACTIONS

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

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category B

    Reproduction studies have been performed in rats, mice and rabbits at doses of 2000, 4000 and 240 mg/kg/day or 1 to 3 times the maximum recommended human dose on a body surface area basis. There was no evidence of impaired fertility or harm to the fetus due to cefazolin.

    8.2 Labor and Delivery

    When cefazolin has been administered prior to caesarean section, drug concentrations 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.

    8.3 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.

    8.4 Pediatric Use

    Safety and effectiveness for use in premature infants and neonates have not been established. See Dosage and Administration (2.4) for recommended dosage in pediatric patients older than 1 month.

    8.5 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 Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

    8.6 Patients with Renal Impairment

    When Cefazolin for Injection is administered to patients with low urinary output because of impaired renal function (creatinine clearance less than 55 mL/min.), lower daily dosage is required [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

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  • 11 DESCRIPTION

    Cefazolin for Injection USP 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.

    Cefazolin sodium USP has the following structural formula:

    structural formula cefazolin

    C14H13N8NaO4S3 M.W. 476.5

    The pH of the reconstituted solution is between 4 and 6.

    Cefazolin for Injection, USP is a sterile white to cream powder supplied in vials. Each vial contains, cefazolin sodium equivalent to 500 mg or 1 gram cefazolin. The sodium content is approximately 24 mg (1 mEq)/500 mg of cefazolin sodium or approximately 48 mg (2.1 mEq)/1 gram of cefazolin sodium. The color of Cefazolin for Injection, USP solutions may range from pale yellow to yellow without a change in potency.

    Cefazolin for Injection, USP is to be administered by intramuscular or intravenous routes.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Cefazolin is an antibacterial drug [see Microbiology (12.4)].

    12.2 Pharmacodynamics

    The pharmacokinetic/pharmacodynamic relationship for cefazolin has not been evaluated in patients.

    12.3 Pharmacokinetics

    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 g 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 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 (less than 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. 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 (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 (3 patients), and 72 mcg/mL (range 26 to 142 mcg/mL) with 150 mg/L (6 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.

    12.4 Microbiology

    Mechanism of Action

    Cefazolin is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis.

    Mechanism of Resistance

    Predominant mechanisms of bacterial resistance to cephalosporins include the presence of extended-spectrum beta-lactamases and enzymatic hydrolysis.

    Lists of Microorganisms

    Cefazolin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE (1) section.

    Gram-Positive Bacteria

    Staphylococcus aureus

    Staphylococcus epidermidis

    Streptococcus pyogenes, and Streptococcus agalactiae

    Streptococcus pneumoniae

    Methicillin-resistant staphylococci are uniformly resistant to cefazolin.

    Gram-Negative Bacteria

    Escherichia coli

    Proteus mirabilis

    Most isolates of indole positive Proteus (Proteus vulgaris), Enterobacter spp., Morganella morganii, Providencia rettgeri, Serratia spp., and Pseudomonas spp. are resistant to cefazolin.

    Susceptibility Test Methods

    When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

    Dilution Techniques

    Quantitative methods are used to determine minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standard test1, 2 (broth and/or agar). The MIC values obtained should be interpreted according to criteria as provided in Table 5.

    Diffusion Techniques

    Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be interpreted using a standard test method2, 3. This procedure uses paper disks impregnated with 30 mcg cefazolin to test the susceptibility of microorganisms to cefazolin. The disk diffusion interpretive criteria are provided in Table 5.

    Table 5: Susceptibility Test Interpretive Criteria for Cefazolina

    Pathogen

    Minimum Inhibitory Concentration (mcg/mL)

    Disk Diffusion Zone Diameter (mm)b

    S

    I

    R

    S

    I

    R

    Escherichia coli

    Proteus mirabilis

    ≤1

    2

    ≥4

    -

    -

    -

    Staphylococcus aureus

    ≤8

    16

    ≥32

    ≥18

    15 to 17

    ≤14

    Abbreviations: S= susceptible, I= intermediate, R= resistant

    a Interpretive criteria are based on 1 g every 8 hr

    bThe cefazolin disk should not be used for determining susceptibility to other cephalosporins

    NOTE:

    S. pyogenes and S. agalactiae that have a penicillin MIC of ≤ 0.12 mcg/mL, or disk diffusion zone diameters of ≥ 24 mm with a 10 mcg penicillin disk, may be interpreted as susceptible to cefazolin. Non-meningitis isolates of S. pneumoniae that have a penicillin MIC of ≤ 0.06 mcg/ml, may be interpreted as susceptible to cefazolin.

    A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen.

    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 product is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

    Quality Control

    Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test1, 2, 3. Standard cefazolin powder should provide the following MIC values noted in Table 6. For the diffusion technique using the 30 mcg disk, the criteria in Table 6 should be achieved.

    Table 6: Acceptable Quality Control Ranges for Cefazolin

    QC Isolate

    Minimum Inhibitory Concentration

    mcg/mL

    Disk Diffusion Zone Diameters

    (mm)

    E. coli ATCC® 25922

    1 to 4

    21 to 27

    S. aureus ATCC® 29213

    0.25 to 1

    ---------

    S. aureus ATCC® 25923

    ----------

    29 to 35

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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  • 15 REFERENCES

    1. Clinical Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Ninth Edition. CLSI Document M07-A9. CLSI, 940 West Valley Road, Suite 2500, Wayne, PA, 2012.

    2. Clinical Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement. CLSI document M100-S20. CLSI, Wayne, PA. 2010.

    3. Clinical Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Eleventh Edition. CLSI Document M02-A11. CLSI, Wayne, PA, 2012.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Cefazolin for Injection, USP equivalent to 500 mg or 1 gram cefazolin per vial is supplied as follows:

    NDC 44567-706-25 500 mg vial (carton of 25)

    NDC 44567-707-25 1 gram vial (carton of 25)

    Also available:

    Cefazolin for Injection USP is supplied in 10 gram Pharmacy Bulk Package bottles. Each Pharmacy Bulk Package contains cefazolin sodium equivalent to 10 grams of cefazolin and is supplied as follows:

    NDC 44567-708-10 10 gram Pharmacy Bulk Package (carton of 10)

    As with other cephalosporins, Cefazolin for Injection, USP 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 Controlled Room Temperature 20° to 25°C (68° to 77°F).

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  • 17 PATIENT COUNSELING INFORMATION

    Patients should be advised that allergic reactions, including serious allergic reactions could occur and that serious reactions require immediate treatment and discontinuation of cefazolin. Patients should report to their health care provider any previous allergic reactions to cefazolin, cephalosporins, penicillins, or other similar antibacterials.

    Patients should be advised that diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibacterials, 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 antibacterials. If this occurs, patients should contact a physician as soon as possible.

    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.

    Rx only

    ATCC is a registered trademark of American Type Culture Collection.

    CLINITEST is a registered trademark of Siemens Medical Solutions Diagnostics.

    CLINISTIX is a registered trademark of Bayer Healthcare LLC.

    Manufactured for:

    WG Critical Care, LLC

    Paramus, NJ 07652

    Made in Italy

    Revised: 09/2014

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  • PRINCIPAL DISPLAY PANEL - 500 mg

    NDC 44567-706-25

    CEFAZOLIN FOR INJECTION, USP

    500 MG PER VIAL

    FOR IV OR IM USE

    Rx only

    500 MG VIAL LABEL
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  • PRINCIPAL DISPLAY PANEL – 1 gram

    NDC 44567-707-25

    CEFAZOLIN FOR INJECTION, USP

    1 GRAM PER VIAL

    FOR IV OR IM USE

    Rx only

    1 gram vial label
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  • INGREDIENTS AND APPEARANCE
    CEFAZOLIN 
    cefazolin injection, powder, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:44567-706
    Route of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    CEFAZOLIN SODIUM (UNII: P380M0454Z) (CEFAZOLIN - UNII:IHS69L0Y4T) CEFAZOLIN 500 mg
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:44567-706-25 25 in 1 CARTON
    1 1 in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA065303 03/06/2015
    CEFAZOLIN 
    cefazolin injection, powder, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:44567-707
    Route of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    CEFAZOLIN SODIUM (UNII: P380M0454Z) (CEFAZOLIN - UNII:IHS69L0Y4T) CEFAZOLIN 1 g
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:44567-707-25 25 in 1 CARTON
    1 1 in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA065303 03/06/2015
    Labeler - WG Critical Care, LLC (829274633)
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