CEFAZOLIN (Page 3 of 4)

5.4 Risk of Development of Drug-resistant Bacteria

Prescribing Cefazolin for Injection, USP 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, USP 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.

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.

7 DRUG INTERACTIONS

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

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 1-3 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 is administered to a nursing woman.

8.4 Pediatric Use

Cefazolin for Injection USP, Pharmacy Bulk Package bag, SmartPak ® should not be used in pediatric patients who require less than a 250 mg adult of cefazolin.

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

Cefazolin for Injection USP, Pharmacy Bulk Package bag, SmartPak ® should not be used in patients with renal impairment who require less than a 250 mg dose of Cefazolin. When cefazolin is administered to patients with low urinary output because of impaired renal function (creatinine clearance less than 55 mL/minute), lower daily dosage is required [see Dosage and Administration (2.3) and Warnings and Precautions (5.2) ].

11 DESCRIPTION

Cefazolin for Injection USP, Pharmacy Bulk Package bag SmartPak ® should not be used in patients who require less than a 250 mg dose of cefazolin.

Cefazolin for Injection, USP, is a sterile, lyophilized, semisynthetic cephalosporin for intravenous 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. Each Pharmacy Bulk Package contains 48 mg (2.1 mEq) of sodium per 1 gram of cefazolin sodium. Cefazolin for Injection, USP, is supplied in 100 grams and 300 grams SmartPak® Pharmacy Bulk Packages bags equivalent. Each SmartPak® Pharmacy Bulk Package bag contains cefazolin sodium equivalent to 100 grams or 300 grams of cefazolin.

BEFORE ADMINISTRATION, THIS PHARMACY BULK PACKAGE REQUIRES RECONSTITUTION USING STERILE WATER FOR INJECTION, USP TO A CONCENTRATION OF 100 mg per mL AND FURTHER DILUTION IN 50 mL OF A COMPATIBLE SOLUTION AND INFUSED INTRAVENOUSLY.

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.

The molecular formula is C14 H13 N8 NaO4 S3 . The molecular weight is 476.49.

The structural formula is as follows:

Structural Formula

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

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

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

Plasma pharmacokinetic parameters of cefazolin in normal volunteers (N=12) following a single 15-minute intravenous infusion of 2 grams of Cefazolin for Injection, USP are summarized in Table 3.

Table 3: Mean (Standard Deviation) Plasma Pharmacokinetic Parameters of Cefazolin in Normal Volunteers

*Tmax reported as median( range)

N = number of subjects observed; Cmax = maximum plasma concentration; Tmax = time to maximum plasma concentration; AUC0-inf = area under the plasma concentration-time curve extrapolated to infinity; t½ = apparent plasma terminal elimination half-life; CL = total clearance; Vz = volume of distribution

N C max (mcg/mL) T max * (h) AUC 0-inf (mcg*h/mL) t ½ (h) CL (L/h) V z (L)
Single 2 g Dose as a 15-Minute I.V. Infusion 12 280.9 (45.9) 0.25(0.25-0.33) 509.9 (89.3) 2.01 (0.28) 4.03 (0.68) 11.5 (1.53)

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 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.

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