Cefoxitin and Dextrose (Page 5 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cefoxitin is an antibacterial drug [ seeMicrobiology (12.4)].

12.2 Pharmacodynamics

The pharmacodynamic properties of cefoxitin are unknown.

12.3 Pharmacokinetics

Absorption

Following an intravenous dose of 1 gram, serum concentrations were 110 mcg/mL at 5 minutes, declining to less than 1 mcg/mL at 4 hours.

Distribution

Cefoxitin passes into pleural and joint fluids and is detectable in antibacterial concentrations in bile.

Elimination

Metabolism

The half-life after an intravenous dose is 41 to 59 minutes.

Excretion

Approximately 85 percent of cefoxitin is excreted unchanged by the kidneys over a 6-hour period, resulting in high urinary concentrations. Probenecid slows tubular excretion and produces higher serum levels and increases the duration of measurable serum concentrations.

Specific Populations

Geriatric Patients

In a published study of geriatric patients ranging in age from 64 to 88 years with normal renal function for their age (creatinine clearance ranging from 31.5 to 174.0 mL/min), the half-life for cefoxitin ranged from 51 to 90 minutes, resulting in higher plasma concentrations than in younger adults. These changes were attributed to decreased renal function associated with the aging process.

12.4 Microbiology

Mechanism of Action

Cefoxitin is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefoxitin has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

Resistance

Resistance to Cefoxitin is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

Antimicrobial Activity

Cefoxitin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage(1)].

Gram-positive bacteria

Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes

Gram-negative bacteria

Escherichia coli
Haemophilus influenzae
Klebsiella spp.
Morganella morganii
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Providencia spp.

Anaerobic bacteria

Clostridium spp.
Peptococcus niger
Peptostreptococcus spp.
Bacteroides distasonis
Bacteroides fragilis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides spp.

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefoxitin against isolates of similar genus or organism group. However, the efficacy of cefoxitin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-negative bacteria

Eikenella corrodens [non- β-lactamase producers]

Anaerobic bacteria

Clostridium perfringens Prevotella bivia

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long term studies in animals have not been performed with cefoxitin to evaluate carcinogenic potential.

Mutagenesis

Long term studies in animals have not been performed with cefoxitin to evaluate mutagenic potential.

Impairment of Fertility

Studies in rats treated intravenously with 400 mg/kg of cefoxitin (approximately three times the maximum recommended human dose) revealed no effects on fertility or mating ability.

14 CLINICAL STUDIES

14.1 Prophylaxis

A prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to determine the efficacy of short-term prophylaxis with cefoxitin in patients undergoing cesarean section who were at high risk for subsequent endometritis because of ruptured membranes. Patients were randomized to receive either three doses of placebo (n=58), a single dose of cefoxitin (2 g) followed by two doses of placebo (n=64), or a three-dose regimen of cefoxitin (each dose consisting of 2 g) (n=60), given intravenously, usually beginning at the time of clamping of the umbilical cord, with the second and third doses given 4 and 8 hours post-operatively. Endometritis occurred in 16/58 (27.6%) patients given placebo, 5/63 (7.9%) patients given a single dose of cefoxitin, and 3/58 (5.2%) patients given three doses of cefoxitin. The differences between the two groups treated with cefoxitin and placebo with respect to endometritis were statistically significant (p<0.01) in favor of cefoxitin. The differences between the one-dose and three-dose regimens of cefoxitin were not statistically significant.

Two double-blind, randomized studies compared the efficacy of a single 2 gram intravenous dose of cefoxitin to a single 2 gram intravenous dose of cefotetan in the prevention of surgical site-related infection (major morbidity) and non-site-related infections (minor morbidity) in patients following cesarean section. In the first study, 82/98 (83.7%) patients treated with cefoxitin and 71/95 (74.7%) patients treated with cefotetan experienced no major or minor morbidity. The difference in the outcomes in this study (95% CI: -0.03, +0.21) was not statistically significant. In the second study, 65/75 (86.7%) patients treated with cefoxitin and 62/76 (81.6%) patients treated with cefotetan experienced no major or minor morbidity. The difference in the outcomes in this study (95% CI: -0.08, +0.18) was not statistically significant.

14.2 Intra-abdominal Infections

In clinical trials of patients with intra-abdominal infections due to Bacteroides fragilis group microorganisms, eradication rates at 1 to 2 weeks post-treatment for isolates were in the range of 70% to 80%. Eradication rates for individual species are listed below:

Bacteroides distasonis 7/10 (70%)

Bacteroides fragilis 26/33 (79%)

Bacteroides ovatus 10/13 (77%)

B. thetaiotaomicron 13/18 (72%)

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Cefoxitin for Injection and Dextrose Injection in the DUPLEX® Container is a flexible dual chamber single-dose container supplied in two concentrations. After reconstitution, the delivered doses are equivalent to 1 g and 2 g cefoxitin. The diluent chamber contains approximately 50 mL of Dextrose Injection. Dextrose Injection has been adjusted to 4% w/v and 2.2% w/v for the 1 g and 2 g doses, respectively, such that the reconstituted solution is iso-osmotic.

Cefoxitin for Injection and Dextrose Injection is supplied sterile and nonpyrogenic in the DUPLEX® Container packaged 24 units per case.

NDC	REF	Dose	Volume
0264-3123-11	3123-11	1 g	50 mL
0264-3125-11	3125-11	2 g	50 mL

Not made with natural rubber latex, PVC or Di(2-ethylhexyl)phthalate (DEHP).

Storage

Store the unactivated unit at 20-25°C (68-77°F). Excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.] Do not freeze.

As with other cephalosporins, reconstituted Cefoxitin for Injection and Dextrose Injection tends to darken depending on storage conditions, within the stated recommendations. However, product potency is not adversely affected.

Use only if prepared solution is clear and free from particulate matter.