Cefoxitin For Injection, Usp

PHARMACY BULK PACKAGE – NOT FOR DIRECT INFUSION

Cefoxitin for Injection USP, Pharmacy Bulk Package bag SmartPak^® should be used only in patients who require a 1 gram dose and not any fraction thereof.

Cefoxitin for Injection USP, Pharmacy Bulk Package bag SmartPak^® should not be used in patients who require less than the 1 gram dose of cefoxitin.

THE INTENT OF THIS PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF SOLUTIONS FOR INTRAVENOUS INFUSION ONLY. BEFORE ADMINISTRATION, THIS PHARMACY BULK PACKAGE REQUIRES RECONSTITUTION TO A CONCENTRATION OF 100 MG/ML AND FURTHER DILUTION IN 50 mL OF A COMPATIBLE SOLUTION.

Increased nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefoxitin for Injection, USP and other antibacterial drugs, Cefoxitin for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Special storage instructions

Cefoxitin for Injection, USP in the dry state should be stored between 2-25°C (36-77°F). Avoid exposure to temperatures above 50°C. The dry material as well as solutions tend to darken, depending on storage conditions; product potency, however, is not adversely affected.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Bag Label

NDC 66288-4100-1

Cefoxitin for Injection, USP

100 grams (ONE HUNDRED GRAMS) per Pharmacy Bulk

Package Bag

PHARMACY BULK PACKAGE -

NOT FOR DIRECT INFUSION

FOR INTRAVENOUS USE ONLY

NOT TO BE DISPENSED AS A UNIT

Rx only

This formulation of Cefoxitin for Injection USP – Pharmacy Bulk Package bags SmartPak® should not be used in renally impaired patients who require less than the 1 gram dose of cefoxitin. The total daily dose should be reduced when cefoxitin is administered to patients with transient or persistent reduction of urinary output due to renal insufficiency (see DOSAGE AND ADMINISTRATION ), because high and prolonged serum antibiotic concentrations can occur in such individuals from usual doses.

Antibiotics (including cephalosporins) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

As with other antibiotics, prolonged use of cefoxitin may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing Cefoxitin for Injection 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.

Pregnancy Category B. Reproduction studies performed in rats and mice at parenteral doses of approximately one to seven and one-half times the maximum recommended human dose did not reveal teratogenic or fetal toxic effects, although a slight decrease in fetal weight was observed.

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.

In the rabbit, cefoxitin was associated with a high incidence of abortion and maternal death. This was not considered to be a teratogenic effect but an expected consequence of the rabbit's unusual sensitivity to antibiotic-induced changes in the population of the microflora of the intestine.

Cefoxitin for Injection, USP is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below.

• Lower respiratory tract infections, including pneumonia and lung abscess, caused by Streptococcus pneumoniae, other streptococci (excluding enterococci, e.g., Enterococcus faecalis [formerly Streptococcus faecalis]), Staphylococcus aureus (including penicillinase-producing strains), Escherichia coli, Klebsiella species, Haemophilus influenzae, and Bacteroides species.
• Urinary tract infections caused by Escherichia coli, Klebsiella species, Proteus mirabilis, Morganella morganii, Proteus vulgaris and Providencia species (including P. rettgeri).
• Intra-abdominal infections, including peritonitis and intra-abdominal abscess, caused by Escherichia coli, Klebsiella species, Bacteroides species including Bacteroides fragilis, and Clostridium species.
• Gynecological infections, including endometritis, pelvic cellulitis, and pelvic inflammatory disease caused by Escherichia coli, Neisseria gonorrhoeae (including penicillinase-producing strains), Bacteroides species including B. fragilis, Clostridium species, Peptococcus niger, Peptostreptococcus species, and Streptococcus agalactiae. Cefoxitin for Injection, USP, like cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when Cefoxitin for Injection, USP is used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial coverage should be added.
• Septicemia caused by Streptococcus pneumoniae, Staphylococcus aureus (including penicillinase-producing strains), Escherichia coli, Klebsiella species, and Bacteroides species including B. fragilis.
• Bone and joint infections caused by Staphylococcus aureus (including penicillinase-producing strains).
• Skin and skin structure infections caused by Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pyogenes and other streptococci (excluding enterococci e.g., Enterococcus faecalis [formerly Streptococcus faecalis]), Escherichia coli, Proteus mirabilis, Klebsiella species, Bacteroides species including B. fragilis, Clostridium species, Peptococcus niger, and Peptostreptococcus species.

Appropriate culture and susceptibility studies should be performed to determine the susceptibility of the causative organisms to cefoxitin. Therapy may be started while awaiting the results of these studies.

In randomized comparative studies, cefoxitin and cephalothin were comparably safe and effective in the management of infections caused by gram-positive cocci and gram-negative rods susceptible to the cephalosporins. Cefoxitin has a high degree of stability in the presence of bacterial beta-lactamases, both penicillinases and cephalosporinases.

Many infections caused by aerobic and anaerobic gram-negative bacteria resistant to some cephalosporins respond to cefoxitin. Similarly, many infections caused by aerobic and anaerobic bacteria resistant to some penicillin antibiotics (ampicillin, carbenicillin, penicillin G) respond to treatment with cefoxitin. Many infections caused by mixtures of susceptible aerobic and anaerobic bacteria respond to treatment with cefoxitin.

BEFORE THERAPY WITH CEFOXITIN IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOXITIN, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN WITH CAUTION TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. IF AN ALLERGIC REACTION TO CEFOXITIN OCCURS, DISCONTINUE THE DRUG. SERIOUS HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.

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

Cefoxitin for Injection, USP is indicated for the prophylaxis of infection in patients undergoing uncontaminated gastrointestinal surgery, vaginal hysterectomy, abdominal hysterectomy, or cesarean section.

If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate treatment may be instituted.

The acute intravenous LD₅₀ in the adult female mouse and rabbit was about 8 grams/kg and greater than 1 gram/kg, respectively. The acute intraperitoneal LD₅₀ in the adult rat was greater than 10 grams/kg.

Cefoxitin for Injection, USP, Pharmacy Bulk Package bag SmartPak® should be used only in patients who require a 1 gram dose and not any fraction thereof. Cefoxitin for Injection USP, Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than the 1 gram dose of cefoxitin.

Cefoxitin for Injection, USP is a semi-synthetic, broad-spectrum cepha antibiotic for intravenous administration. It is derived from cephamycin C, which is produced by Streptomyces lactamdurans. Its chemical name is sodium (6R,7S)-3-(hydroxymethyl)-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate carbamate (ester).

The empirical formula is C₁₆H₁₆N₃NaO₇S₂, and the structural formula is:

Cefoxitin for Injection contains approximately 53.8 mg (2.3 mEq) of sodium per gram of cefoxitin.

Solutions of Cefoxitin for Injection, USP range from colorless to light amber in color. The pH of freshly constituted solutions usually ranges from 4.2 to 7.0.

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.

THIS PRODUCT IS NOT INTENDED TO BE USED IN PEDIATRIC AND RENALLY IMPAIRED PATIENTS WHO REQUIRE LESS THAN A 1 GRAM DOSE.

Each SmartPak^® Pharmacy Bulk Package contains sterile Cefoxitin Sodium, USP equivalent to 100 grams of cefoxitin and is intended for intravenous infusion only.  A Pharmacy Bulk Package is a container of a sterile preparation for parenteral 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.  FURTHER DILUTION IS REQUIRED BEFORE USE.  RECONSITITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION.

CEFOXITIN FOR INJECTION, USP SMARTPAK^® PHARMACY BULK PACKAGE SHOULD NOT BE USED IN PATIENTS WHO REQUIRE LESS THAN A 1 GRAM DOSE OF CEFOXTIN.

Of the 1,775 subjects who received cefoxitin in clinical studies, 424 (24%) were 65 and over, while 124 (7%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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 (see CLINICAL PHARMACOLOGY ).

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 and PRECAUTIONS ).

Cefoxitin for Injection, USP is a dry white to off-white powder available in the following SmartPak^® Pharmacy Bulk Package:

   100 grams* (1 Pharmacy Bulk Package) Product No. 4100 NDC 66288-4100-1 sold in individual bags.

   *Each 100 gram Pharmacy Bulk Package contains sterile cefoxitin sodium equivalent to 100 grams of cefoxitin.

SmartPak^® system components are not made with natural rubber latex.

Cefoxitin for Injection USP, Pharmacy Bulk Package bag, SmartPak® should not be used in pediatric patients who require less than the 1 gram adult dose of cefoxitin.

Safety and efficacy in pediatric patients from birth to three months of age have not yet been established. In pediatric patients three months of age and older, higher doses of cefoxitin have been associated with an increased incidence of eosinophilia and elevated SGOT.

Cefoxitin is excreted in human milk in low concentrations. Caution should be exercised when cefoxitin is administered to a nursing woman.

As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

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 grams) followed by two doses of placebo (n=64), or a three-dose regimen of cefoxitin (each dose consisting of 2 grams) (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.

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

Smartpak is a registered trademark of Samson Medical Technologies, L.L.C. †Registered trademark of Siemens Healthcare Diagnostics Inc.

Cefoxitin is generally well tolerated. The most common adverse reactions have been local reactions following intravenous injection. Other adverse reactions have been encountered infrequently.

Local Reactions

Thrombophlebitis has occurred with intravenous administration.

Allergic Reactions

Rash (including exfoliative dermatitis and toxic epidermal necrolysis), urticaria, flushing, pruritus, eosinophilia, fever, dyspnea, and other allergic reactions including anaphylaxis, interstitial nephritis and angioedema have been noted.

Cardiovascular

Hypotension.

Gastrointestinal

Diarrhea, including documented pseudomembranous colitis, which can appear during or after antibiotic treatment. Nausea and vomiting have been reported rarely.

Neuromuscular

Possible exacerbation of myasthenia gravis.

Blood

Eosinophilia, leukopenia including granulocytopenia, neutropenia, anemia, including hemolytic anemia, thrombocytopenia, and bone marrow depression. A positive direct Coombs test may develop in some individuals, especially those with azotemia.

Liver Function

Transient elevations in SGOT, SGPT, serum LDH, and serum alkaline phosphatase; and jaundice have been reported.

Renal Function

Cefoxitin for Injection USP, Pharmacy Bulk Package bag, SmartPak^® should not be used in patients with renal impairment who  require less than the 1 gram adult dose of cefoxitin.

Elevations in serum creatinine and/or blood urea nitrogen levels have been observed. As with the cephalosporins, acute renal failure has been reported rarely. The role of cefoxitin in changes in renal function tests is difficult to assess, since factors predisposing to prerenal azotemia or to impaired renal function usually have been present.

In addition to the adverse reactions listed above which have been observed in patients treated with Cefoxitin for Injection, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics:

Urticaria, erythema multiforme, Stevens-Johnson syndrome, serum sickness-like reactions, abdominal pain, colitis, renal dysfunction, toxic nephropathy, false-positive test for urinary glucose, hepatic dysfunction including cholestasis, elevated bilirubin, aplastic anemia, hemorrhage, prolonged prothrombin time, pancytopenia, agranulocytosis, superinfection, vaginitis including vaginal candidiasis.

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.

Cefoxitin for Injection is contraindicated in patients who have shown hypersensitivity to cefoxitin and the cephalosporin group of antibiotics.

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.

Following an intravenous dose of 1 gram of cefoxitin, serum concentrations were 110 mcg/mL at 5 minutes, declining to less than 1 mcg/mL at 4 hours. The half-life after an intravenous dose is 41 to 59 minutes. 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.

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

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 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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefoxitin and other antibacterial drugs, Cefoxitin 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.

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

Cefoxitin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive bacteria

      Staphylococcus aureus (methicillin-susceptible isolates only)

      Staphylococcus epidermidis (methicillin-susceptible isolates only)

      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 microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefoxitin. However, the efficacy of cefoxitin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled studies.

Gram-negative bacteria

      Eikenella corrodens [non-ß-lactamase producers]

Anaerobic bacteria

      Clostridium perfringens

      Prevotella bivia

Patients should be counseled that antibacterial drugs including Cefoxitin for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefoxitin 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 cefoxitin or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, 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 antibiotic. If this occurs, patients should contact their physician as soon as possible.

As with cephalothin, high concentrations of cefoxitin (>100 mcg/mL) may interfere with measurement of serum and urine creatinine levels by the Jaffé reaction, and produce false increases of modest degree in the levels of creatinine reported. Serum samples from patients treated with cefoxitin should not be analyzed for creatinine if withdrawn within 2 hours of drug administration.

High concentrations of cefoxitin in the urine may interfere with measurement of urinary 17-hydroxy-corticosteroids by the Porter-Silber reaction, and produce false increases of modest degree in the levels reported.

A false-positive reaction for glucose in the urine may occur. This has been observed with CLINITEST^† reagent tablets.

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

PHARMACY BULK PACKAGE – NOT FOR DIRECT INFUSION

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefoxitin for Injection, USP and other antibacterial drugs, Cefoxitin for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Special storage instructions

Cefoxitin for Injection, USP in the dry state should be stored between 2-25°C (36-77°F). Avoid exposure to temperatures above 50°C. The dry material as well as solutions tend to darken, depending on storage conditions; product potency, however, is not adversely affected.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Bag Label

NDC 66288-4100-1

Cefoxitin for Injection, USP

100 grams (ONE HUNDRED GRAMS) per Pharmacy Bulk

Package Bag

PHARMACY BULK PACKAGE -

NOT FOR DIRECT INFUSION

FOR INTRAVENOUS USE ONLY

NOT TO BE DISPENSED AS A UNIT

Rx only

This formulation of Cefoxitin for Injection USP – Pharmacy Bulk Package bags SmartPak® should not be used in renally impaired patients who require less than the 1 gram dose of cefoxitin. The total daily dose should be reduced when cefoxitin is administered to patients with transient or persistent reduction of urinary output due to renal insufficiency (see DOSAGE AND ADMINISTRATION ), because high and prolonged serum antibiotic concentrations can occur in such individuals from usual doses.

Antibiotics (including cephalosporins) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

As with other antibiotics, prolonged use of cefoxitin may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing Cefoxitin for Injection 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.

Pregnancy Category B. Reproduction studies performed in rats and mice at parenteral doses of approximately one to seven and one-half times the maximum recommended human dose did not reveal teratogenic or fetal toxic effects, although a slight decrease in fetal weight was observed.

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.

In the rabbit, cefoxitin was associated with a high incidence of abortion and maternal death. This was not considered to be a teratogenic effect but an expected consequence of the rabbit's unusual sensitivity to antibiotic-induced changes in the population of the microflora of the intestine.

Cefoxitin for Injection, USP is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below.

• Lower respiratory tract infections, including pneumonia and lung abscess, caused by Streptococcus pneumoniae, other streptococci (excluding enterococci, e.g., Enterococcus faecalis [formerly Streptococcus faecalis]), Staphylococcus aureus (including penicillinase-producing strains), Escherichia coli, Klebsiella species, Haemophilus influenzae, and Bacteroides species.
• Urinary tract infections caused by Escherichia coli, Klebsiella species, Proteus mirabilis, Morganella morganii, Proteus vulgaris and Providencia species (including P. rettgeri).
• Intra-abdominal infections, including peritonitis and intra-abdominal abscess, caused by Escherichia coli, Klebsiella species, Bacteroides species including Bacteroides fragilis, and Clostridium species.
• Gynecological infections, including endometritis, pelvic cellulitis, and pelvic inflammatory disease caused by Escherichia coli, Neisseria gonorrhoeae (including penicillinase-producing strains), Bacteroides species including B. fragilis, Clostridium species, Peptococcus niger, Peptostreptococcus species, and Streptococcus agalactiae. Cefoxitin for Injection, USP, like cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when Cefoxitin for Injection, USP is used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial coverage should be added.
• Septicemia caused by Streptococcus pneumoniae, Staphylococcus aureus (including penicillinase-producing strains), Escherichia coli, Klebsiella species, and Bacteroides species including B. fragilis.
• Bone and joint infections caused by Staphylococcus aureus (including penicillinase-producing strains).
• Skin and skin structure infections caused by Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pyogenes and other streptococci (excluding enterococci e.g., Enterococcus faecalis [formerly Streptococcus faecalis]), Escherichia coli, Proteus mirabilis, Klebsiella species, Bacteroides species including B. fragilis, Clostridium species, Peptococcus niger, and Peptostreptococcus species.

Appropriate culture and susceptibility studies should be performed to determine the susceptibility of the causative organisms to cefoxitin. Therapy may be started while awaiting the results of these studies.

In randomized comparative studies, cefoxitin and cephalothin were comparably safe and effective in the management of infections caused by gram-positive cocci and gram-negative rods susceptible to the cephalosporins. Cefoxitin has a high degree of stability in the presence of bacterial beta-lactamases, both penicillinases and cephalosporinases.

Many infections caused by aerobic and anaerobic gram-negative bacteria resistant to some cephalosporins respond to cefoxitin. Similarly, many infections caused by aerobic and anaerobic bacteria resistant to some penicillin antibiotics (ampicillin, carbenicillin, penicillin G) respond to treatment with cefoxitin. Many infections caused by mixtures of susceptible aerobic and anaerobic bacteria respond to treatment with cefoxitin.

BEFORE THERAPY WITH CEFOXITIN IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOXITIN, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN WITH CAUTION TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. IF AN ALLERGIC REACTION TO CEFOXITIN OCCURS, DISCONTINUE THE DRUG. SERIOUS HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.

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

Cefoxitin for Injection, USP is indicated for the prophylaxis of infection in patients undergoing uncontaminated gastrointestinal surgery, vaginal hysterectomy, abdominal hysterectomy, or cesarean section.

If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate treatment may be instituted.

The acute intravenous LD₅₀ in the adult female mouse and rabbit was about 8 grams/kg and greater than 1 gram/kg, respectively. The acute intraperitoneal LD₅₀ in the adult rat was greater than 10 grams/kg.

Cefoxitin for Injection, USP, Pharmacy Bulk Package bag SmartPak® should be used only in patients who require a 1 gram dose and not any fraction thereof. Cefoxitin for Injection USP, Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than the 1 gram dose of cefoxitin.

Cefoxitin for Injection, USP is a semi-synthetic, broad-spectrum cepha antibiotic for intravenous administration. It is derived from cephamycin C, which is produced by Streptomyces lactamdurans. Its chemical name is sodium (6R,7S)-3-(hydroxymethyl)-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate carbamate (ester).

The empirical formula is C₁₆H₁₆N₃NaO₇S₂, and the structural formula is:

Cefoxitin for Injection contains approximately 53.8 mg (2.3 mEq) of sodium per gram of cefoxitin.

Solutions of Cefoxitin for Injection, USP range from colorless to light amber in color. The pH of freshly constituted solutions usually ranges from 4.2 to 7.0.

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.

THIS PRODUCT IS NOT INTENDED TO BE USED IN PEDIATRIC AND RENALLY IMPAIRED PATIENTS WHO REQUIRE LESS THAN A 1 GRAM DOSE.

Each SmartPak^® Pharmacy Bulk Package contains sterile Cefoxitin Sodium, USP equivalent to 100 grams of cefoxitin and is intended for intravenous infusion only.  A Pharmacy Bulk Package is a container of a sterile preparation for parenteral 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.  FURTHER DILUTION IS REQUIRED BEFORE USE.  RECONSITITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION.

CEFOXITIN FOR INJECTION, USP SMARTPAK^® PHARMACY BULK PACKAGE SHOULD NOT BE USED IN PATIENTS WHO REQUIRE LESS THAN A 1 GRAM DOSE OF CEFOXTIN.

Of the 1,775 subjects who received cefoxitin in clinical studies, 424 (24%) were 65 and over, while 124 (7%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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 (see CLINICAL PHARMACOLOGY ).

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 and PRECAUTIONS ).

Cefoxitin for Injection, USP is a dry white to off-white powder available in the following SmartPak^® Pharmacy Bulk Package:

   100 grams* (1 Pharmacy Bulk Package) Product No. 4100 NDC 66288-4100-1 sold in individual bags.

   *Each 100 gram Pharmacy Bulk Package contains sterile cefoxitin sodium equivalent to 100 grams of cefoxitin.

SmartPak^® system components are not made with natural rubber latex.

Cefoxitin for Injection USP, Pharmacy Bulk Package bag, SmartPak® should not be used in pediatric patients who require less than the 1 gram adult dose of cefoxitin.

Safety and efficacy in pediatric patients from birth to three months of age have not yet been established. In pediatric patients three months of age and older, higher doses of cefoxitin have been associated with an increased incidence of eosinophilia and elevated SGOT.

Cefoxitin is excreted in human milk in low concentrations. Caution should be exercised when cefoxitin is administered to a nursing woman.

As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

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 grams) followed by two doses of placebo (n=64), or a three-dose regimen of cefoxitin (each dose consisting of 2 grams) (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.

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

Smartpak is a registered trademark of Samson Medical Technologies, L.L.C. †Registered trademark of Siemens Healthcare Diagnostics Inc.

Increased nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics.

Cefoxitin is generally well tolerated. The most common adverse reactions have been local reactions following intravenous injection. Other adverse reactions have been encountered infrequently.

Local Reactions

Thrombophlebitis has occurred with intravenous administration.

Allergic Reactions

Rash (including exfoliative dermatitis and toxic epidermal necrolysis), urticaria, flushing, pruritus, eosinophilia, fever, dyspnea, and other allergic reactions including anaphylaxis, interstitial nephritis and angioedema have been noted.

Cardiovascular

Hypotension.

Gastrointestinal

Diarrhea, including documented pseudomembranous colitis, which can appear during or after antibiotic treatment. Nausea and vomiting have been reported rarely.

Neuromuscular

Possible exacerbation of myasthenia gravis.

Blood

Eosinophilia, leukopenia including granulocytopenia, neutropenia, anemia, including hemolytic anemia, thrombocytopenia, and bone marrow depression. A positive direct Coombs test may develop in some individuals, especially those with azotemia.

Liver Function

Transient elevations in SGOT, SGPT, serum LDH, and serum alkaline phosphatase; and jaundice have been reported.

Renal Function

Cefoxitin for Injection USP, Pharmacy Bulk Package bag, SmartPak^® should not be used in patients with renal impairment who  require less than the 1 gram adult dose of cefoxitin.

Elevations in serum creatinine and/or blood urea nitrogen levels have been observed. As with the cephalosporins, acute renal failure has been reported rarely. The role of cefoxitin in changes in renal function tests is difficult to assess, since factors predisposing to prerenal azotemia or to impaired renal function usually have been present.

In addition to the adverse reactions listed above which have been observed in patients treated with Cefoxitin for Injection, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics:

Urticaria, erythema multiforme, Stevens-Johnson syndrome, serum sickness-like reactions, abdominal pain, colitis, renal dysfunction, toxic nephropathy, false-positive test for urinary glucose, hepatic dysfunction including cholestasis, elevated bilirubin, aplastic anemia, hemorrhage, prolonged prothrombin time, pancytopenia, agranulocytosis, superinfection, vaginitis including vaginal candidiasis.

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.

Cefoxitin for Injection is contraindicated in patients who have shown hypersensitivity to cefoxitin and the cephalosporin group of antibiotics.

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.

Following an intravenous dose of 1 gram of cefoxitin, serum concentrations were 110 mcg/mL at 5 minutes, declining to less than 1 mcg/mL at 4 hours. The half-life after an intravenous dose is 41 to 59 minutes. 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.

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

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 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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefoxitin and other antibacterial drugs, Cefoxitin 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.

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

Cefoxitin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive bacteria

      Staphylococcus aureus (methicillin-susceptible isolates only)

      Staphylococcus epidermidis (methicillin-susceptible isolates only)

      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 microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefoxitin. However, the efficacy of cefoxitin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled studies.

Gram-negative bacteria

      Eikenella corrodens [non-ß-lactamase producers]

Anaerobic bacteria

      Clostridium perfringens

      Prevotella bivia

Patients should be counseled that antibacterial drugs including Cefoxitin for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefoxitin 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 cefoxitin or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, 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 antibiotic. If this occurs, patients should contact their physician as soon as possible.

Cefoxitin for Injection USP, Pharmacy Bulk Package bag SmartPak^® should be used only in patients who require a 1 gram dose and not any fraction thereof.

Cefoxitin for Injection USP, Pharmacy Bulk Package bag SmartPak^® should not be used in patients who require less than the 1 gram dose of cefoxitin.

THE INTENT OF THIS PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF SOLUTIONS FOR INTRAVENOUS INFUSION ONLY. BEFORE ADMINISTRATION, THIS PHARMACY BULK PACKAGE REQUIRES RECONSTITUTION TO A CONCENTRATION OF 100 MG/ML AND FURTHER DILUTION IN 50 mL OF A COMPATIBLE SOLUTION.

As with cephalothin, high concentrations of cefoxitin (>100 mcg/mL) may interfere with measurement of serum and urine creatinine levels by the Jaffé reaction, and produce false increases of modest degree in the levels of creatinine reported. Serum samples from patients treated with cefoxitin should not be analyzed for creatinine if withdrawn within 2 hours of drug administration.

High concentrations of cefoxitin in the urine may interfere with measurement of urinary 17-hydroxy-corticosteroids by the Porter-Silber reaction, and produce false increases of modest degree in the levels reported.

A false-positive reaction for glucose in the urine may occur. This has been observed with CLINITEST^† reagent tablets.

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