RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED 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.

Cefoxitin for Injection, USP contains cefoxitin sodium a semisynthetic,broad-spectrum cephalosporin antibiotic for parenteral administration. It is derived from cephalosporin C, which is produced by Cephalosporium Acremonium. Its chemical name is sodium (6R,7S)-3-(hydroxymethyl)-7methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate carbamate (ester).

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

Cefoxitin for Injection, USP is supplied as a dry powder in vials and contains approximately 53.8 mg (2.3 milliequivalents) of sodium per gram of cefoxitin activity. 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.

Each pharmacy bulk package bottle contains sterile cefoxitin sodium, USP equivalent to 10 g 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. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION.

Clinical Pharmacology

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. 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.

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.

Mechanism of Resistance

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 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 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: https://www.fda.gov/STIC.

Treatment

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.

(1) 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.

(2) Urinary tract infections caused by Escherichia coli, Klebsiella species, Proteus mirabilis, Morganella morganii, Proteus vulgaris and Providencia species (including P. rettgeri ).

(3) Intra-abdominal infections, including peritonitis and intra-abdominal abscess, caused by Escherichia coli, Klebsiella species, Bacteroides species including Bacteroides fragilis, and Clostridium species.

(4) 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.

(5) Septicemia caused by Streptococcus pneumoniae, Staphylococcus aureus (including penicillinase-producing strains), Escherichia coli, Klebsiella species, and Bacteroides species including B. fragilis.

(6) Bone and joint infections caused by Staphylococcus aureus (including penicillinase-producing strains).

(7) 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 for Injection, USP. Therapy may be started while awaiting the results of these studies.

In randomized comparative studies, Cefoxitin for Injection, USP 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 for Injection, USP 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 for Injection, USP. Similarly, many infections caused by aerobic and anaerobic bacteria resistant to some penicillin antibiotics (ampicillin, carbenicillin, penicillin G) respond to treatment with Cefoxitin for Injection, USP. Many infections caused by mixtures of susceptible aerobic and anaerobic bacteria respond to treatment with Cefoxitin for Injection, USP.

Prevention

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.

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 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.

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

BEFORE THERAPY WITH CEFOXITIN FOR INJECTION 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 FOR INJECTION OCCURS, DISCONTINUE THE DRUG. SERIOUS HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.

Clostridium difficile associated diarrhea (CDAD) has been reported with the 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 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

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 for Injection 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.

To report SUSPECTED ADVERSE EVENTS, contact WG Critical Care, LLC at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www.fda.gov.

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

The intent of this pharmacy bulk package is for the preparation of solutions for intravenous infusion only.

Treatment

Adults

The usual adult dosage range is 1 gram to 2 grams every 6 to 8 hours. Dosage should be determined by susceptibility of the causative organisms, severity of infection, and the condition of the patient (see Table 1 for dosage guidelines).

If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefoxitin sodium has no activity against this organism.

Cefoxitin for Injection may be used in patients with reduced renal function with the following dosage adjustments:

In adults with renal insufficiency, an initial loading dose of 1 gram to 2 grams may be given. After a loading dose, the recommendations for maintenance dosage (Table 2) may be used as a guide.

When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

Females: 0.85 x above value

In patients undergoing hemodialysis, the loading dose of 1 gram to 2 grams should be given after each hemodialysis, and the maintenance dose should be given as indicated in Table 2.

Antibiotic therapy for group A beta-hemolytic streptococcal infections should be maintained for at least 10 days to guard against the risk of rheumatic fever or glomerulonephritis. In staphylococcal and other infections involving a collection of pus, surgical drainage should be carried out where indicated.

Pediatric Patients

The recommended dosage in pediatric patients 3 months of age and older is 80 to 160 mg/kg of body weight per day divided into four to six equal doses. The higher dosages should be used for more severe or serious infections. The total daily dosage should not exceed 12 grams.

At this time no recommendation is made for pediatric patients from birth to three months of age (see PRECAUTIONS).

In pediatric patients with renal insufficiency, the dosage and frequency of dosage should be modified consistent with the recommendations for adults (see Table 2).

Prevention

Effective prophylactic use depends on the time of administration. Cefoxitin for Injection usually should be given one-half to one hour before the operation, which is sufficient time to achieve effective levels in the wound during the procedure. Prophylactic administration should usually be stopped within 24 hours since continuing administration of any antibiotic increases the possibility of adverse reactions but, in the majority of surgical procedures, does not reduce the incidence of subsequent infection.

For prophylactic use in uncontaminated gastrointestinal surgery, vaginal hysterectomy, or abdominal hysterectomy, the following doses are recommended:

Adults:

2 grams administered intravenously just prior to surgery (approximately one-half to one hour before the initial incision) followed by 2 grams every 6 hours after the first dose for no more than 24 hours.

Pediatric Patients (3 months and older):

30 to 40 mg/kg doses may be given at the times designated above.

Cesarean Section Patients:

For patients undergoing cesarean section, either a single 2 gram dose administered intravenously as soon as the umbilical cord is clamped OR a 3-dose regimen consisting of 2 grams given intravenously as soon as the umbilical cord is clamped followed by 2 grams 4 and 8 hours after the initial dose is recommended. (See CLINICAL STUDIES.)

Table 1 - Guidelines for Dosage of Cefoxitin for Injection

*Including patients in whom bacteremia is absent or unlikely.

Table 2 - Maintenance Dosage of Cefoxitin for Injection in Adults with Reduced Renal Function

Table 3 - Preparation of Solution for Intravenous Administration

**Shake to dissolve and let stand until clear.

Preparation of Solution

Table 3 is provided for convenience in constituting Cefoxitin for Injection for intravenous administration.

The 10 gram pharmacy bulk package bottle should be constituted with 43 mL or 93 mL of Sterile Water for Injection, Bacteriostatic Water for Injection, 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose Injection. CAUTION: THE 10 GRAM BULK STOCK SOLUTION IS NOT FOR DIRECT INFUSION. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION. These primary solutions may be further diluted in 50 mL to 1000 mL of the diluents listed under the Bulk Packages portion of the Compatibility and Stabilitysection.

Benzyl alcohol as a preservative has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than 3 months of age, in whom use of Cefoxitin for Injection may be indicated, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity. Therefore, diluent containing benzyl alcohol should not be used when Cefoxitin for Injection is constituted for administration to pediatric patients in this age range.

Administration

Cefoxitin for Injection may be administered intravenously after constitution.

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

Intravenous Administration

The intravenous route is preferable for patients with bacteremia, bacterial septicemia, or other severe or life threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending.

For intermittent intravenous administration: Using an infusion system, a solution containing 1 gram or 2 grams may be given over a period of time through the tubing system by which the patient may be receiving other intravenous solutions. However, during infusion of the solution containing Cefoxitin for Injection, it is advisable to temporarily discontinue administration of any other solutions at the same site.

For the administration of higher doses by continuous intravenous infusion, a solution of Cefoxitin for Injection may be added to an intravenous bottle containing 5 percent Dextrose Injection, 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose and 0.9 percent Sodium Chloride Injection. BUTTERFLY®†† or scalp vein-type needles are preferred for this type of infusion.

Solutions of Cefoxitin for Injection, like those of most beta-lactam antibiotics, should not be added to aminoglycoside solutions (e.g., gentamicin sulfate, tobramycin sulfate, amikacin sulfate) because of potential interaction. However, Cefoxitin for Injection and aminoglycosides may be administered separately to the same patient.

Directions for Proper Use of Pharmacy Bulk Package bottle:

RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION

The Pharmacy Bulk Package bottle is for use in a pharmacy admixture service under a laminar flow hood. Penetration into the Pharmacy Bulk Package bottle should be made only one time after reconstitution with a sterile transfer set or other sterile dispensing device, which allows measured distribution of the contents. Dispense the contents in aliquots using aseptic technique. The use of a syringe with a needle is not recommended as it may cause leakage. AFTER INITIAL ENTRY USE ENTIRE CONTENTS OF THE PHARMACY BULK PACKAGE PROMPTLY. A maximum time of 4 HOURS from initial entry is permitted to complete fluid transfer operations. ANY UNUSED PORTION MUST BE DISCARDED WITHIN 4 HOURS. This time limit should begin with the introducing of solvent or diluent into the Pharmacy Bulk Package bottle. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION.

Compatibility and Stability

Pharmacy Bulk Package

Cefoxitin for Injection, as supplied in pharmacy bulk package bottles and constituted to 1 gram/10 mL with Sterile Water for Injection, Bacteriostatic Water for Injection, (see Preparation of Solution), 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose Injection, should be DISCARDED 4 HOURS AFTER INITIAL ENTRY. FURTHER DILUTION IS REQUIRED BEFORE USE. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION.

These primary solutions may be further diluted in 50 mL to 1000 mL of the following diluents and maintain potency for an additional 18 hours at room temperature or an additional 48 hours under refrigeration:

 

0.9 percent Sodium Chloride Injection

 

5 percent or 10 percent Dextrose Injection

 

5 percent Dextrose and 0.9 percent Sodium Chloride Injection

 

5 percent Dextrose Injection with 0.2 percent or 0.45 percent saline solution

 

Lactated Ringer’s Injection

 

5 percent Dextrose in Lactated Ringer’s Injection

 

5 percent Sodium Bicarbonate Injection

 

M/6 sodium lactate solution

 

Mannitol 5% and 10%

After the periods mentioned above, any unused solutions should be discarded.

Cefoxitin for Injection, USP is a dry white to off-white powder supplied in Pharmacy Bulk Package Bottles containing cefoxitin sodium equivalent to10 grams of cefoxitin as follows:

The container closure is not made with natural rubber latex.

Special storage instructions

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

Also available as vials of:

A prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to determine the efficacy of short-term prophylaxis with Cefoxitin for Injection 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 for Injection (2 g) followed by two doses of placebo (n=64), or a three-dose regimen of Cefoxitin for Injection (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 for Injection, and 3/58 (5.2%) patients given three doses of Cefoxitin for Injection. The differences between the two groups treated with Cefoxitin for Injection and placebo with respect to endometritis were statistically significant (p<0.01) in favor of Cefoxitin for Injection. The differences between the one-dose and three-dose regimens of Cefoxitin for Injection were not statistically significant.

Two double-blind, randomized studies compared the efficacy of a single 2 gram intravenous dose of Cefoxitin for Injection 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 for Injection 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 for Injection and 62/76 (81.6%) patients treated with cefotetan experienced no major or minor morbidity. The difference in the outcomes in this study (95% Cl: -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:

NOTES:

† Clinitest is a trademark of Siemens Healthcare Diagnostics Inc.

†† Registered trademark of Abbott Laboratories, Inc.

Manufactured for:

WG Critical Care, LLC

Paramus, NJ 07652

Made in Italy

Revised: March 2019

NDC 44567-247-10

Cefoxitin for Injection, USP

PHARMACY BULK PACKAGE - NOT FOR DIRECT INFUSION

10 grams per Pharmacy Bulk Package

NOT TO BE DISPENSED AS A UNIT

For Intravenous Use

Rx only