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Name:Cefoxitin
Manufacturer:Sagent Pharmaceuticals
Category:Prescription Marketed Drugs


CEFOXITIN FOR INJECTION, USP

CEFOXITIN - cefoxitin sodium injection 
Sagent Pharmaceuticals

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CEFOXITIN FOR INJECTION, USP

PHARMACY BULK PACKAGE –
NOT FOR DIRECT INFUSION

SAGENT

Rx only
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.

DESCRIPTION

Cefoxitin for Injection, USP contains cefoxitin sodium a semi-synthetic, 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)-7-methoxy-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:

structural formula

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

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

The bactericidal action of cefoxitin results from inhibition of cell wall synthesis. Cefoxitin has in vitro activity against a wide range of gram-positive and gram-negative organisms. The methoxy group in the 7α position provides cefoxitin with a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases, of gram-negative bacteria.

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

Aerobic gram-positive microorganisms

 
Staphylococcus aureusa, (including penicillinase-producing strains)
 
Staphylococcus epidermidisa
 
Streptococcus agalactiae
 
Streptococcus pneumoniae
 
Streptococcus pyogenes
 
a Staphylococci resistant to methicillin/oxacillin should be considered resistant to cefoxitin.

Most strains of enterococci, e.g., Enterococcus faecalis, are resistant.

Aerobic gram-negative microorganisms

 
Escherichia coli
 
Haemophilus influenzae
 
Klebsiella spp. (including K. pneumoniae)
 
Morganella morganii
 
Neisseria gonorrhoeae (including penicillinase-producing strains)
 
Proteus mirabilis
 
Proteus vulgaris
 
Providencia spp. (including Providencia rettgeri)

Anaerobic gram-positive microorganisms

 
Clostridium spp.
 
Peptococcus niger
 
Peptostreptococcus spp.

Anaerobic gram-negative microorganisms

 
Bacteroides distasonis
 
Bacteroides fragilis
 
Bacteroides ovatus
 
Bacteroides thetaiotaomicron
 
Bacteroides spp.

The following in vitro data are available, but their clinical significance is unknown.

Cefoxitin exhibits in vitro minimum inhibitory concentrations (MIC's) of 8 mcg/mL or less for aerobic microorganisms and 16 mcg/mL or less for anaerobic microorganisms against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of cefoxitin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-negative microorganisms

 
Eikenella corrodens (non-β-lactamase producers)
 
Klebsiella oxytoca

Anaerobic gram-positive microorganisms

 
Clostridium perfringens

Anaerobic gram-negative microorganisms

 
Prevotella bivia (formerly Bacteroides bivius)

Cefoxitin is inactive in vitro against most strains of Pseudomonas aeruginosa and enterococci and many strains of Enterobacter cloacae.

Susceptibility Tests

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefoxitin powder. The MIC values should be interpreted according to the following criteria:

For testing aerobic microorganismsa,b,c other than Neisseria gonorrhoeae:

a Staphylococci exhibiting resistance to methicillin/oxacillin should be reported as also resistant to cefoxitin despite apparent in vitro susceptibility.

b For testing Haemophilus influenzae these interpretative criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM)1.

c For testing streptococci these interpretative criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood1.

MIC (mcg/mL) Interpretation
≤ 8 Susceptible (S)
16 Intermediate (I)
≥ 32 Resistant (R)

For testing Neisseria gonorrhoeaed:

d Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement and incubated in 5% CO21.

MIC (mcg/mL) Interpretation
≤ 2 Susceptible (S)
4 Intermediate (I)
≥ 8 Resistant (R)

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

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefoxitin powder should provide the following MIC values:

a Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement and incubated in 5% CO21.

Microorganism MIC (mcg/mL)
Escherichia coli ATCC 25922 1-4
Neisseria gonorrhoeaea ATCC 49226 0.5-2
Staphylococcus aureus ATCC 29213 1-4

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg cefoxitin to test the susceptibility of microorganisms to cefoxitin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg cefoxitin disk should be interpreted according to the following criteria:

For testing aerobic microorganismsa,b,c other than Neisseria gonorrhoeae:

a Staphylococci exhibiting resistance to methicillin/oxacillin should be reported as also resistant to cefoxitin despite apparent in vitro susceptibility.

b For testing Haemophilus influenzae these interpretative criteria applicable only to tests performed by disk diffusion method using Haemophilus Test Medium (HTM)1.

c For testing streptococci these interpretative criteria applicable only to tests performed by disk diffusion method using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO2 2.

Zone Diameter (mm) Interpretation
≥ 18 Susceptible (S)
15-17 Intermediate (I)
≤ 14 Resistant (R)

For testing Neisseria gonorrhoeaed:

d Interpretative criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement and incubated in 5% CO22.

Zone Diameter (mm) Interpretation
≥ 28 Susceptible (S)
24-27 Intermediate (I)
≤ 23 Resistant (R)

Interpretation should be as stated above for results using dilution techniques.

Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefoxitin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg cefoxitin disk should provide the following zone diameters in these laboratory test quality control strains:

a Interpretative criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement and incubated in 5% CO22.

Microorganism Zone Diameter (mm)
Escherichia coli ATCC 25922 23-29
Neisseria gonorrhoeaea ATCC 49226 33-41
Staphylococcus aureus ATCC 25923 23-29

Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to cefoxitin as MIC's can be determined by standardized test methods3. The MIC values obtained should be interpreted according to the following criteria:

MIC (mcg/mL) Interpretation
≤ 16 Susceptible (S)
32 Intermediate (I)
≥ 64 Resistant (R)

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standard cefoxitin powder should provide the following MIC values:

Using either an Agar Dilution Methoda or Using a Brothb Microdilution Method:

a Range applicable only to tests performed using either Brucella blood or Wilkins-Chalgren agar.

b Range applicable only to tests performed in the broth formulation of Wilkins-Chalgren agar3.

Microorganism MIC (mcg/mL)
Bacteroides fragilis ATCC 25285 4-16
Bacteroides thetaiotaomicron ATCC 29741 8-32

INDICATIONS AND USAGE

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 is 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.

CONTRAINDICATIONS

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

WARNINGS

BEFORE THERAPY WITH CEFOXITIN FOR INJECTION, USP 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, USP 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.

PRECAUTIONS

General

The total daily dose should be reduced when Cefoxitin for Injection, USP 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 for Injection, USP 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, USP 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.

Information for Patients

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

Laboratory Tests

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

Drug Interactions

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

Drug/Laboratory Test Interactions

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Pregnancy

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.

Nursing Mothers

Cefoxitin for Injection, USP is excreted in human milk in low concentrations. Caution should be exercised when Cefoxitin for Injection, USP is administered to a nursing woman.

Pediatric Use

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 for Injection, USP have been associated with an increased incidence of eosinophilia and elevated SGOT.

Geriatric Use

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).

ADVERSE REACTIONS

Cefoxitin for Injection, USP 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, USP 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, USP, 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 FDA at 1-800-FDA-1088 or www.fda.gov.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

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 six to eight 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, USP 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.

Males:                     Weight (Kg) x (140 –age)      
                          72 x serum creatinine (mg/100ml)

Females:       0.85 x above value

In patients undergoing hemodialysis, the loading dose of 1 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 three 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, USP 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, USP

+ Including patients in whom bacteremia is absent or unlikely.

Type of Infection Daily Dosage Frequency and Route
Uncomplicated forms+ of infections such as pneumonia, urinary tract infection, cutaneous infection 3-4 grams 1 gram every 6-8 hours IV
Moderately severe or severe infections 6-8 grams 1 gram every 4 hours
or
2 grams every 6-8 hours IV
Infections commonly needing antibiotics in higher dosage (e.g., gas gangrene) 12 grams 2 grams every 4 hours
or
3 grams every 6 hours IV
Table 2 - Maintenance Dosage of Cefoxitin for Injection, USP in Adults with Reduced Renal Function
Renal Function Creatinine
Clearance
(mL/min)
Dose
(grams)
Frequency
Mild impairment 50-30 1-2 every 8-12 hours
Moderate impairment 29-10 1-2 every 12-24 hours
Severe impairment 9-5 0.5-1 every 12-24 hours
Essentially no function <5 0.5-1 every 24-48 hours
Table 3 - Preparation of Solution for Intravenous Administration

++ Shake to dissolve and let stand until clear.

Strength Amount of Diluent to be Added
(mL)++
Approximate
Withdrawable
Volume (mL)
Approximate Average
Concentration
(mg/mL)
Pharmacy Bulk Package – 10 grams 43 or 93 49 or 98.5 200 or 100

PREPARATION OF SOLUTION

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

The 10 gram pharmacy bulk package bottle should be constituted with 43 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 to 1000 mL of the diluents listed under the Bulk Packages portion of the COMPATIBILITY AND STABILITY section.

Benzyl alcohol as a preservative has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, in whom use of Cefoxitin for Injection, USP 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, USP is constituted for administration to pediatric patients in this age range.

ADMINISTRATION

Cefoxitin for Injection, USP 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, USP, 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, USP 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, USP, 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, USP and aminoglycosides may be administered separately to the same patient.

Directions for Proper Use of Pharmacy Bulk Package bottle:

Pharmacy Bulk Package
Not for Direct Infusion

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, USP 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 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.

HOW SUPPLIED

Cefoxitin for Injection, USP is supplied in pharmacy bulk package bottles containing cefoxitin sodium as follows:

NDC Cefoxitin for Injection, USP Package Factor
25021-111-99 10 grams per Pharmacy Bulk Package Bottle
(10 grams of cefoxitin equivalent)
10 bottles per carton

Cefoxitin for Injection, USP is a dry white to off-white powder.

Cefoxitin for Injection, USP is also available as follows:

NDC Cefoxitin for Injection, USP Package Factor
25021-109-10 Equivalent to 1 gram of cefoxitin
in Single-Dose Vial
10 vials per carton
25021-110-20 Equivalent to 2 grams of cefoxitin
in Single-Dose Vial
10 vials per carton

Storage Conditions

Store dry powder between 2° to 25°C (36° to 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.

LATEX-FREE
Sterile, Nonpyrogenic, Preservative-free.

CLINICAL STUDIES

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

Two double-blind, randomized studies compared the efficacy of a single 2 gram intravenous dose of Cefoxitin for Injection, USP 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, USP 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, USP 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:

 
Bacteroides distasonis      7/10          (70%)
 
Bacteroides fragilis            26/33       (79%)
 
Bacteroides ovatus          10/13        (77%)
 
B. thetaiotaomicron          13/18        (72%)

REFERENCES

  1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January 1997.
  2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January 1997.
  3. National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – Fourth Edition. Approved Standard NCCLS Document M11-A4, Vol. 17, No. 22, NCCLS, Villanova, PA, December 1997.

NOTES:

Registered trademark of Ames Company, Division of Miles Laboratories, Inc.
Registered trademark of Abbott Laboratories, Inc.

SAGENT

Mfd. for SAGENT Pharmaceuticals
Schaumburg, IL 60195 (USA)
Made in Italy
©2010 Sagent Pharmaceuticals, Inc.

June 2010

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – BOTTLE LABEL

NDC 25021-111-99

Cefoxitin for Injection, USP

PHARMACY BULK PACKAGE

NOT FOR DIRECT INFUSION

10 Grams* per Pharmacy Bulk Package

NOT TO BE DISPENSED AS A UNIT

Rx only

For IV Use**

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – BOTTLE LABEL

CEFOXITIN 
cefoxitin injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:25021-111
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Cefoxitin Sodium (Cefoxitin) Cefoxitin Sodium 10 g
Product Characteristics
Color      Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:25021-111-99 10 INJECTION (10 BOTTLE) in 1 CARTON None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA065415 08/12/2010

Labeler - Sagent Pharmaceuticals (796852890)
Registrant - ACS Dobfar (429243025)
Establishment
Name Address ID/FEI Operations
GSK 338773877 MANUFACTURE

Revised: 08/2010 Sagent Pharmaceuticals



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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