PRODUCT MONOGRAPH

CEFOXITIN FOR INJECTION, USP

1 g, 2 g and 10 g vials

Antibiotic

Teva Canada Limited Date of Preparation:

30 Novopharm Court November 19, 2013
Toronto, Ontario
Canada
M1B 2K9

Control #: 168706
 1

PRODUCT MONOGRAPH

CEFOXITIN FOR INJECTION, USP

1 g, 2 g and 10 g vials

Therapeutic Classification
Antibiotic

ACTION AND CLINICAL PHARMACOLOGY

Cefoxitin is a cephamycin derived from cephamycin C. Evidence from in vitro studies suggests
that Cefoxitin exerts its bactericidal action through the inhibition of bacterial cell wall synthesis.
Studies have indicated that the resistance of Cefoxitin to degradation by bacterial beta-
lactamases is due to the methoxy group in the 7a position.

After intravenous or intramuscular administration of a 1 g dose, high serum concentrations are

attained which rapidly decline to about 2µg/mL at 3 hours in persons with normal renal function.
The area under the plasma level-time curve is comparable after bolus injection or intravenous
infusion over a period of 120 minutes.

INDICATIONS AND CLINICAL USE

TREATMENT
For the treatment of the following infections when due to susceptible organisms:
1 - Intra-abdominal infections such as peritonitis and intra-abdominal abscess
2 - Gynecological infections such as endometritis and pelvic cellulitis
3 - Septicemia
4 - Urinary tract infections (including those caused by Serratia marcescens and Serratia spp.)
5 - Lower respiratory tract infections
6 - Bone and joint infections caused by Staphylococcus aureus
7 - Soft tissue infections such as cellulitis, abscesses and wound infections

The susceptibility of the causative organism(s) to Cefoxitin for Injection, USP should be
determined by conducting appropriate culture and susceptibility studies. Therapy may be
initiated while awaiting these test results. Adjustments in treatment may be required once these
results become available.

Organisms particularly appropriate for therapy with Cefoxitin for Injection, USP are:
 2

Gram positive
Staphylococci: penicillinase producing and non-producing
Streptococci excluding enterococci

Gram negative (beta-lactamase producing and non-producing strains)

E. coli
Klebsiella species (including K. pneumoniae)
Proteus: indole positive and negative
Haemophilus influenzae
Providencia species

Anaerobes
Bacteroides fragilis

Cefoxitin for Injection, USP may also be used for the treatment of infections involving both
aerobic and anaerobic strains of susceptible bacteria.

Clinical evidence suggests that Cefoxitin therapy may be administered to patients who are also
receiving gentamicin, tobramycin, carbenicillin, or amikacin ( see PRECAUTIONS and
ADMINISTRATION).

PROPHYLACTIC USE
Cefoxitin for Injection, USP may be administered perioperatively (preoperatively,
intraoperatively, and postoperatively) in patients undergoing abdominal surgery and vaginal or
abdominal hysterectomy when there is a significant risk of postoperative infection or where the
occurrence of postoperative infection is considered to be especially serious.

Intraoperative (after clamping the umbilical cord) and postoperative administration of Cefoxitin
for Injection, USP may reduce the incidence of surgery-related postoperative infections in
patients undergoing cesarean section.

Cefoxitin for Injection, USP should be administered one-half to one hour before the surgical
procedure. Prophylactic administration should usually be stopped within 12 hours.
Administration of any antibiotic continued beyond 24 hours following surgery has been reported
to increase the possibility of adverse reactions but, in the majority of surgical procedures, does
not reduce the incidence of subsequent infection.

Should signs of postsurgical infection appear, specimens for culture should be obtained for
identification of the causative organism(s) so that appropriate therapy can be instituted.

CONTRAINDICATIONS

Cefoxitin for Injection, USP is contraindicated in patients who have previously shown
hypersensitivity to Cefoxitin or to other cephalosporin antibiotics.
 3

Cefoxitin for Injection, USP is not recommended for the treatment of meningitis. Appropriate
antibiotic therapy should be instituted if meningitis is suspected.

WARNINGS

Before initiating therapy with Cefoxitin for Injection, USP it should be determined whether the
patient has had previous hypersensitivity reactions to Cefoxitin, cephalosporins, penicillins or
other drugs. Exercise caution when administering Cefoxitin for Injection, USP to penicillin-
sensitive patients.

There is clinical and laboratory evidence to suggest a partial cross-allergenicity between

cephamycins and the other beta-lactam antibiotics, penicillins and cephalosporins. Severe
reactions including anaphylaxis, have been observed with most beta-lactam antibiotics.

Exercise caution when administering Cefoxitin for Injection, USP and other antibiotics to
patients who have demonstrated any form of allergy, particularly to drugs.

Discontinue treatment should an allergic reaction to Cefoxitin for Injection, USP occur. Serious
hypersensitivity reactions may require treatment with epinephrine and other emergency
measures.

Pseudomembranous colitis has been reported with the use of virtually all antibiotics including
Cefoxitin; therefore, it is important to consider its diagnosis in patients who develop diarrhea
during the administration of Cefoxitin sodium. Antibiotics should be prescribed with caution in
patients with a history of gastrointestinal disease, particularly colitis. This colitis can range from
mild to life-threatening in severity. Studies have indicated that a toxin produced by Clostridium
difficile is one primary cause of antibiotic-associated colitis, however, other causes should also
be considered.
PRECAUTIONS

General
When Cefoxitin for Injection, USP is administered to patients with transient or persistent
reduction of urinary output due to renal insufficiency, the total daily dose should be reduced
because high and prolonged serum antibiotic concentrations may result from usual doses (see
DOSAGE and ADMINISTRATION).

Prolonged Cefoxitin sodium treatment can result in the overgrowth of non-susceptible

organisms. Repeated evaluation of the patient's condition is essential. If super-infection occurs
during therapy appropriate supportive measures should be taken. Resistance may develop during
antibiotic therapy and in such cases another antibiotic may be substituted.
 4

Laboratory Tests
A false-positive reaction to glucose in the urine may occur with Benedict's or Fehling's solutions
in patients on Cefoxitin for Injection, USP therapy. No false-positive reactions have been
observed with the use of specific glucose oxidase methods.
Analysis of serum creatinine levels using the Jaffe method may yield falsely high creatinine
levels if the serum concentration of Cefoxitin exceeds 100µg/mL. Serum samples taken for
analysis of creatinine levels from patients on Cefoxitin sodium therapy should not be analyzed if
withdrawn within two hours of drug administration.

Drug Interactions
Increased nephrotoxicity has been reported following concomitant administration of
cephalosporins and aminoglycoside antibiotics.
Use in Pregnancy
The safety of Cefoxitin for Injection, USP in the treatment of infections during pregnancy has
not been established. If the administration of Cefoxitin sodium to pregnant patients is considered
necessary, its use requires that the anticipated benefits be weighed against possible hazards to the
fetus. No evidence of impaired fertility or harm to the fetus has been reported from reproductive
and teratogenic studies where Cefoxitin sodium was administered to both mice and rats.

Nursing Mothers
Cefoxitin has been found to be secreted in breast milk of nursing mothers.

Use in Children
In children 3 months of age or older, higher doses of Cefoxitin for Injection, USP (100
mg/kg/day and above) have been associated with an increased incidence of eosinophilia and
elevated SGOT.

ADVERSE REACTIONS

Cefoxitin for Injection, USP is generally well tolerated. Adverse reactions have been mild and
transient and rarely require cessation of treatment.

Local Reactions
Thrombophlebitis has been reported after intravenous administration. Some degree of pain and
tenderness is usually experienced after intramuscular injections using water. Induration has
occasionally been reported.

Allergic
Maculopapular rash, urticaria, pruritus, eosinophilia, fever and other allergic reactions including
anaphylaxis have been reported.
Gastrointestinal
Symptoms of pseudomembranous colitis can appear during or after antibiotic treatment. Nausea
and vomiting have been known to occur in rare cases.
 5

Blood
Eosinophilia, leukopenia, neutropenia, hemolytic anemia, thrombocytopenia and bone marrow
depression have been noted. During Cefoxitin sodium therapy, some individuals, particularly
those with azotemia, may develop positive direct Coombs tests.

Liver Function
Transient elevations in SGOT, SGPT, serum LDH and serum alkaline phosphatase have been
reported. Jaundice has also been noted.

Cardiovascular
Hypotension.

Kidney
Elevations in blood urea nitrogen and/or serum creatinine levels have been reported. Acute renal
failure has been reported rarely, but is known to occur, as with other cephalosporins. Since
factors predisposing to prerenal azotemia or to impaired renal function have been present, it is
difficult to assess the role of Cefoxitin sodium in renal function test changes.

TREATMENT OF OVERDOSE

No specific antidote is known. In case of an overdose of Cefoxitin for Injection, USP, institute
general supportive therapy. In patients with renal insufficiency dialysis may be performed to
eliminate Cefoxitin.
DOSAGE AND ADMINISTRATION
Dosage:
Cefoxitin for Injection, USP may be administered intravenously or intramuscularly as required
(See RECONSTITUTION below for each route.)

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

Adults with Normal Renal Function:

The usual adult dose of Cefoxitin for Injection, USP is 1 to 2 g every 6 to 8 hours. Dosage and
route of administration depend on severity of infection, susceptibility of the causative organisms,
and the patient's condition. The usual adult dosages are shown in the table below.
 6

Usual Adult Dosage

Type of Infection Daily Dosage Frequency and Route
Uncomplicated forms* of
infections such as 3-4 g 1 g every 6-8 h
pneumonia, urinary tract I.V. or I.M.
infection, soft tissue
infection
Moderately severe or 1 g every 4 h or
severe infections 6-8 g 2 g every 6 - 8 h I.V.
Infections commonly 2 g every 4 h or
needing antibiotics in 12 g 3 g every 6 h I.V.
higher dosage (e.g. gas
gangrene)
*Including patients in whom bacteremia is absent or unlikely

Therapy may be initiated while awaiting the results of susceptibility tests.

Antibiotic therapy for group A beta-hemolytic streptococcal infections should continue for a
minimum of 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.

Adults with Impaired Renal Function:

Patients with reduced renal function may require a reduced dose of Cefoxitin for Injection, USP.
Serum levels should be monitored in patients with severe renal impairment.

In adults with renal insufficiency a loading dose of 1 to 2 g should be administered. In patients

undergoing hemodialysis a loading dose should be given after each hemodialysis procedure. The
table below presents recommended maintenance doses for patients with various levels of renal
impairment and patients undergoing hemodialysis.

RENAL CREATININE DOSE FREQUENCY

FUNCTION CLEARANCE
mL/min mL/sec
Mild impairment 50-30 0.83-0.50 1-2 g every 8 -12 h
Moderate 29-10 0.48-0.17 1-2 g every 12 - 24 h
impairment
Severe impairment 9-5 0.15-0.08 0.5-1 g every 12 -24 h
Essentially no <5 <0.08 0.5 - 1 g every 24 - 48 h
function
 7

Creatinine Clearance
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 (mL/sec.)
Males: Weight (kg) X (140 - age)
49 X serum creatinine (mM/L)

Females: 0.85 X the above value

Neonates (Including Premature Infants, Infants and Children)

Warning for Neonates:

Solutions containing preservatives should not be used for injection or for flushing catheters
in treating neonates.

Benzyl alcohol as a preservative in Bacteriostatic Water for Injection and Bacteriostatic

Sodium Chloride Injection has been associated with toxicity in neonates. At present, data
are unavailable on the toxicity of other preservatives in this age group. Therefore, any
diluents used with Cefoxitin for Injection, USP in the treatment of neonates should not
contain any preservatives.

Premature Infants with Body

Weights 20-40 mg/kg every 12 h I.V.
Above 1500 g
Neonates
0-1 week of age 20-40 mg/kg every 12 h I.V.
1-4 weeks of age 20-40 mg/kg every 8 h I.V.
Infants 20-40 mg/kg every 6 h or
1 month to 2 years of age every 8 h I.M. or I.V.
Children 20-40 mg/kg every 6 h or every 8 h I.M.
or I.V.

The total daily dosage in infants and children with severe infections may be increased to 200
mg/kg, but should not exceed 12 g per day.

Cefoxitin for Injection, USP is not recommended for the treatment of meningitis. Appropriate
antibiotic therapy should be instituted if meningitis is suspected.

Sufficient data is not yet available to recommend a specific dosage schedule for children with
renal impairment. If Cefoxitin sodium therapy proves to be necessary the dosage should be
modified consistent with the recommendations for adults. (see table above).
 8

PROPHYLACTIC USE

In Vaginal or Abdominal Hysterectomy and Abdominal Surgery:

The first 2 g dose should be administered intravenously or intramuscularly just prior to surgery
(approximately one-half to one hour before initial incision), followed by the second and third 2 g
doses at 2 to 6 hour intervals.

Cesarean Section:
Two grams administered intravenously as soon as the umbilical cord has been clamped. The
second and third 2 g doses should be given at four and eight hours after the first dose by
intravenous or intramuscular administration.

Administration

Intramuscular
Intramuscularly administered Cefoxitin for Injection, USP should be injected into a large muscle
mass such as the upper outer quadrant of the buttock (i.e. gluteus maximus). Maintain aspiration
to avoid inadvertent injection into a blood vessel.

Intravenous
The intravenous route is preferable for patients with severe life-threatening infections.

Cefoxitin for Injection, USP may be administered by intravenous injection either by continuous
or intermittent infusion. The reconstituted Cefoxitin for Injection, USP must be further diluted to
the desired volume with any of the recommended diluents.

Intermittent intravenous administration

Cefoxitin sodium may be administered slowly over a period of three to five minutes.
Using an infusion system Cefoxitin sodium may be given through the tubing by which
the patient is receiving other parenteral solutions. However, during infusion of the
solution containing Cefoxitin sodium it is advisable to temporarily discontinue
administration of any other infusion solution at the same site (by using an appropriate
I.V. infusion set). Any unused portions of Cefoxitin for Injection, USP must be
discarded.

Continuous intravenous infusions

A Cefoxitin sodium solution may be added to an intravenous bottle containing an
appropriate intravenous infusion fluid in the amounts calculated to give the desired
antibiotic dose. BUTTERFLY* or scalp vein-type needles are preferred for this type of
infusion.

*Registered trademark of Abbott Laboratories

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PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Cefoxitin sodium

Chemical Name: Sodium 6(R)7(S)-3-(hydroxymethy)-7a-methoxy-8-oxo-7-

[2-(2-thienyl) acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylate carbamate (ester).
Structural Formula:

MeO H
CH2CONH S
S

N
O CH2OCONH2
COONa

Molecular Formula: C16H16N3NaO7S2

Molecular Weight: 449.43

Description:
Cefoxitin sodium is a white to off-white granular or powder-like substance with a slight
characteristic odor. Cefoxitin sodium solutions range from clear to a light amber color. It is
very soluble in water and methanol, slightly soluble in ethanol and acetone and insoluble in ether
or chloroform. [Cefoxitin granules have a melting point of 149-150ºC.]

Composition: Vials of Cefoxitin for Injection, USP contain Cefoxitin sodium. The pH values of
freshly constituted solutions range from 4.2 to 7.0. Each gram of Cefoxitin sodium contains
approximately 2.3 mEq of sodium.

Stability and Storage Recommendations: Cefoxitin for Injection, USP should be stored at
room temperature between 15 and 30ºC. Protect from light.

The dry material as well as solutions tend to darken, depending on storage conditions, however,
product potency is not adversely affected. Dark brown solution should not be used.
 10

Reconstituted Solutions:
As with all parenteral drug products, intravenous admixtures should be inspected visually for
clarity, particulate matter, precipitate, discoloration and leakage prior to administration whenever
solution and container permit.

For intramuscular use, the following solutions can be used for reconstitution:
Sterile Water for Injection or, if required Bacteriostatic Water for Injection

I.M. RECONSTITUTION TABLE

Strength Amount of Approximate

Diluent to Withdrawable Nominal
be Added* Volume Concentration
(mL) (mL) (mg/mL)
1 g vial 2 2.5 400
2 g vial 4 5.0 400
*Shake to dissolve and let stand until clear.

For intravenous use, the following solutions can be used for reconstitution:
Sterile Water for Injection or, if required, Sterile Sodium Chloride 0.9% or,
Sterile Dextrose Injection 5% or 10%

I.V. RECONSTITUTION TABLE

Strength Amount of Approximate Nominal
Diluent to Withdrawable Concentration
be Added* Volume (mg/mL)
(mL) (mL)
1 g vial 10 10.5 95
2 g vial 10 or 20 11.1 or 21.0 180 or 95

* Shake to dissolve and let stand until clear. The prepared solution may be further diluted to the
desired volume with any of the solutions for I.V. infusion listed below.

Pharmacy Bulk Vial: The 10 g Pharmacy Bulk Vial contains many single doses for multiple
dispensing. The closure shall be penetrated only one time after reconstitution (single puncture).
Any unused stock solution remaining alter a period of 8 hours should be promptly discarded.
 11

PHARMACY BULK VIAL RECONSTITUTION TABLE

Strength Amount of Diluent Approximate Nominal
to be Added* (mL) Withdrawable Volume Concentration
(mL) (mg/mL)
10 g vial 96 102 100
*Shake to dissolve and let stand until clear

The Pharmacy Bulk Vial is intended for use in hospitals with a recognized IV admixture
program, and is restricted to the preparation of admixtures for infusion. It is not for direct
infusion.

For direct intravenous injection: Reconstitute as directed in the I.V. Reconstitution Table.
For intermittent intravenous infusion: Reconstitute as directed in the I.V. Reconstitution
Table.
For continuous intravenous infusion: Reconstitute with Sterile Water for Injection. The
reconstituted solution may be added to an appropriate intravenous bottle or bag containing any of
the solutions for I.V. infusion listed below. A freshly reconstituted solution should be used for
further dilution with solutions for I.V. infusion. The following solutions can be used for IV
infusion:

Sodium Chloride Injection 0.9%

Dextrose Injection 5% or 10%
Dextrose 5% with 0.2% or 0.45% Saline solution
Dextrose Injection 5% and Sodium Chloride Injection 0.2%, 0.45%, or 0.9%
Ringer's Injection
Lactated Ringer's Injection
Dextrose 5% in Lactated Ringer's Injection
10% Invert Sugar in saline Solution
NORMOSOL* - M in D5W
*Registered Trademark of Abbott Laboratories

Cefoxitin for Injection, USP has also been found compatible when admixed in intravenous
infusions with the following:
Heparin 100 units/mL in Sodium Chloride Injection 0.9%
Heparin 100 units/mL in Dextrose Injection 5%
Heparin 0.1 unit/mL (at room temperature 8 hours) in Sodium Chloride Injection 0.9%
Heparin 0.1 unit/mL (at room temperature 8 hours) in Dextrose Injection 5%

Stability of Reconstituted or Diluted Solutions:

Reconstituted solution for intramuscular injection and intravenous injection should be used
within 8 hours if kept at room temperature or 72 hours if stored under refrigeration (2-8ºC).
 12

The further diluted solutions for intravenous infusions should be used within 12 hours if kept at
room temperature or 24 hours if stored under refrigeration (2-8ºC).

Incompatibility:
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.
 13

AVAILABILITY OF DOSAGE FORMS

Cefoxitin for Injection, USP for IM or IV use is supplied in vials as sterile powder containing 1
g or 2 g of Cefoxitin as the sodium salt.
Cefoxitin for Injection, USP for IV use is also available as a Pharmacy Bulk Vial containing 10
g of Cefoxitin as the sodium salt.

MICROBIOLOGY

In Vitro Susceptibility Results

The in vitro susceptibility of clinical isolates to Cefoxitin is shown in the following table (Table
1).

Cefoxitin is not active against Pseudomonas species, most strains of enterococci, many strains
of Enterobacter cloacae, methicillin-resistant staphylococci and Listeria monocytogenes.
 14
TABLE 1

SUSCEPTIBILITY OF AEROBIC & ANAEROBIC BACTERIA TO Cefoxitin

Cumulative Percentage of Strains Inhibited by Cefoxitin Concentration ( g/mL)

ORGANISM No. of
Strain 0.05 0.1 0.2 0.4 0.8 1.56 3.1 6.25 12.5 25 50 100 200
s
AEROBES
Gram-negative
Acinetobacter 21 5 10 24 76 100
calcoacetus 9 11 89 100
Citrobacter sp. 15 7 7 100
Enterobacter sp. 354 3 39 86 96 99 99 100
Escherichia coli 61 2 2 3 13 80 90 98 100
Haemophilus sp. 88 1 23 88 91 97 99
Klebsiella pneumoniae 48 15 88 94 100
Nesseria gonorrhoeae 74 72 91 97 99
Proteus mirabilis 390 9 31 44 68 82 92 96
Proteus (not P. 17 12 77 82 88 88 94 100 2
mirabilis) 207
Providencia sp. 23 13 70 96 100
Pseudomonas 55 51 94 94 96 100
aeruginosa
Salmonella sp.
Shigella sp.
Gram-Positive
Staphylococcus aureus 55 42 100
Staphylococcus 29 11 30 48 74 96 100
epidermidis
ANAEROBES
Gram-negative
Bacteroides fragilis 50 3 6 9 48 79 84 97 97 100
Fusobacterium sp. 11 46 55 64 73 82
 15
Gram-positive
Clostridium perfringens 15 7 35 67 93 100
Clostridium difficile 15 7 20 40 93 100
Clostridium sp. 16 25 44 50 69 75 81 87 100
Peptococcus sp. 33 81 92 97 97 100
Peptostreptococcus 39 49 67 77 87 97
Veillonella 9 11 50 74 100
 16

Beta-lactamase Stability
Cefoxitin is resistant to hydrolysis by Bacteroides fragilis, by beta-lactamase from
Staphylococcus aureus (penicillinase), and by all types of beta-lactamases (Ia, Ib, Id, IIIa, IVc)
from the Enterobacteriaceae family.

Susceptibility Testing
a) Aerobes
Antibiotic susceptibility testing is recommended using the Kirby-Bauer or WHO disc
methods using a disc 6 mm in diameter containing 30 µg of Cefoxitin. For testing
susceptibility to Cefoxitin, the Cefoxitin disc should be used.

In vitro tests have shown Cefoxitin to have activity against certain strains of
Enterobacteriaceae which were found resistant when tested with the cephalosporin class
disc. Therefore, the cephalosporin disc should not be used for testing susceptibility to
Cefoxitin, and the Cefoxitin disc should not be used for testing susceptibility to
cephalosporins.

NOTE
Serratia marcescens strains should be tested by the broth dilution test to determine minimal
inhibitory concentration.

b) Anaerobes
For susceptibility testing of obligate anaerobes, tube or agar dilution methods are more
applicable and should be used.

Organisms are considered to be susceptible according to the following table:

Aerobes: Zone (mm) Sensitivity
≥ 18 Susceptible
15-17 Intermediate susceptibility
≤ 14 Resistant

Anaerobes: MIC (ug/mL) Sensitivity

≤8 Susceptible
16 Intermediate susceptibility
≥ 32 Resistant
 17

PHARMACOLOGY

Animal Pharmacology
Studies performed on a number of species to evaluate the pharmacological profile of Cefoxitin
at meaningful dose levels, did not detect specific or significant pharmacologic effects on the
cardiovascular, central nervous, gastrointestinal and respiratory systems. The only exceptions
were transient G.I. motility in dogs and transient changes in blood pressure and arterial blood
flow in dogs and cats at doses of 100-300 mg/kg of Cefoxitin sodium.

Human Pharmacology
Cefoxitin is poorly absorbed in both animals and humans after oral administration. High serum
and urine concentrations of Cefoxitin are produced with parenteral administration (see below).
The active form of Cefoxitin is largely excreted unchanged by the kidneys (up to 6% is excreted
as the deacylated metabolite). The active unchanged form of Cefoxitin has a mean terminal
serum half-life of approximately one hour in adults. The mean terminal serum half-life in
neonates 0-7 days of age is 5.6  0.5 hrs, in neonates 7 days to 1 month of age 2.5  0.5 hrs and in
infants 1-3 months of age 1.7  0.4 hrs. Cefoxitin is rapidly discharged into the bile. Tubular
excretion of Cefoxitin is slowed with probenecid. Probenecid also increases and prolongs blood
levels of Cefoxitin. Absorption or elimination of Cefoxitin were not shown to be affected by
administration of lidocaine.

Intravenous Administration in Adults

The mean (and range) peak serum concentrations of Cefoxitin, after a single 0.5, 1.0 and 2.0 g
I.V. dose of Cefoxitin sodium administered over 3 minutes, were 47 µg/mL (25-69 µg/mL), 110
µg/mL (82-131µg/mL) and 221 µg/mL (119-318 µg/mL), respectively.

The mean urinary recovery during a 12 hour collection period was approximately 78%, 77%,
and 78% of the respective doses (see Figure 1).
 18

Figure 1:

Serum Concentrations of Cefoxitin (mean of 9 volunteers)

following 0.5, 1.0 and 2.0 g Intravenous Cefoxitin over 3 Minutes

300

0.5 g

1.0 g

2.0 g
200
ug/mL

100

0
0 10 20 30 40 50 60 70 80 90

Minutes after Infusion

Adapted from Sonneville et. al. 16

Lower peak serum levels were achieved with a longer intravenous infusion period. After a 1.0 g
infusion of Cefoxitin over 3, 30, and 120 minutes the peak serum concentrations were 125
µg/mL, 72 µg/mL and 25 µg/mL, respectively (see Figure 2).

During a 12 hour collection period the mean values of total urinary recovery of 1.0 g of
Cefoxitin infused over 3, 30 and 120 min, were approximately 74% (0.74 g), 80% (0.80 g) and
76% (0.76 g), respectively, of the original dose.
 19

Figure 2:

Serum Concentrations of Cefoxitin (mean of 6 volunteers)

After 1.0 g over 3, 30 and 120 Minutes

200

1g - 3 minutes

1g - 30 minutes
(ug/mL)

1g - 120 minutes

100
Concentration

0
0 30 60 90 120

Time (minutes)

Adapted from Goodwin et. al. 8

In summary, after intravenous administration over a 3-5 minute period, Cefoxitin is rapidly
distributed into plasma and has a serum half-life of 40-60 minutes.

Renal clearance of Cefoxitin is reduced and serum levels are prolonged with pretreatment
administration of probenecid. The terminal half-life with and without probenecid pretreatment
was 83 minutes and 41 minutes (respectively) after 1.0 g of I.V. Cefoxitin sodium (see Figure
3).
 20

Figure 3:

Serum concentrations of Cefoxitin (mean of 6 volunteers)

after 1.0 g over 3 minutes and preceded by 1.0 g Probenicid IV

150

1g Cefoxitin over 3 Minutes

1g Cefoxitin after Probenicid (1 g i.v.)

100

50

0
0 30 60 90 120

Time (minutes)

Adopted from Goodwin et. al. 8

The mean urinary recovery was less in the first hour after administration with prior probenecid
treatment (30.5% vs 54.6% without probenecid), but after 12 hours the recoveries were
comparable (68.4% and 74.1%, respectively). (See Table 2).

TABLE 2
URINARY RECOVERY (mg) OF Cefoxitin AFTER 1 g I.V.
OVER 3 MINUTES, ALONE OR WITH PRIOR PROBENECID.
Hours 0-1 1-2 2-3 3-4 4 - 12 Total
Cefoxitin 546 127 38 15 16 741
Cefoxitin + 305 135 103 65 77 685
Probenecid
 21

Intravenous Administration in Neonates and Infants

Pharmacokinetic and demographic data for pediatric patients are contained in the following table
and figure:

TABLE 3
GROUP 1 GROUP 2 GROUP 3
NEONATES NEONATES INFANTS
(0-7 DAYS) (7 DAYS-1 MO.) (1-3 MOS.)
Number 19 12 7
Age, mean (days) 1.1 (0 - 2)* 13.4 (7-26) 47.4 (33 -73)
Dose, mean (mg/kg) 32.9 (29 - 40) 34.9 (30-40) 30.3 (27-35)
Weight, mean (kg) 2.2 2.5 3.2
Volume of distribution,
mean (mL/kg) 422 ± 52 526 ± 108 482 ± 109
t½, mean ± SE (hours) 5.6 ± 0.5 2.5 ± 0.5 1.7 ± 0.4
*Range is in parentheses
 22

Figure. 4:

Serum Concentrations of Cefoxitin vs. Time

For Pediatric Age Groups
100

Neonates 0-7 Days

Neonates 7 Days - 1 Months

80
Infants 1-3 Months
Concentration (ug/mL)

60

40

20

0
0 2 4 Hours 6 8 10

Urinary Excretion and Concentrations in Adults

Cefoxitin is rapidly excreted intact into the urine by glomerular filtration, and renal tubular
secretion; high urinary concentrations result. Renal clearance is greater than 250 mL/min/1.73m2
and about 75% of each dose administered is recovered within the first 3 hours after dosing.
Approximately 75 to 90% of an intramuscular or intravenous dose of Cefoxitin sodium is
excreted over a 12- hour period and relatively high urinary concentrations result during this
period, e.g., an average of 1105 µg/mL following 0.5 g I.M., 2208 µg/mL following 1.0 g I.M.
and 6574 µg/mL following a 2.0 g I.V. dose. (See Table 4 for additional details).
 23

TABLE 4
MEAN TOTAL Cefoxitin (mg) EXCRETED IN URINE
AFTER SINGLE-DOSE ADMINISTRATION OF Cefoxitin SODIUM
FOR INJECTION
HOURS AFTER ADMINISTRATION Total % OF
0-1 1-2 2-3 3-4 4-12 mg DOSE
1.0 g I.V. 546 127 38 15 16 742 74.2%
(3 min.)
1.0 g I.V. 542 174 45 19 20 800 80.0%
(30 min.)
2.0 g I.V. 1396 325 150 46 62 1979 98.9%
(3 min.)
500 mg 176 138 67 32 22 435 87.1%
I.M.
1.0 g I.M. 425 263 100 58 56 902 90.2%

Intramuscular Administration in Adults

After a single 0.5 and 1.0 g dose of Cefoxitin sodium without lidocaine HCl a serum level of
10.2 and 19.4 µg/mL respectively was obtained within 10 minutes. A mean peak serum
concentration of 10.9 and 22.5µg/mL respectively was attained. The mean terminal serum half-
lives were 46 and 45 minutes respectively. The mean values of total urinary recovery after doses
of 0.5 and 1.0 g were 87.1% (0.44 g) and 90.1% (0.90 g) of the dose during a 0-12 hour
collection period (see Figure 5).
 24

Figure 5:
Serum Concentrations of Cefoxitin
After Intramuscular Administration
30

Cefoxitin-0.5 g
Cefoxitin-1.0g
Serum Concentration (ug/mL)

20

10

0
0 30 60 90 120 150 180 210 240
Minutes

Adapted from Brumfitt et. al. 5

When Cefoxitin sodium was reconstituted for intramuscular injection with 0.5% or 1.0%
lidocaine HCl, the lidocaine had no effect on the absorption or elimination of Cefoxitin. After
intramuscular administration, peak serum levels are achieved in 20-30 minutes and virtually all
of the dose administered is available to the systemic circulation.

Fluid and Tissue Levels in Adults

Cefoxitin was detected in the following fluids and tissues.

TABLE 5
Route and Dose Tissue or Fluid
Concentrations
I.V. 2 g bolus Gallbladder tissue 26 µg/g
I.V. 2 g bolus Bile 127 µg/mL
I.V. 2 g multi-dose Bronchial secretions 1.5 - 3.75 µg/mL
I.V. 2 g multi-dose Pleural fluid 4 - 8 µg/mL
I.V. 2 g multi-dose Pus (liver abscess) 4 µg/mL
I.V. 2 g infusion Sputum 1.8 µg/mL
I.V. 1 g bolus Breast milk 5 - 6 mg/mL

Adapted from Brogden et al.3

 25

C.S.F. PROTEINS
Normal Elevated
I.V. 2 g bolus Penetration in 3/6 Penetration in 3/3
4 hourly patients (50%) patients (100%)
C.S.F. 1.25 µg/mL C.S.F. 5.0 µg/mL
serum 75 µg/mL serum 80 µg/mL
I.V. 2 g bolus Penetration in 7/7 Penetration in 3/3
with 0.5 g probenicid p.o. patients (100%) patients (100%)
4 hourly C.S.F. 2.5 µg/mL C.S.F. 2.5 µg/mL
serum 102 µg/mL serum 66.6 µg/mL

Multiple doses of Cefoxitin for Injection, USP (Cefoxitin sodium) plus probenecid facilitates
C.S.F. penetration and maintenance of higher levels.

Adults with Renal Impairment

Since Cefoxitin is eliminated primarily by the kidneys, serum levels of Cefoxitin are greatly
prolonged in patients with renal insufficiency, particularly in those patients with creatinine
clearance less than 30 mL/min. The following table presents data on the relationship between
creatinine clearance and serum half-life of Cefoxitin in patients with renal impairment who were
given 30 mg/kg of Cefoxitin in a 30-minute intravenous infusion:

Creatinine Serum t½ Cefoxitin

Clearance Creatinine hours Serum Concentration (µg/mL)
mL/min.1.73 m2 µg/mL 10 min. 30 60 120 240
normal 11.1 0.8 80 125 33 10 2
30-80 22.5 1.15 81 168 93 58 29
10-30 51.2 6.3 68 151 104 89 66
<10 115.4 13.2 63 158 118 103 79
end stage
renal function 118.8 21.5a 74 189 147 114 108
3.7b
a-Pre-dialysis
b-During Dialysis
 26

TOXICOLOGY

Acute Toxicity
The acute toxicity data for Cefoxitin is summarized below:
Species Route LD50 (g/kg)
Mouse I.V. 50 - 7.95
Rat-young adult I.P. >10.0
Rat-weanling I.P. >10.0
Rat-infant I.P. >5.0
Rabbit I.V. >1.0

Signs of drug toxicity in mouse and rat included ataxia, bradypnea, stiff hind limbs and
decreased activity, and were visible with all routes of administration. To alter the acute toxicity
of carbenicillin or gentamicin, in mice, pretreatment with large doses of Cefoxitin (>1.0 g/kg and
greater) was required. Doses of 4 to 8 g/kg of Cefoxitin were required pretreatment to alter the
significant increase in toxicity of digoxin in mice. Because the doses of Cefoxitin required are
high, the interactions with carbenicillin, gentamicin and digoxin are probably of little clinical
significance. Acute studies with aqueous solutions of Cefoxitin sodium (100 mg/mL) showed no
signs of irritation to the rabbit eye in acute studies and caused no hemolysis of dog erythrocytes
(0.02 - 0.10 mg/mL) in vitro.

Acute Comparative Renal Studies

Single IV studies:
Acute I.V. injections of 100 to 1000 mg/kg of Cefoxitin or cephalothin into mice, rats, rabbits,
and monkeys showed no evidence of elevation in serum urea nitrogen or creatinine
concentration. While there was no histologic damage to the kidney in rats or monkeys, a slight
histologic damage was observed in rabbits.
The same experiment performed with single doses of cephaloridine of 80-480 mg/kg showed
signs of renal lesions in rabbits and monkeys but not in mice or rats. Other studies have shown
that pretreatment with furosemide (20 mg/kg I.V.) potentiates the severity of renal lesions in
mice given 1250 to 5000 mg/kg of cephaloridine. However, several other studies revealed no
renal lesions in mice given similar doses of Cefoxitin or cephalothin, regardless of furosemide
pretreatment.

Renal lesions were not observed in mice given single doses (up to 5000 mg/kg) of four lots of
Cefoxitin with or without pretreatment with furosemide. Slight renal lesions were seen in one
mouse who received 5000 mg/kg of Cefoxitin after pretreatment with furosemide.

Two other repeat studies were performed using the same lot. Very slight renal lesions were seen
in only one mouse given 5000 mg/kg of Cefoxitin after pretreatment with furosemide (20 mg/kg
I.V.).
 27

Subacute or Chronic Toxicity

Subcutaneous injections of 100 to 900 mg/kg/day of Cefoxitin sodium were tolerated in rats and
monkeys for periods as long as six months. All animals displayed dose-related tissue damage at
the site of injection which included necrosis, cavitation, hemorrhage, hemosiderosis, granulation
and fibroplasia. At the highest dosage levels some anemia and weight loss was observed. Soft
stool in monkeys and an increase in cecal size in rats were observed at all dosage levels.
Detectable serum albumin levels were decreased at all doses in both studies performed. (See
under PHARMACOLOGY)

A 27-week study performed on female monkeys where Cefoxitin sodium was administered
subcutaneously, showed an increase in both absolute and relative mean kidney weights. Gross or
microscopic changes were not observed. A dose-related enlargement and discoloration of the
inguinal, axillary and sublumbar lymph nodes were noted. These changes are associated with
local tissue damage at the site of injection. A similar study performed on rats showed an
increase in relative kidney weight in males receiving 300 and 900 mg/kg doses of Cefoxitin.
This was not accompanied by any gross or microscopic changes.

A 14-week intravenous study in monkeys revealed drug-related changes similar to the ones
discussed above. The subcutaneous route was used for periods of 1 to 10 days because of
difficulties with venipuncture. At doses of 300 mg/kg (in 1/6 monkeys) and 900 mg/kg (in 3/6
monkeys) small amounts of strainable lipid were detected in the cytoplasm of the proximal
convoluted tubular epithelium. Other studies included the I.V. administration of 25 to 100
mg/kg/day and 100 to 900 mg/kg/day of Cefoxitin sodium for eight and 30 days, respectively.
Drug-related changes were observed only at high dosage levels. A low occurrence of soft stool
was observed. Focal tubular dilation, inflammation, and cast formation in the kidney were seen
in only one monkey treated with 900 mg/kg/day of Cefoxitin sodium for 30 days.

One out of six rabbits receiving Cefoxitin sodium I.V. in doses of 50 mg/kg/day and 4/6 rabbits
receiving Cefoxitin sodium I.V. in doses of 100 mg/kg/day showed small amounts of lipid and
brownish cast in the tubular epithelium of the corticomedullary junction. Only one rabbit
showed an elevation of serum creatinine and BUN levels.

A 9 day intravenous study performed on rabbits receiving 100 to 300 mg/kg/day of Cefoxitin
sodium showed various changes (anorexia, decreased water intake, weight loss, diarrhea, gastric
esophageal ulcers, cecal edema and hemorrhage) over a 14-day observation period.

A 30-day or 14 week intramuscular study in adult beagles given 100 mg/kg/day of Cefoxitin
sodium displayed only inflammatory tissue changes at the injection site. Except for a decrease in
detectable serum albumin, no other drug-related systemic changes were visible.

A 30-day subcutaneous study in beagle puppies given 200 or 400 mg/kg/day of Cefoxitin sodium
showed no treatment-related effects except for a decrease in detectable serum albumin. Changes
observed with 800 mg/kg/day for 30 days and with 1600 mg/kg/day included tissue damage at
 28

the site of injection, increase in kidney weight, and a decrease in detectable serum albumin. A
decrease in weight gain was observed in puppies receiving 1600 mg/kg/day of Cefoxitin sodium.
Only one puppy who received 1600 mg/kg/day of Cefoxitin sodium showed small amounts of fat
in tubular epithelium of the kidney cortex. All treatment-related changes were reversible upon
discontinuation of drug.

Reproduction Studies
No evidence of fetal toxicity or teratogenicity was observed in pregnant mice and pregnant rats
receiving intravenous injections (100, 300 and 900 mg/kg/day of Cefoxitin sodium) and
intraperitoneal injections (100, 200 and 300 mg/kg/day of Cefoxitin sodium) respectively, on
days 6 through 15 of gestation. A minimal post-treatment natural weight gain of rats and a
decrease of fetal weight were observed. Gestational time or pup survival were not adversely
affected by subcutaneous administration of 300 to 900 mg/kg/day of Cefoxitin sodium on day 15
of gestation to parturition. On days 4 and 13 post-partum a slight decrease (p<0.05) in average
pup weight was observed, but the weight was similar to controls on day 21 postpartum.
Subcutaneously repeated injections of Cefoxitin sodium in a dose of 100 mg/kg/day in male rats
for 70 consecutive days before mating had no adverse effect on fertility or reproductive
performance. Repeated injections of Cefoxitin sodium in a dose of 100 mg/kg/day
subcutaneously in female rats 14 days before breeding continued to day 14 of gestation in 12 rats
and to parturition in another 12 rats, revealed no adverse effects on fertility or reproductive
performance, although a minimal increase in fetal resorption was observed.
 29

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 30

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