INFORMATION FOR HEALTH PROFESSIONALS
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1g vials
A white to off-white powder in a 1g glass vial with a green cap.
MEFOXIN is a beta-lactam antibiotic.
MEFOXIN is indicated for the treatment of the following infections when due to susceptible organisms:
MEFOXIN is a broad-spectrum bactericidal antibiotic indicated for the treatment of infections caused by susceptible strains of gram-positive and gram-negative pathogens both aerobic and anaerobic (see Microbiology). MEFOXIN has been clinically effective not only in infections due to antibiotic-sensitive organisms, but also in infections due to organisms resistant to one or more of the following antibacterial agents: penicillin, ampicillin, carbenicillin, tetracyclines, erythromycin, chloramphenicol, cephalosporins, kanamycin, gentamicin, tobramycin, and sulfamethoxazole-trimethoprim.
Many gram-negative pathogens are resistant to penicillins and cephalosporins through the action of the beta-lactamases which are produced by these pathogens. MEFOXIN is remarkably stable in the presence of these bacterial beta-lactamases, both penicillinases and cephalosporinases. Hence, the clinical efficacy of MEFOXIN extends to many infections caused by such pathogens, of which the following are of particular clinical importance: E. coli; Klebsiella; Proteus mirabilis; Proteus, indole-positive (which include the organisms now called Morganella morganii and Proteus vulgaris); Serratia marcescens; Providencia (including Providencia rettgeri); and the anaerobic Bacteroides fragilis.
MEFOXIN is indicated for the treatment of mixed infections caused by susceptible strains of aerobic and anaerobic bacteria. The majority of these mixed infections are associated with contamination by faecal flora as well as flora originating from the vagina, skin and mouth. In these mixed infections, Bacteroides fragilis is the most commonly encountered anaerobic pathogen and is usually resistant to aminoglycosides, cephalosporins, and virtually all penicillins. However, Bacteroides fragilis is usually susceptible to MEFOXIN.
MEFOXIN is indicated for adjunctive therapy in the surgical treatment of infections, including abscesses, infection complicating hollow viscus perforations, cutaneous infections and infections of serous surfaces, whether caused by aerobes, mixed aerobes and anaerobes or anaerobes.
Clinical experience has demonstrated that MEFOXIN can be administered to patients who are also receiving carbenicillin, kanamycin, gentamicin, tobramycin, or amikacin (see Warnings and Precautions and Dosage and Administration).
MEFOXIN is indicated for the prevention of certain post-operative infections in patients undergoing surgical procedures that are classified as contaminated, potentially contaminated, or where the occurrence of post-operative infection could be especially serious.
MEFOXIN may be administered intravenously or intramuscularly. (See reconstitution directions for each route below).
Dosage and route of administration should be determined by severity of infection, susceptibility of the causative organisms, and condition of the patient.
Therapy may be started while awaiting the results of susceptibility testing.
The usual adult dosage is 1g or 2g of MEFOXIN every eight hours (see chart).
| TYPE OF INFECTION | DOSE | FREQUENCY | TOTAL DAILY DOSAGE |
|---|---|---|---|
| Uncomplicated | 1g | Every 8 hours (occasionally every 6 hours) |
3g (4g) |
| Moderately severe Or severe | 2g | Every 8 hours (occasionally every 6 hours) |
6g (8g) |
| Infections generally Needing antibiotics In higher dosage |
3g | Every 6 hours | 12g |
| (2g) | (Every 4 hours) |
In adults with renal insufficiency, an initial loading dose of 1g to 2g may be
given. After a loading dose, the recommendations for maintenance dosage may be
used as a guide.
In the patients undergoing haemodialysis, the loading dose of 1-2g should be given after each haemodialysis, and the maintenance dose should be given as indicated in the following table.
| RENAL FUNCTION | CREATININE CLEARANCE (mL/min) |
DOSE | FREQUENCY |
|---|---|---|---|
| Mild impairment | 50-30 | 1-2g | Every 8-12hrs |
| Moderate impairment | 29-10 | 1-2g | Every 12-24hrs |
| Severe impairment | 9-5 | 0.5-1g | Every 12-24hrs |
| Essentially no function | <5 | 0.5-1g | Every 24-48hrs |
For calculation of creatinine clearance see creatinine clearance under
additional dosage information.
In uncomplicated urinary tract infections due to susceptible organisms, 1g intramuscularly twice a day has been shown to be effective.
For single dose therapy of uncomplicated gonorrhoea, including that caused by penicillinase-producing strains, the recommended dose is 2g of MEFOXIN intramuscularly given with 1g of probenecid by mouth (at the same time or up to one hour before).
Neonates** (Including Premature Infants, Infants and Children)
| AGE GROUP | DOSE | FREQUENCY |
|---|---|---|
| Premature Infants* With body weights above 1500gm |
20-40mg/kg | Every 12 hours |
| Neonates* 0-1 week of age 1-4 weeks of age |
20-40mg/kg 20-40mg/kg |
Every 12 hours Every 8 hours |
| Infants | 20-40mg/kg | Every 6 hours OR Every 8 hours |
| Children | 20-40mg/kg | Every 6 hours OR Every 8 hours |
* Clinical data are insufficient to recommend the use of the intramuscular
formulation in infants less than 3 months of age.
** See Warning for Neonates under Administration.
In severe infections, the total daily dosage may be increased to 200mg/kg, but not to exceed 12g per day.
MEFOXIN is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used.
In children with renal insufficiency the dosage frequency should be reduced as indicated for adults.
For prophylactic use in surgery, the following doses are recommended:
2 grams administered intramuscularly or intravenously 1/2 to 1 hour before initial incision; then 2 grams every six hours. Ordinarily, prophylactic therapy does not extend beyond 24 hours.
In case of infants and children, 30-40mg/kg doses may be given at times designated above. However, in neonates 30-40mg/kg doses may be given one half to one hour before initial incision and the second and third dose may be given every 8-12 hours.
Clinical data are insufficient to recommend use of the intramuscular formulation in infants less than 3 months of age.
For patients undergoing caesarean section a single 2g dose should be administered intravenously as soon as the umbilical cord is clamped.
For prophylactic use in gynaecologic surgical procedures a single 2g dose administered intravenously or intramuscularly one-half to one hour prior to surgery has been effective.
For prolonged or heavily contaminated procedures, additional 2g doses may be given at six hour intervals. Ordinarily, prophylactic therapy does not extend beyond 24 hours.
** See Warning for Neonates under Administration
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. Data are unavailable on the toxicity of other preservatives in this age group.
Therefore, any diluent used with MEFOXIN in the treatment of neonates should be free of any preservative.
Reconstitute MEFOXIN with Sterile Water for Injection: 1g is soluble in 2mL. Although MEFOXIN is very soluble, for intravenous use it is preferable to add 10mL of Sterile Water for Injection to the 1g vial. Shake to dissolve and then withdraw entire contents of vial into syringe.
For direct intravenous injection, MEFOXIN may be slowly injected into the vein over a period of 3 to 5 minutes or may be given through the tubing when the patient is receiving parenteral solutions.
An intermittent intravenous infusion of MEFOXIN may be employed when large amounts of fluid are to be given. However, during infusion of the solution containing MEFOXIN, it may be advisable temporarily to discontinue administration of any other infusion solution at the same site by using an appropriate IV infusion set.
A solution of MEFOXIN may also be given by continuous intravenous infusion (see below for compatibility and stability).
Reconstitute MEFOXIN 1g with 2mL of Sterile Water for Injection or 0.5 percent or 1 percent lidocaine HC1 (without epinephrine) solution. For the 0.5g dosage form, one half the volume of diluent recommended for 1g cefoxitin may be used. MEFOXIN is given by deep injection into a large muscle mass. Avoid injection into a blood vessel.
Note: Some patients may be hypersensitive to lidocaine.
The following table is provided for convenience in constituting MEFOXIN for both intravenous and intramuscular administration.
| STRENGTH | AMOUNT OF DILUENT TO BE ADDED (mL**) |
APPROXIMATE AVERAGE CONCENTRATION (mg/mL) |
|
|---|---|---|---|
| IV | IM | ||
| 1g Vial | 2 | 400 | |
| 1g Vial | 10 | 95 | |
** Shake to dissolve and let stand until clear.
The compatibility and stability of cefoxitin sodium in solution with the following series of frequently used intravenous infusion fluids and injectable additives have been established:
0.9% Sodium Chloride Injection
5% or 10% Dextrose Injection
5% Dextrose and 0.9% Sodium Chloride Injection
5% Dextrose Injection with 0.02% sodium bicarbonate solution
5% Dextrose Injection with 0.2% or 0.45% saline solution
Lactated Ringer's Injection
5% Dextrose in Lactated Ringer's Injection
5% or 10% invert sugar in water
10% invert sugar in saline solution
5% Sodium Bicarbonate Injection
M/6 Sodium Lactate solution
Insulin in normal saline
Insulin in 10% invert sugar
Heparin, 100 units/mL and 0.1 unit/mL
Mannitol 2.5% and 5%
Mannitol 10%
MEFOXIN has been shown to be chemically and visually compatible with aminoglycosides such as amikacin, gentamicin, kanamycin, and tobramycin when admixed in 200mL of 0.9% sodium chloride or 5% dextrose in water.
MEFOXIN, as constituted with Sterile Water for Injection, Bacteriostatic Water for Injection (see warning for Neonates under Dosage and Adminstration) preserved with parabens or benzyl alcohol, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or 0.5% and 1.0% lidocaine HC1 (preserve paraben), maintains satisfactory potency for 24 hours at room temperature, for one week under refrigeration (below 5°C) and for at least 30 weeks in the frozen state and will maintain potency immediately after thawing and for at least 24 hours at room temperature thereafter.
After constitution with Sterile Water for Injection and subsequent storage in disposable plastic syringes, MEFOXIN is stable for 24 hours at room temperature and 48 hours under refrigeration.
After the periods mentioned above, any unused solutions or frozen material should be discarded. Do not refreeze.
Note: MEFOXIN in the dry state should be stored below 30°C. Avoid exposure to temperatures above 50°C. The dry material as well as solutions tends to darken, depending on storage conditions; product potency, however, is not adversely affected.
The dosage should be determined by the severity of the infection, the susceptibility of the causative organisms, the patient's clinical condition, body weight and renal function.
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 should represent a steady state of renal function.
Males: Weight (kg) x (140 - age )
72 x serum creatinine (mg/100 mL)
Females:
0.85 x above value
MEFOXIN is contraindicated in persons who have shown hypersensitivity to cefoxitin. In the absence of clinical experience, MEFOXIN should not be administered to patients who have shown hypersensitivity to cephalosporins.
There is some clinical and laboratory evidence of partial cross-allergenicity between cephamycins and the other beta-lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most beta-lactam antibiotics.
Before therapy with MEFOXIN, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. MEFOXIN should be given cautiously to penicillin allergic patients.
Any patient who has demonstrated some form of allergy, particularly to medicines, should be given antibiotics cautiously. If an allergic reaction to MEFOXIN occurs, the medicine should be discontinued.
Pseudomembranous colitis has been reported with virtually all antibiotics. This colitis can range from mild to life threatening in severity. Antibiotics should therefore be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. It is important to consider a diagnosis of pseudomembranous colitis in patients who develop diarrhoea in association with antibiotic use. While studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis, other causes should also be considered.
The total daily dosage should be reduced when MEFOXIN 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 from usual doses.
There are no controlled studies in pregnant women.
Use of the medicine during pregnancy requires that the anticipated benefits can be weighed against possible hazards.
MEFOXIN is excreted in human milk. Caution should be exercised if use is indicated.
The acute intravenous LD50 in the adult female mouse and rabbit was about 8.0g/kg and greater than 1.0g/kg, respectively. The acute intraperitoneal LD50 in the adult rat was greater than 10.0g/kg.
Long-term studies in animals have not been performed with cefoxitin to evaluate carcinogenic or mutagenic potential. Studies in rats treated intravenously with 400mg/kg of cefoxitin (approximately three times the maximum recommended human dose) revealed no effects on fertility or mating ability.
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.
MEFOXIN is generally well tolerated. Side effects rarely required cessation of treatment and usually have been mild and transient. The most common side effects have been local reactions following the intravenous or intramuscular injection.
Local Reactions: Thrombophlebitis has occurred with intravenous
administration.
Pain, induration, and tenderness after intramuscular injections have been
reported.
Allergic: Rash (including exfoliative dermatitis and toxic epidermal necrolysis), urticaria, flushing, pruritus, eosinophilia, fever and other allergic reactions including anaphylaxis, interstitial nephritis and angioedema have been reported.
Cardiovascular: Hypotension
Gastrointestinal: Diarrhoea, including pseudomembranous colitis can appear during or after antibiotic treatment. Nausea and vomiting have been reported rarely.
Haematologic: Eosinophilia, leukopaenia including granulocytopaenia, neutropenia, anaemia (including haemolytic anaemia), thrombocytopenia, and bone marrow depression have been reported. Some individuals, particularly those with azotemia, may develop positive direct Coombs tests during therapy with MEFOXIN.
Musculoskeletal: Worsening myasthenia gravis (single case).
Hepatic 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 MEFOXIN 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.
No clinical data on medicine interaction between cefoxitin and other medication is available.
A false-positive reaction to glucose in the urine may occur with reducing substances but not with the use of specific glucose oxidase methods.
Using the Jaffe Technique, falsely high creatinine values in serum may occur if MEFOXIN serum concentrations exceed 100mcg/mL. Serum samples from patients treated with MEFOXIN should not be analysed for creatinine if withdrawn within two hours of medicine 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.
No specific information is available on the treatment of overdose with MEFOXIN.
MEFOXIN is a cephamycin with a broad spectrum of antibacterial activity against gram-positive and gram-negative pathogens, both aerobic and anaerobic. MEFOXIN inhibits bacterial cell wall synthesis and is bactericidal. The unique molecular structure of MEFOXIN gives it a particularly high degree of resistance to beta-lactamases, a major mechanism of bacterial resistance to penicillins and cephalosporins. A high percentage of gram-negative rods which are beta-lactamase producing and resistant to penicillins or cephalosporins is susceptible to MEFOXIN. In addition, a high percentage of penicillinase-producing, penicillin-resistant gram-positive and gram-negative cocci is susceptible to MEFOXIN.
With respect to the clinical reliability and predictability of MEFOXIN, analysis of the overall clinical experience with this antibiotic revealed a high correlation between the results of sensitivity tests with MEFOXIN, the bacteriological efficacy of the antibiotic in humans, and the clinical efficacy of the antibiotic.
MEFOXIN is active against the following microorganisms in vitro:
Aerobic Bacteria
Gram-positive cocci including: Staphylococci (including
coagulase-positive, coagulase-negative and penicillinase-producing strains)
Group A beta-haemolytic streptococci (Streptococcus pyogenes)
Group B betaphaemolytic streptococci (Streptococcus agalactiae)
Streptococcus pneumoniae (Diplococcus pneumoniae)
Other streptococci (except group D streptococci including enterococci, most
strains of which are resistant, e.g. Streptococcus faecalis)
Gram-negative cocci including: Neisseria gonorrhoeae
(including penicillinase-producing strains)
Neisseria meningitidis
Gram-negative rods (faculative anaerobes) including: Escherichia coli, Haemophilus influenzae, Klebsiella spp., Klebsiella pneumoniae, Proteus (indole-positive):, Morganella morganii , formerly Proteus morganii), Proteus vulgaris, Proteus mirabilis, Providencia spp., Providenciaa rettgeri (formerly Proteus rettgeri), Salmonella spp., Serratia marcescens, Shigella spp.,
Anaerobic Bacteria
Gram-positive cocci including: Peptococcus spp., Peptostreptococcus spp., Microaerophilic streptococcus
Gram-positive rods including: Clostridium spp., Clostridium perfringens, Eubacterium spp., Propionibacterium acnes
Gram-negative cocci including: Veillonella spp.
Gram-negative rods including: Bacteroides spp. (including both penicillin-susceptible and penicillin- resistant strains), Bacteroides fragilis, Bacteroides melaninogenicus, Fusobacterium spp.
MEFOXIN is active against some strains of the following bacteria: Acinetobacter baumannii (formerly) Acinetobacter calcoaceticus var. anitratum, (Herellea vaginicola), Acinetobacter calcoaceticus var. Iwoffi, (formerly Mima polymorpha), Alcaligenes faecalis, Citrobacter spp., Enterobacter spp., Flavobacterium spp.
MEFOXIN is not active against Pseudomonas spp., most strains of enterococci, many strains of Enterobacter cloacae, methicillin-resistant staphylococci and Listeria monocytogenes.
a) Aerobes
The Kirby-Bauer1 or WHO2 technique of antibiotic disc susceptibility testing is recommended* using a 30mcg cefoxitin disc of 6mm in diameter.
A zone size of 18mm or more in diameter indicates susceptibility.
A zone size of 15 to 17mm in diameter indicates intermediate susceptibility.
A zone size of 14mm or less indicates resistance.
The cefoxitin disc should be used for testing cefoxitin susceptibility. Cefoxitin has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found resistant when tested with the cephalosporin class disc. For this reason, the cefoxitin disc should not be used for testing susceptibility to cephalosporins, and cephalosporin discs should not be used for testing susceptibility to cefoxitin.
b) Anaerobes
For susceptibility testing of obligate anaerobes, the tube or agar dilution methods are more applicable and should be used. Organisms may be considered susceptible to cefoxitin when the minimal inhibitory concentration (MIC) is 16mcg/mL or less. Organisms are considered resistant if the MIC is greater than 32mcg/mL.
* It is advisable to test strains of Serratia marcesens by the broth dilution test to determine MIC.
MEFOXIN, administered parenterally, produces high serum and urine concentrations. It is excreted virtually unchanged as active MEFOXIN by the kidneys, and has a mean terminal serum half-life of approximately one hour. MEFOXIN passes rapidly into body fluids such as pleural, bile and ascitic fluids. Probenecid slows tubular excretion and increases and prolongs blood levels.
Adults peak serum concentration of MEFOXIN following 1g infused intravenously over three minutes was 125mcg/mL, infused over 30 minutes was 72mcg/mL, and infused over 120 minutes was 25mcg/mL. Following 2g infused intravenously over three minutes, peak serum concentration was 221mcg/mL.
In a number of studies using 0.5g, 1g or 2g intravenous doses of MEFOXIN, mean total urinary recovery ranged from 77 percent to 99 percent of the cefoxitin dose.
When MEFOXIN was reconstituted for intramuscular injection with 0.5 percent or 1 percent lidocaine HC1, the lidocaine had no effect on the absorption or elimination of MEFOXIN.
Intramuscular injections of 1g of MEFOXIN in 0.5 percent lidocaine HC1 solution produced a peak serum concentration of 30mcg/mL at 20 minutes. Approximately 85 percent of an intramuscular dose is excreted by the kidneys in the first six hours; this results in high urine levels, (e.g. >3,000mcg/mL between one and two hours after a 1g dose).
After reconstitution MEFOXIN maintains satisfactory potency for 24 hours at room temperature, or one week under refrigeration (below 5°C) and for at least 30 weeks in the frozen state. Store dry material below 30°C. Avoid exposure to temperatures above 50°C.
Prescription Medicine
MEFOXIN is supplied in vials containing 1g of cefoxitin as the sodium salt.
MEFOXIN (cefoxitin sodium, MSD) is a beta-lactam antibiotic derived by chemical modification of cephamycin C (a naturally occurring antibiotic substance produced by Streptomyces lactamdurans, a novel filamentous bacterium). MEFOXIN is a bactericidal broad-spectrum, semi-synthetic antibiotic for parenteral administration.
This class of beta-lactam antibiotics, the cephamycins, is characterised by a 7 alpha-methoxy-beta-lactam. The methoxy group is responsible for the property of resistance to degradation by bacterial beta-lactamases (penicillinases and cephalosporinases). Side chains, attached by chemical modification of the basic cephamycin nucleus, determine some of the specific antibacterial actions and other properties.
The chemical name of sodium cefoxitin is sodium 3 - (hydroxymethyl) - 7 alpha - methoxy - 8 - oxo - 7 - [2-(2-thienyl) acetamido] - 5 - thia - 1 -azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylate carbamate (ester). The structural formula is:
Solutions of MEFOXIN range from clear to light amber in colour. The pH of freshly constituted solutions usually ranges from 4.2 to 7.0. Each gram of cefoxitin sodium contains approximately 2.3 mEq sodium.
References
Merck Sharp & Dohme (New Zealand) Limited
P O Box 99 851
Newmarket
Auckland
Tel: 0800 500 673
26 November 2003
DP/I-MFI-0203(210203)
®Registered Trademark of Merck & Co Inc., Whitehouse Station, NJ, USA
