To reduce the development of drug-resistant bacteria and maintain the
effectiveness of CLAFORAN® (cefotaxime sodium) and other antibacterial
drugs, CLAFORAN should be used only to treat or prevent infections that
are proven or strongly suspected to be caused by bacteria.
Sterile CLAFORAN® (cefotaxime sodium) is a semisynthetic, broad spectrum cephalosporin antibiotic for parenteral administration. It is the sodium salt of 7-[2-(2-amino-4-thiazolyl) glyoxylamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 72 (Z)-(o-methyloxime), acetate (ester). CLAFORAN contains approximately 50.5 mg (2.2 mEq) of sodium per gram of cefotaxime activity. Solutions of CLAFORAN range from very pale yellow to light amber depending on the concentration and the diluent used. The pH of the injectable solutions usually ranges from 5.0 to 7.5. The CAS Registry Number is 64485-93-4.
CLAFORAN is supplied as a dry powder in conventional and ADD-Vantage® System compatible vials, infusion bottles, pharmacy bulk package bottles, and as a frozen, premixed, iso-osmotic injection in a buffered diluent solution in plastic containers. CLAFORAN, equivalent to 1 gram and 2 grams cefotaxime, is supplied as frozen, premixed, iso-osmotic injections in plastic containers. Solutions range from very pale yellow to light amber. Dextrose Hydrous, USP has been added to adjust osmolality (approximately 1.7 g and 700 mg to the 1 g and 2 g cefotaxime dosages, respectively). The injections are buffered with sodium citrate hydrous, USP. The pH is adjusted with hydrochloric acid and may be adjusted with sodium hydroxide.
The plastic container is fabricated from a specially designed multilayer plastic (PL 2040). Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.
Following IM administration of a single 500 mg or 1 g dose of CLAFORAN to normal volunteers, mean peak serum concentrations of 11.7 and 20.5 mcg/mL respectively were attained within 30 minutes and declined with an elimination half-life of approximately 1 hour. There was a dose-dependent increase in serum levels after the IV administration of 500 mg, 1 g, and 2 g of CLAFORAN (38.9, 101.7, and 214.4 mcg/mL respectively) without alteration in the elimination half-life. There is no evidence of accumulation following repetitive IV infusion of 1 g doses every 6 hours for 14 days as there are no alterations of serum or renal clearance. About 60% of the administered dose was recovered from urine during the first 6 hours following the start of the infusion.
Approximately 20-36% of an intravenously administered dose of 14C-cefotaxime is excreted by the kidney as unchanged cefotaxime and 15-25% as the desacetyl derivative, the major metabolite. The desacetyl metabolite has been shown to contribute to the bactericidal activity. Two other urinary metabolites (M2 and M3) account for about 20-25%. They lack bactericidal activity.
A single 50 mg/kg dose of CLAFORAN was administered as an intravenous infusion over a 10- to 15-minute period to 29 newborn infants grouped according to birth weight and age. The mean half-life of cefotaxime in infants with lower birth weights (<1500 grams), regardless of age, was longer (4.6 hours) than the mean half-life (3.4 hours) in infants whose birth weight was greater than 1500 grams. Mean serum clearance was also smaller in the lower birth weight infants. Although the differences in mean half-life values are statistically significant for weight, they are not clinically important. Therefore, dosage should be based solely on age. (See DOSAGE AND ADMINISTRATION section.)
Additionally, no disulfiram-like reactions were reported in a study conducted in 22 healthy volunteers administered CLAFORAN and ethanol.
*Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to cefotaxime sodium.
NOTE: Many strains of the above organisms that are multiply resistant to other antibiotics, e.g. penicillins, cephalosporins, and aminoglycosides, are susceptible to cefotaxime sodium. Cefotaxime sodium is active against some strains of Pseudomonas aeruginosa.
Cefotaxime sodium also demonstrates in vitro activity against the following microorganisms but the clinical significance is unknown. Cefotaxime sodium exhibits in vitro minimal inhibitory concentrations (MIC’s) of 8 mcg/mL or less against most (>90%) strains of the following microorganisms; however, the safety and effectiveness of cefotaxime sodium in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:
Cefotaxime sodium is highly stable in vitro to four of the five major classes of 5-lactamases described by Richmond et al.1, including type IIIa (TEM) which is produced by many gram-negative bacteria. The drug is also stable to ß-lactamase (penicillinase) produced by staphylococci. In addition, cefotaxime sodium shows high affinity for penicillin-binding proteins in the cell wall, including PBP: Ib and III.
Cefotaxime sodium and aminoglycosides have been shown to be synergistic in vitro against some strains of Pseudomonas aeruginosa but the clinical significance is unknown.
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 that 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 procedure. Standard cefotaxime sodium powder should provide the following MIC values:
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 cefotaxime sodium.
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 cefotaxime sodium disk should provide the following zone diameters in these laboratory test quality control strains:
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. Standardized cefotaxime sodium powder should provide the following MIC values:
(*) Efficacy for this organism, in this organ system, has been studied in fewer than 10 infections.
Although many strains of enterococci (e.g., S. faecalis) and Pseudomonas species are resistant to cefotaxime sodium in vitro, CLAFORAN has been used successfully in treating patients with infections caused by susceptible organisms.
Specimens for bacteriologic culture should be obtained prior to therapy in order to isolate and identify causative organisms and to determine their susceptibilities to CLAFORAN. Therapy may be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly.
In certain cases of confirmed or suspected gram-positive or gram-negative sepsis or in patients with other serious infections in which the causative organism has not been identified, CLAFORAN may be used concomitantly with an aminoglycoside. The dosage recommended in the labeling of both antibiotics may be given and depends on the severity of the infection and the patient’s condition. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. It is possible that nephrotoxicity may be potentiated if CLAFORAN is used concomitantly with an aminoglycoside.
In patients undergoing cesarean section, intraoperative (after clamping the umbilical cord) and postoperative use of CLAFORAN may also reduce the incidence of certain postoperative infections. See DOSAGE AND ADMINISTRATION section.
Effective use for elective surgery depends on the time of administration. To achieve effective tissue levels, CLAFORAN should be given 1/2 or 1 1/2 hours before surgery. See DOSAGE AND ADMINISTRATION section.
For patients undergoing gastrointestinal surgery, preoperative bowel preparation by mechanical cleansing as well as with a non-absorbable antibiotic (e.g., neomycin) is recommended.
If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate therapy may be instituted.
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of CLAFORAN and other antibacterial drugs, CLAFORAN should
be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying
antibacterial therapy. In the absence of such data, local epidemiology
and susceptibility patterns may contribute to the empiric selection of
CLAFORAN is contraindicated in patients who have shown hypersensitivity to cefotaxime sodium or the cephalosporin group of antibiotics.
BEFORE THERAPY WITH CLAFORAN IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOTAXIME SODIUM, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN WITH CAUTION TO PATIENTS WITH TYPE I HYPERSENSITIVITY REACTIONS TO PENICILLIN. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. IF AN ALLERGIC REACTION TO CLAFORAN OCCURS, DISCONTINUE TREATMENT WITH THE DRUG. SERIOUS HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.
During post-marketing surveillance, a potentially life-threatening arrhythmia was reported in each of six patients who received a rapid (less than 60 seconds) bolus injection of cefotaxime through a central venous catheter. Therefore, cefotaxime should only be administered as instructed in the DOSAGE AND ADMINISTRATION section.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefotaxime, and may range from mild to life threatening. Therefore, it is important to consider its diagnosis in patients with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis.
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of colitis may respond to drug discontinuance alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
When the colitis is not relieved by drug discontinuance or when it is severe, oral vancomycin is the treatment of choice for antibiotic-associated pseudomembranous colitis produced by C. difficile. Other causes of colitis should also be considered.
CLAFORAN should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
Because high and prolonged serum antibiotic concentrations can occur from usual doses in patients with transient or persistent reduction of urinary output because of renal insufficiency, the total daily dosage should be reduced when CLAFORAN is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organism.
Although there is no clinical evidence supporting the necessity of changing the dosage of cefotaxime sodium in patients with even profound renal dysfunction, it is suggested that, until further data are obtained, the dose of cefotaxime sodium be halved in patients with estimated creatinine clearances of less than 20 mL/min/1.73 m2.
When only serum creatinine is available, the following formula5 (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.
As with other antibiotics, prolonged use of CLAFORAN 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.
As with other beta-lactam antibiotics, granulocytopenia and, more rarely, agranulocytosis may develop during treatment with CLAFORAN, particularly if given over long periods. For courses of treatment lasting longer than 10 days, blood counts should therefore be monitored.
CLAFORAN, like other parenteral anti-infective drugs, may be locally irritating to tissues. In most cases, perivascular extravasation of CLAFORAN responds to changing of the infusion site. In rare instances, extensive perivascular extravasation of CLAFORAN may result in tissue damage and require surgical treatment. To minimize the potential for tissue inflammation, infusion sites should be monitored regularly and changed when appropriate.
Information for patients
Drug/Laboratory Test Interactions
Pregnancy: Teratogenic Effects: Pregnancy Category B:
In perinatal and postnatal studies with rats, the pups in the group given 1200 mg/kg/day of CLAFORAN were significantly lighter in weight at birth and remained smaller than pups in the control group during the 21 days of nursing.
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 PRECAUTIONS, General).
CLAFORAN is generally well tolerated. The most common adverse reactions have been local reactions following IM or IV injection. Other adverse reactions have been encountered infrequently.
The most frequent adverse reactions (greater than 1%) are:
Less frequent adverse reactions (less than 1%) are:
Cephalosporin Class Labeling
Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. See DOSAGE AND ADMINISTRATION and OVERDOSAGE. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
Cefotaxime sodium overdosage has occurred in patients. Most cases have shown no overt toxicity. The most frequent reactions were elevations of BUN and creatinine. Patients who receive an acute overdosage should be carefully observed and given supportive treatment.
DOSAGE AND ADMINISTRATION
If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefotaxime sodium has no activity against this organism.
To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended dose is a single 1 gram IM or IV administered 30 to 90 minutes prior to start of surgery.
Cesarean Section Patients
Neonates, Infants, and Children
Neonates (birth to 1 month):
It is not necessary to differentiate between premature and normal-gestational age infants.
Infants and Children (1 month to 12 years):
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 PRECAUTIONS, General and PRECAUTIONS, Geriatric Use.)
Impaired Renal Function—see PRECAUTIONS,
Preparation of CLAFORAN Sterile
(*) in conventional vials
Shake to dissolve; inspect for particulate matter and discoloration prior to use. Solutions of CLAFORAN range from very pale yellow to light amber, depending on concentration, diluent used, and length and condition of storage.
For intramuscular use: Reconstitute VIALS with Sterile Water for Injection or Bacteriostatic Water for Injection as described above.
For intravenous use: Reconstitute VIALS with at least 10 mL of Sterile Water for Injection. Reconstitute INFUSION BOTTLES with 50 or 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. For other diluents, see COMPATIBILITY AND STABILITY section.
NOTE: Solutions of CLAFORAN must not be admixed with aminoglycoside solutions. If CLAFORAN and aminoglycosides are to be administered to the same patient, they must be administered separately and not as mixed injection.
A SOLUTION OF 1 G CLAFORAN IN 14 ML OF STERILE WATER FOR INJECTION IS ISOTONIC.
IM Administration: As with all IM preparations, CLAFORAN should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock (i.e., gluteus maximus); aspiration is necessary to avoid inadvertent injection into a blood vessel. Individual IM doses of 2 grams may be given if the dose is divided and is administered in different intramuscular sites.
IV Administration: The IV route is preferable for patients with bacteremia, bacterial septicemia, peritonitis, meningitis, 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 IV administration, a solution containing 1 gram or 2 grams in 10 mL of Sterile Water for Injection can be injected over a period of three to five minutes. Cefotaxime should not be administered over a period of less than three minutes. (See WARNINGS). With an infusion system, it may also be given over a longer period of time through the tubing system by which the patient may be receiving other IV solutions. However, during infusion of the solution containing CLAFORAN, it is advisable to discontinue temporarily the administration of other solutions at the same site.
For the administration of higher doses by continuous IV infusion, a solution of CLAFORAN may be added to IV bottles containing the solutions discussed below.
for use of CLAFORAN Injection in Galaxy Container (PL 2040 Plastic)
Thawing of Plastic Container
Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
The container should be visually inspected. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection the solution remains cloudy or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded.
The thawed solution is stable for 10 days under refrigeration (at or below 5°C) or 24 hours at or below 22°C. Do not refreeze thawed antibiotics.
CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.
Preparation for Intravenous Administration:
Preparation of CLAFORAN Sterile in ADD-Vantage® System
CLAFORAN Sterile 1 g or 2 g may be reconstituted in 50 mL or 100 mL of 5% Dextrose or 0.9% Sodium Chloride in the ADD-Vantage® diluent container. Refer to enclosed, separate INSTRUCTIONS FOR ADD-VANTAGE® SYSTEM.
Compatibility and Stability
Reconstituted solutions stored in original containers and plastic syringes remain stable for 13 weeks frozen.
Reconstituted solutions may be further diluted up to 1000 mL with the following solutions and maintain satisfactory potency for 24 hours at or below 22°C, and at least 5 days under refrigeration (at or below 5°C): 0.9% Sodium Chloride Injection; 5 or 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.2% Sodium Chloride Injection; Lactated Ringer’s Solution; Sodium Lactate Injection (M/6); 10% Invert Sugar Injection, 8.5% TRAVASOL® (Amino Acid) Injection without Electrolytes.
Solutions of CLAFORAN Sterile reconstituted in 0.9% Sodium Chloride Injection or 5% Dextrose Injection in Viaflex® plastic containers maintain satisfactory potency for 24 hours at or below 22°C, 5 days under refrigeration (at or below 5°C) and 13 weeks frozen. Solutions of CLAFORAN Sterile reconstituted in 0.9% Sodium Chloride Injection or 5% Dextrose Injection in the ADD-Vantage® flexible containers maintain satisfactory potency for 24 hours at or below 22°C. DO NOT FREEZE.
Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution and
Sterile CLAFORAN is a dry off-white to pale yellow crystalline powder supplied in vials and bottles containing cefotaxime sodium as follows:
ADD-Vantage® System diluents (5% Dextrose or 0.9% Sodium Chloride) are available from Abbott Laboratories.
Premixed CLAFORAN Injection is supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in 50 mL single dose Galaxy® containers (PL 2040 plastic) as follows:
Claforan® Injection supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in Galaxy® containers (PL 2040 plastic) is manufactured for Aventis Pharmaceuticals by Baxter Healthcare Corporation.