Lifetime studies in animals to evaluate carcinogenic potential have not been conducted. Cefotaxime for injection was not mutagenic in the mouse micronucleus test or in the Ames test. Cefotaxime for injection did not impair fertility to rats when administered subcutaneously at doses up to 250 mg/kg/day (0.2 times the maximum recommended human dose based on mg/m2) or in mice when administered intravenously at doses up to 2000 mg/kg/day (0.7 times the recommended human dose based on mg/m2).
Pregnancy: Teratogenic Effects: Pregnancy Category B:
Reproduction studies have been performed in pregnant mice given cefotaxime for injection intravenously at doses up to 1200 mg/kg/day (0.4 times the recommended human dose based on mg/m2) or in pregnant rats when administered intravenously at doses up to 1200 mg/kg/day (0.8 times the recommended human dose based on mg/m2). No evidence of embryotoxicity or teratogenicity was seen in these studies. Although cefotaxime has been reported to cross the placental barrier and appear in cord blood, the effect on the human fetus is not known. There are no well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
In perinatal and postnatal studies with rats, the pups in the group given 1200 mg/kg/day of cefotaxime were significantly lighter in weight at birth and remained smaller than pups in the control group during the 21 days of nursing.
Of the 1409 subjects in clinical studies of cefotaxime, 632 (45%) were 65 and over, while 258 (18%) 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.
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).
Cefotaxime for injection 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:
Local (4.3%) — Injection site inflammation with IV administration. Pain, induration, and tenderness after IM injection.
Hypersensitivity (2.4%) — Rash, pruritus, fever, eosinophilia.
Gastrointestinal (1.4%) — Colitis, diarrhea, nausea, and vomiting.
Symptoms of pseudomembranous colitis can appear during or after antibiotic treatment.
Nausea and vomiting have been reported rarely.
Less frequent adverse reactions (less than 1%) are:
Hematologic System — Neutropenia, leukopenia, have been reported. Some individuals have developed positive direct Coombs Tests during treatment with cefotaxime for injection and other cephalosporin antibiotics.
Genitourinary System — Moniliasis, vaginitis.
Central Nervous System — Headache.
Liver — Transient elevations in AST, ALT, serum LDH, and serum alkaline phosphatase levels have been reported.
Kidney — As with some other cephalosporins, transient elevations of BUN have been occasionally observed with cefotaxime for injection.
The following adverse reactions have been identified during post-approval use of cefotaxime for injection. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular System — Potentially life-threatening arrhythmias following rapid (less than 60 seconds) bolus administration via central venous catheter have been observed.
Central Nervous System — Administration of high doses of beta-lactam antibiotics, including cefotaxime, particularly in patients with renal insufficiency may result in encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions). Dizziness has also been reported.
Cutaneous — As with other cephalosporins, isolated cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have been reported. Acute generalized exanthematous pustulosis (AGEP) has also been reported.
General disorders and administration site conditions — Inflammatory reactions at the injection site, including phlebitis/thrombophlebitis.
Hematologic System — Hemolytic anemia, agranulocytosis, thrombocytopenia, pancytopenia, bone marrow failure.
Hypersensitivity — Anaphylaxis (e.g., angioedema, bronchospasm, malaise possibly culminating in shock), urticaria.
Kidney — Interstitial nephritis, transient elevations of creatinine, acute renal failure.
Liver — Hepatitis, jaundice, cholestasis, elevations of gamma GT and bilirubin.
Cephalosporin Class Labeling
In addition to the adverse reactions listed above which have been observed in patients treated with cefotaxime sodium, the following adverse reactions and altered laboratory tests have been reported for cephalosporin class antibiotics: allergic reactions, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and false-positive test for urinary glucose.
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.
The acute toxicity of cefotaxime was evaluated in neonatal and adult mice and rats. Significant mortality was seen at parenteral doses in excess of 6000 mg/kg/day in all groups. Common toxic signs in animals that died were a decrease in spontaneous activity, tonic and clonic convulsions, dyspnea, hypothermia, and cyanosis. Cefotaxime sodium overdosage has occurred in patients. Most cases have shown no overt toxicity. The most frequent reactions were elevations of BUN and creatinine. There is a risk of reversible encephalopathy in cases of administration of high doses of beta-lactam antibiotics including cefotaxime. No specific antidote exists. Patients who receive an acute overdosage should be carefully observed and given supportive treatment.
Dosage and route of administration should be determined by susceptibility of the causative organisms, severity of the infection, and the condition of the patient (see table for dosage guideline). Cefotaxime for injection may be administered IM or IV after reconstitution. The maximum daily dosage should not exceed 12 grams.
|GUIDELINES FOR DOSAGE OF CEFOTAXIME FOR INJECTION|
|Type of Infection||Daily Dose (grams)||Frequency and Route|
|Gonococcal urethritis/cervicitis in males and females||0.5||0.5 gram IM (single dose)|
|Rectal gonorrhea in females||0.5||0.5 gram IM (single dose)|
|Rectal gonorrhea in males||1||1 gram IM (single dose)|
|Uncomplicated infections||2||1 gram every 12 hours IM or IV|
|Moderate to severe infections||3 to 6||1 to 2 grams every 8 hours IM or IV|
|Infections commonly needing antibiotics in higher dosage (e.g., septicemia)||6 to 8||2 grams every 6 to 8 hours IV|
|Life-threatening infections||up to 12||2 grams every 4 hours IV|
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
The first dose of 1 gram is administered intravenously as soon as the umbilical cord is clamped. The second and third doses should be given as 1 gram intravenously or intramuscularly at 6 and 12 hours after the first dose.
Neonates, Infants, and Children
The following dosage schedule is recommended:
Neonates (birth to 1 month):
0 to 1 week of age 50 mg/kg per dose every 12 hours IV
1 to 4 weeks of age 50 mg/kg per dose every 8 hours IV
It is not necessary to differentiate between premature and normal-gestational age infants.
Infants and Children (1 month to 12 years):
For body weights less than 50 kg, the recommended daily dose is 50 to 180 mg/kg IM or IV body weight divided into four to six equal doses. The higher dosages should be used for more severe or serious infections, including meningitis. For body weights 50 kg or more, the usual adult dosage should be used; the maximum daily dosage should not exceed 12 grams.
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, General.
NOTE: As with antibiotic therapy in general, administration of cefotaxime for injection should be continued for a minimum of 48 to 72 hours after the patient defervesces or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended for infections caused by Group A beta-hemolytic streptococci in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed; persistent infections may require treatment of several weeks and doses smaller than those indicated above should not be used.
Preparation of Cefotaxime for Injection Sterile
Cefotaxime for injection for IM or IV administration should be reconstituted as follows:
|Strength||Diluent (mL)||Withdrawable Volume (mL)||Approximate Concentration|
|500 mg vial* (IM)||2||2.2||230|
|1g vial* (IM)||3||3.4||300|
|2g vial* (IM)||5||6||330|
|500 mg vial* (IV)||10||10.2||50|
|1g vial* (IV)||10||10.4||95|
|2g vial* (IV)||10||11||180|
|(*) in conventional vials|
Shake to dissolve; inspect for particulate matter and discoloration prior to use. Solutions of cefotaxime for injection 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. For other diluents, see COMPATIBILITY AND STABILITY section.
NOTE: Solutions of cefotaxime for injection must not be admixed with aminoglycoside solutions. If cefotaxime for injection 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 CEFOTAXIME FOR INJECTION IN 14 ML OF STERILE WATER FOR INJECTION IS ISOTONIC.
As with all IM preparations, cefotaxime for injection 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.
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 cefotaxime, 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 cefotaxime may be added to IV bottles containing the solutions discussed below.
Compatibility and Stability
Solutions of cefotaxime for injection reconstituted as described above (Preparation of cefotaxime for injection) remain chemically stable (potency remains above 90%) as follows when stored in original containers and disposable plastic syringes:
|Strength||Reconstituted Concentration||Stability at or below||Stability under Refrigeration (at or below 5°C)|
|mg/mL||22°C||Original Containers||Plastic Syringes|
|500 mg vial IM||230||12 hours||7 days||5 days|
|1 g vial IM||300||12 hours||7 days||5 days|
|2 g vial IM||330||12 hours||7 days||5 days|
|500 mg vial IV||50||24 hours||7 days||5 days|
|1 g vial IV||95||24 hours||7 days||5 days|
|2 g vial IV||180||12 hours||7 days||5 days|
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.
NOTE: Cefotaxime for injection solutions exhibit maximum stability in the pH 5 to 7 range. Solutions of cefotaxime for injection should not be prepared with diluents having a pH above 7.5, such as Sodium Bicarbonate Injection.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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