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Cefotaxime

Pronunciation

Generic Name: Cefotaxime sodium
Dosage Form: injection, powder, for solution

                                                                                                                                                                  Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefotaxime sodium and other antibacterial drugs, Cefotaxime for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Cefotaxime Description

Sterile 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). Cefotaxime for Injection, USP contains approximately 50.5 mg (2.2 mEq) of sodium per gram of Cefotaxime activity. Solutions of Cefotaxime for injection 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 4.5 to 6.5. The molecular formula is C16H16N5NaO7S2 and molecular weight is 477.45. The CAS Registry Number is 64485-93-4.

Cefotaxime for Injection, USP is supplied as a sterile dry powder in 1 gram and 2 gram ADD-VantageTM vials. Each vial contains Cefotaxime sodium equivalent to 1 gram or 2 gram of Cefotaxime. The 1 gram and 2 gram Add-Vantage vials are to be administered through intravenous route only.

Cefotaxime - Clinical Pharmacology

There was a dose-dependent increase in serum levels after the IV administration of 1 gram and 2 gram of Cefotaxime for injection (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 gram 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 to 36% of an intravenously administered dose of 14C-Cefotaxime is excreted by the kidney as unchanged Cefotaxime and 15 to 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 to 25%. They lack bactericidal activity.

A single 50 mg/kg dose of Cefotaxime for injection 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.)

Drug Interactions

A single intravenous dose and oral dose of probenecid (500 mg each) followed by two oral doses of probenecid 500 mg at approximately hourly intervals administered to three healthy male subjects receiving a continuous infusion of Cefotaxime increased the steady-state plasma concentration of Cefotaxime by approximately 80%. In another study, administration of oral probenecid 500 mg every 6 hours to six healthy male subjects with Cefotaxime 1 gram infused over 5 minutes decreased the total clearance of Cefotaxime by approximately 50%.

Additionally, no disulfiram-like reactions were reported in a study conducted in 22 healthy volunteers administered Cefotaxime for injection and ethanol.

Microbiology

Mechanism of Action

Cefotaxime sodium is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefotaxime has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

Mechanism of Resistance

Resistance to Cefotaxime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

Susceptibility to Cefotaxime will vary geographically and may change over time; local susceptibility data should be consulted, if available. Cefotaxime sodium has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive bacteria

Enterococcus spp.1
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pyogenes
(Group A beta-hemolytic streptococci)
Streptococcus spp. (Viridans group streptococci)

Gram-negative bacteria

Acinetobacter spp.
Citrobacter spp.2
Enterobacter spp.2
Escherichia coli 2
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella spp. (including Klebsiella pneumoniae) 2
Morganella morganii 2
Neisseria gonorrhoeae (including beta-lactamase-positive and negative strains)
Neisseria meningitidis
Proteus mirabilis
2
Proteus vulgaris
2
Providencia rettgeri
2
Providencia stuartii
2
Serratia marcescens
2

1 Enterococcus species may be intrinsically resistant to Cefotaxime.

2 Most extended spectrum beta-lactamase (ESBL)-producing and carbapenemase-producing isolates are resistant to Cefotaxime.

Anaerobic bacteria

Bacteroides spp., including some isolates of Bacteroides fragilis
Clostridium spp. (most isolates of Clostridium difficile are resistant)
Fusobacterium spp. (including Fusobacterium nucleatum)
Peptococcus spp.
Peptostreptococcus spp.

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 1 mcg/mL. However, the efficacy of Cefotaxime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-negative bacteria

Providencia spp.
Salmonella spp. (including Salmonella typhi)
Shigella spp.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques

Quantitative methods that are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar) 1,2. The MIC values should be interpreted according to the criteria in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3. This procedure uses paper disks impregnated with 30 mcg Cefotaxime sodium to test the susceptibility of microorganisms to Cefotaxime. The disk diffusion interpretive criteria are provided in Table 1.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to Cefotaxime sodium as MICs can be determined by a standardized agar test method3,4. The MIC values obtained should be interpreted according to the criteria provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Cefotaxime.
Susceptible breakpoints are based on a dose of 1 gram q 8h in patients with normal renal function.
Susceptibility of staphylococci to Cefotaxime may be deduced from testing only penicillin and either cefoxitin or oxacillin.
*The current absence of data on resistant isolates precludes defining any category other than “Susceptible”. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing.
 Haemophilus spp. includes only isolates of H. influenzae and H. parainfluenzae.
Disc diffusion interpretive criteria for Cefotaxime discs against S. pneumoniae are not available, however, isolates of pneumococci with oxacillin zone diameters of >20 mm are susceptible (MIC ≤0.06 mcg/mL) to penicillin and can be considered susceptible to Cefotaxime. S. pneumoniae isolates should not be reported as penicillin (Cefotaxime) resistant or intermediate based solely on an oxacillin zone diameter of ≤19 mm. The Cefotaxime MIC should be determined for those isolates with oxacillin zone diameters ≤19 mm.
§Other Non-Enterobacteriaceae include Pseudomonas spp. and other nonfastidious, glucose-nonfermenting, gram-negative bacilli, but exclude Pseudomonas aeruginosa, Acinetobacter spp., Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, and Stenotrophomonas maltophilia.

Pathogen

Minimum Inhibitory

Concentrations (mcg/mL)

Disk Diffusion Zone
Diameters (mm)

(S)

Susceptible

(I)

Intermediate

(R)

Resistant

(S)

Susceptible

(I)

Intermediate

(R)

Resistant

Acinetobacter spp.

≤l

2

≥4

-

-

-

Enterobacteriaceae

≤l

2

≥4

≥26

23 to 25

≤22

Haemophilus spp. *

≤l

-

-

-

-

Neisseria gonorrhoeae *

≤0.5

-

-

≥31

-

-

Neisseria meningitidis *

≤0.12

-

-

≥34

-

-

Streptococcus pneumoniae  meningitis isolates

≤0.5

1

≥2

-

-

-

Streptococcus pneumoniae 

non-meningitis isolates

≤l

2

≥4

-

-

-

Streptococcus spp.

beta-hemolytic group*

≤0.5

-

-

≥24

-

-

Viridans group streptococci

≤l

2

≥4

≥28

26 to 27

≤25

Other Non-

Enterobacteriaceae§

≤l

2

≥4

-

-

-

Anaerobic bacteria
(agar method)

≤l

2

≥4

-

-

-

A report of Susceptible indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration at the site of infection. 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 a 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 antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the site of infection; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test1,2,3,4. Standard Cefotaxime powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg disk, the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality control Ranges for Cefotaxime
*
Using the Reference Agar Dilution procedure.

QC Strain

Minimum Inhibitory Concentrations (mcq/mL)

Disk Diffusion Zone Diameters (mm)

Escherichia coli ATCC 25922

0.03 to 0.12

29 to 35

Staphylococcus aureus ATCC 29213

1 to 4

-

Staphylococcus aureus ATCC 25923

-

25 to 31

Pseudomonas aernginosa ATCC 27853

8 to 32

18 to 22

Haemophilus influenzae ATCC 4924 7

0.12 to 0.5

31 to 39

Streptococcus pneumoniae ATCC 49619

0.03 to 0.12

31 to 39

Neisseria gonorrhoeae ATCC 49226

0.015 to 0.06

38 to 48

Bacteroides fragilis* ATCC 25285

8 to 32

-

Bacteroides thetaiotaomicron* ATCC 29741

16 to 64

-

Eubacterium lantern* ATCC 43055

64 to 256

-

Indications and Usage for Cefotaxime

Treatment

Cefotaxime for Injection, USP is indicated for the treatment of patients with serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below.

(1) Lower respiratory tract infections, including pneumonia, caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae), Streptococcus pyogenes* (Group A streptococci) and other streptococci (excluding enterococci, e.g., Enterococcus faecalis), Staphylococcus aureus (penicillinase and non-penicillinase producing), Escherichia coli, Klebsiella species, Haemophilus influenzae (including ampicillin resistant strains), Haemophilus parainfluenzae, Proteus mirabilis, Serratia marcescens*, Enterobacter species, indole positive Proteus and Pseudomonas species (including P. aeruginosa).

(2) Genitourinary infections. Urinary tract infections caused by Enterococcus species, Staphylococcus epidermidis, Staphylococcus aureus*, (penicillinase and non-penicillinase producing), Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Proteus mirabilis, Proteus vulgaris*, Providencia stuartii, Morganella morganii*, Providencia rettgeri*, Serratia marcescens and Pseudomonas species (including P. aeruginosa). Also, uncomplicated gonorrhea (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including penicillinase producing strains.

(3) Gynecologic infections, including pelvic inflammatory disease, endometritis and pelvic cellulitis caused by Staphylococcus epidermidis, Streptococcus species, Enterococcus species, Enterobacter species*, Klebsiella species*, Escherichia coli, Proteus mirabilis, Bacteroides species (including Bacteroides fragilis*), Clostridium species, and anaerobic cocci (including Peptostreptococcus species and Peptococcus species) and Fusobacterium species (including F. nucleatum*).

Cefotaxime for Injection, USP like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial coverage should be added.

(4) Bacteremia/Septicemia caused by Escherichia coli, Klebsiella species, and Serratia marcescens, Staphylococcus aureus and Streptococcus species (including S. pneumonia).

(5) Skin and skin structure infections caused by Staphylococcus aureus (penicillinase and non-penicillinase producing), Staphylococcus epidermidis, Streptococcus pyogenes (Group A streptococci) and other streptococci, Enterococcus species, Acinetobacter species*, Escherichia coli, Citrobacter species (including C. freundii*), Enterobacter species, Klebsiella species, Proteus mirabilis, Proteus vulgaris*, Morganella morganii, Providencia rettgeri *, Pseudomonas species, Serratia marcescens, Bacteroides species, and anaerobic cocci (including Peptostreptococcus* species and Peptococcus species).

(6) Intra-abdominal infections including peritonitis caused by Streptococcus species*, Escherichia coli, Klebsiella species, Bacteroides species, and anaerobic cocci (including Peptostreptococcus* species and Peptococcus* species) Proteus mirabilis*, and Clostridium species*.

(7) Bone and/or joint infections caused by Staphylococcus aureus (penicillinase and non-penicillinase producing strains), Streptococcus species (including S. pyogenes*), Pseudomonas species (including P. aeruginosa*), and Proteus mirabilis*.

(8) Central nervous system infections, e.g., meningitis and ventriculitis, caused by Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae* and Escherichia coli*.

(*)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, Cefotaxime for Injection, USP 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 Cefotaxime. 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, Cefotaxime for Injection, USP 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 Cefotaxime for Injection, USP is used concomitantly with an aminoglycoside.

Prevention

The administration of Cefotaxime for Injection, USP preoperatively reduces the incidence of certain infections in patients undergoing surgical procedures (e.g., abdominal or vaginal hysterectomy, gastrointestinal and genitourinary tract surgery) that may be classified as contaminated or potentially contaminated.

In patients undergoing cesarean section, intraoperative (after clamping the umbilical cord) and postoperative use of Cefotaxime for Injection, USP 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, Cefotaxime for Injection, USP 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 Cefotaxime for Injection, USP and other antibacterial drugs, Cefotaxime for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information 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 therapy.

Contraindications

Cefotaxime for injection is contraindicated in patients who have shown hypersensitivity to Cefotaxime sodium, or the cephalosporin group of antibiotics.

Warnings

BEFORE THERAPY WITH Cefotaxime FOR INJECTION 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 Cefotaxime FOR INJECTION 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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefotaxime for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Precautions

General

Prescribing Cefotaxime for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Cefotaxime for Injection 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 Cefotaxime for injection 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.

Weight (kg) x (140 - age)
     Males:        72 x serum creatinine
     Females:     0.85 × above value

As with other antibiotics, prolonged use of Cefotaxime for injection 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.

Leukopenia, neutropenia, granulocytopenia and, more rarely, bone marrow failure, pancytopenia, or agranulocytosis may develop during treatment with Cefotaxime for injection. For courses of treatment lasting longer than 10 days, blood counts should therefore be monitored and treatment discontinuation should be considered in case of abnormal results.

Cefotaxime for Injection, like other parenteral anti-infective drugs, may be locally irritating to tissues. In most cases, perivascular extravasation of Cefotaxime responds to changing of the infusion site. In rare instances, extensive perivascular extravasation of Cefotaxime 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

Patients should be counseled that antibacterial drugs including Cefotaxime for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefotaxime for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefotaxime for injection or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

As with other cephalosporins, Cefotaxime may potentiate the nephrotoxic effects of nephrotoxic drugs such as aminoglycosides, NSAIDs and furosemide.

Probenecid interferes with the renal tubular transfer of Cefotaxime, decreasing the total clearance of Cefotaxime by approximately 50% and increasing the plasma concentrations of Cefotaxime.

Administration of Cefotaxime in excess of 6 grams/day should be avoided in patients receiving probenecid (see CLINICAL PHARMACOLOGY, Drug Interactions).

Drug/Laboratory Test Interactions

Cephalosporins, including Cefotaxime sodium, are known to occasionally induce a positive direct Coombs’ test.

A false-positive reaction for glucose in the urine may occur with copper reduction tests (Benedict’s or Fehling’s solution or with CLINITEST tablets), but not with enzyme-based tests for glycosuria (e.g., CLINISTIX or TesTape). There are no reports in published literature that link elevations of plasma glucose levels to the use of Cefotaxime.

Carcinogenesis, Mutagenesis

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.

Nonteratogenic Effects

Use of the drug in women of child-bearing potential requires that the anticipated benefit be weighed against the possible risks.

In perinatal and postnatal studies with rats, the pups in the group given 1200 mg/kg/day of Cefotaxime for injection were significantly lighter in weight at birth and remained smaller than pups in the control group during the 21 days of nursing.

Nursing Mothers

Cefotaxime is excreted in human milk in low concentrations. Caution should be exercised when Cefotaxime for injection is administered to a nursing woman.

Pediatric Use

See PRECAUTIONS above regarding perivascular extravasation.

Geriatric Use

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).

Adverse Reactions

Clinical Trials Experience

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, transient 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.

Post-Marketing Experience

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.

Overdosage

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.

Cefotaxime Dosage and Administration

Adults

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 in ADD-Vantage vial is intended for IV use only 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

Uncomplicated infections

2

1 gram every 12 hours IV

Moderate to severe infections

3 to 6

1 to 2 grams every 8 hours 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

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 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 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 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.

Geriatric Use

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.

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.

Preparation of Cefotaxime for Injection in ADD-Vantage System

Cefotaxime for injection 1 gram or 2 gram 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, INSTRUCTIONS FOR ADD-VANTAGE SYSTEM.

Compatibility and Stability

Solutions of Cefotaxime for Injection 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 container permit.

How is Cefotaxime Supplied

Cefotaxime for Injection, USP in the dry state, is a sterile off-white to pale yellow crystalline powder.

Cefotaxime for Injection, USP is supplied as follows:

NDC                     Vial                                                             Package Factor

0409-0811-01      Cefotaxime for Injection, USP 1 gram        Carton of 25 vials
0409-0812-01      Cefotaxime for Injection, USP 2 gram        Carton of 25 vials

NOTE: Cefotaxime for Injection, USP in the dry state should be stored at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature]. The dry material as well as solutions tend to darken depending on storage conditions and should be protected from elevated temperatures and excessive light.

REFERENCES

1.
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
2.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobials Susceptibility Tests; Twenty-Fifth Informational Supplement. CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
3.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard - Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
4.
Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
5.
Cockcroft, D.W. and Gault, M.H.: Prediction of Creatinine Clearance from Serum Creatinine, Nephron 16:31–41, 1976.

ADD-VANTAGE VIAL INSTRUCTIONS FOR USE

To Open Diluent Container:

Peel overwrap at corner and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container:

(Use Aseptic Technique)

1.
Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:
a.
To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening (SEE FIGURE 1), then pull straight up to remove the cap (SEE FIGURE 2).
NOTE: Once the breakaway cap has been removed, do not access vial with syringe.

b.
To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover (SEE FIGURE 3).
2.
Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately 1/2 turn (180°) after the first audible click (SEE FIGURE 4). The clicking sound does not assure a seal; the vial must be turned as far as it will go.
NOTE: Once vial is seated, do not attempt to remove (SEE FIGURE 4).
3.
Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.
4.
Label appropriately.

To Reconstitute the Drug:

1.
Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.
2.
With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container (SEE FIGURE 5).
3.
Pull the inner cap from the drug vial (SEE FIGURE 6). Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.
4.
Mix container contents thoroughly and use within the specified time.

Preparation for Administration:

(Use Aseptic Technique)

1.
Confirm the activation and admixture of vial contents.
2.
Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
3.
Close flow control clamp of administration set.
4.
Remove cover from outlet port at bottom of container.
5.
Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.
6.
Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.
7.
Squeeze and release drip chamber to establish proper fluid level in chamber.
8.
Open flow control clamp and clear air from set. Close clamp.
9.
Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
10.
Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

 

Manufactured for:
Hospira, Inc.
Lake Forest, IL 60045 USA
                                                                                                                                                        

Made in India

Revised: 1/2016

EN-4172

CA-4286

CA- 4287

Cefotaxime 
Cefotaxime injection, powder, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0409-0811
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Cefotaxime SODIUM (Cefotaxime) Cefotaxime 1 g
Packaging
# Item Code Package Description
1 NDC:0409-0811-01 25 VIAL, PATENT DELIVERY SYSTEM in 1 CARTON
1 1 INJECTION, POWDER, FOR SOLUTION in 1 VIAL, PATENT DELIVERY SYSTEM
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA203132 02/19/2016
Cefotaxime 
Cefotaxime injection, powder, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0409-0812
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Cefotaxime SODIUM (Cefotaxime) Cefotaxime 2 g
Packaging
# Item Code Package Description
1 NDC:0409-0812-01 25 VIAL, PATENT DELIVERY SYSTEM in 1 CARTON
1 1 INJECTION, POWDER, FOR SOLUTION in 1 VIAL, PATENT DELIVERY SYSTEM
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA203132 02/19/2016
Labeler - Hospira, Inc. (141588017)
Revised: 01/2016
 
Hospira, Inc.
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