Rx Drugs Info

ceftriaxone (Ceftriaxone Sodiuminjection, solution 
[Baxter Healthcare Corporation]

(In Dextrose)

in GALAXY Container

(PL 2040 Plastic)

Rx Only

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

DESCRIPTION

Ceftriaxone Injection, USP is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous administration. Ceftriaxone sodium is (6 R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7²-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate.

The chemical formula of ceftriaxone sodium is C 18H16N8Na2O7S3•7/2 H2O. It has a calculated molecular weight of 661.60 and the following structural formula:

Ceftriaxone Sodium, USP is a white to yellowish-orange crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol.

Ceftriaxone Injection, USP contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity.

Ceftriaxone Injection, USP is supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution premixed in a dextrose diluent. Dextrose has been added to adjust the osmolality. The pH may be adjusted with sodium hydroxide and/or hydrochloric acid. Solutions of premixed Ceftriaxone Injection, USP may range from light yellow to amber in color. After thawing, the solution is intended for intravenous use. The pH of thawed solutions may range from 6.0 to 8.0. See HOW SUPPLIED for package description.

The plastic container for the frozen solution 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.

CLINICAL PHARMACOLOGY

Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0.5, 1 or 2 gm dose in healthy subjects are presented in Table 1.

*
IV doses were infused at a constant rate over 30 minutes.
Table 1 Ceftriaxone Plasma Concentrations After Single Dose Administration
Dose/Route Average Plasma Concentrations (mcg/mL)
  0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 16 hr 24 hr
0.5 gm IV* 82 59 48 37 29 23 15 10 5
1 gm IV* 151 111 88 67 53 43 28 18 9
2 gm IV* 257 192 154 117 89 74 46 31 15

Multiple IV doses ranging from 0.5 to 2 gm at 12- to 24-hour intervals resulted in 15% to 36% accumulation of ceftriaxone above single dose values.

Ceftriaxone concentrations in urine are high, as shown in Table 2.

Table 2 Urinary Concentrations of Ceftriaxone After Single Dose Administration
Dose/Route Average Urinary Concentrations (mcg/mL)
0-2 hr 2-4 hr 4-8 hr 8-12 hr 12-24 hr 24-48 hr
0.5 gm IV 526 366 142 87 70 15
1 gm IV 995 855 293 147 132 32
2 gm IV 2692 1976 757 274 198 40

Thirty-three percent to 67% of a ceftriaxone dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After a 1 gm IV dose, average concentrations of ceftriaxone, determined from 1 to 3 hours after dosing, were 581 mcg/mL in the gallbladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/gm in the gallbladder wall and 62.1 mcg/mL in the concurrent plasma.

Over a 0.15 to 3 gm dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours; apparent volume of distribution from 5.78 to 13.5 L; plasma clearance from 0.58 to 1.45 L/hour; and renal clearance from 0.32 to 0.73 L/hour. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of <25 mcg/mL to a value of 85% bound at 300 mcg/mL. Ceftriaxone crosses the blood placenta barrier.

The average values of maximum plasma concentration, elimination half-life, plasma clearance and volume of distribution after a 50 mg/kg IV dose and after a 75 mg/kg IV dose in pediatric patients suffering from bacterial meningitis are shown in Table 3. Ceftriaxone penetrated the inflamed meninges of infants and pediatric patients; CSF concentrations after a 50 mg/kg IV dose and after a 75 mg/kg IV dose are also shown in Table 3.

Table 3 Average Pharmacokinetic Parameters of Ceftriaxone in Pediatric Patients
With Meningitis
50 mg/kg IV 75 mg/kg IV
Maximum Plasma Concentrations (mcg/mL) 216 275
Elimination Half-life (hr) 4.6 4.3
Plasma Clearance (mL/hr/kg) 49 60
Volume of Distribution (mL/kg) 338 373
CSF Concentration- inflamed meninges (mcg/mL) 5.6 6.4
Range (mcg/mL) 1.3-18.5 1.3-44
Time after dose (hr) 3.7 (± 1.6) 3.3 (± 1.4)

Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction (Table 4); therefore, dosage adjustments are not necessary for these patients with ceftriaxone dosages up to 2 gm per day. Ceftriaxone was not removed to any significant extent from the plasma by hemodialysis. In 6 of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced, suggesting that plasma concentrations of ceftriaxone should be monitored in these patients to determine if dosage adjustments are necessary.

*
Creatinine clearance
Table 4 Average Pharmacokinetic Parameters of Ceftriaxone in Humans
Subject Group Elimination Half-life (hr) Plasma Clearance (L/hr) Volume of Distribution (L)
Healthy Subjects 5.8-8.7 0.58-1.45 5.8-13.5
Elderly Subjects (mean age, 70.5 yr) 8.9 0.83 10.7
Patients With Renal Impairment
Hemodialysis Patients (0-5 mL/min)* 14.7 0.65 13.7
Severe (5-15 mL/min) 15.7 0.56 12.5
Moderate (16-30 mL/min) 11.4 0.72 11.8
Mild (31-60 mL/min) 12.4 0.70 13.3
Patients With Liver Disease 8.8 1.1 13.6

Microbiology

The bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria.

Ceftriaxone has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections described in the INDICATIONS AND USAGE section.

Aerobic gram-negative microorganisms:

Acinetobacter calcoaceticus

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae (including ampicillin-resistant and beta-lactamase producing strains)

Haemophilus parainfluenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Moraxella catarrhalis (including beta-lactamase producing strains)

Morganella morganii

Neisseria gonorrhoeae (including penicillinase- and nonpenicillinase-producing strains)

Neisseria meningitidis

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Ceftriaxone is also active against many strains of Pseudomonas aeruginosa.

NOTE: Many strains of the above organisms that are multiply resistant to other antibiotics, e.g., penicillins, cephalosporins, and aminoglycosides, are susceptible to ceftriaxone.

Aerobic gram-positive microorganisms:

Staphylococcus aureus (including penicillinase-producing strains)

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group streptococci

NOTE: Methicillin-resistant staphylococci are resistant to cephalosporins, including ceftriaxone. Most strains of Group D streptococci and enterococci, e.g., Enterococcus (Streptococcus) faecalis, are resistant.

Anaerobic microorganisms:

Bacteroides fragilis

Clostridium species

Peptostreptococcus species

NOTE: Most strains of Clostridium difficile are resistant.

The following in vitro data are available, but their clinical significance is unknown. Ceftriaxone exhibits in vitro minimal inhibitory concentrations (MICs) of ≤8 mcg/mL or less against most strains of the following microorganisms, however, the safety and effectiveness of ceftriaxone in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-negative microorganisms:

Citrobacter diversus

Citrobacter freundii

Providencia species (including Providencia rettgeri)

Salmonella species (including Salmonella typhi)

Shigella species

Aerobic gram-positive microorganisms:

Streptococcus agalactiae

Anaerobic microorganisms:

Prevotella (Bacteroides) bivius

Porphyromonas (Bacteroides) melaninogenicus

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. 1 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ceftriaxone powder. The MIC values should be interpreted according to the following criteria2 for aerobic organisms other than Haemophilus spp, Neisseria gonorrhoeae, and Streptococcus spp, including Streptococcus pneumoniae:

MIC (mcg/mL) Interpretation
≤8 (S) Susceptible
16-32 (I) Intermediate
≥64 (R) Resistant

The following interpretive criteria 2 should be used when testing Haemophilus species using Haemophilus Test Media (HTM).

MIC (mcg/mL) Interpretation
≤2 (S) Susceptible

The absence of resistant strains precludes defining any categories other than “Susceptible”. Strains yielding results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing.

The following interpretive criteria 2 should be used when testing Neisseria gonorrhoeae when using GC agar base and 1% defined growth supplement.

MIC (mcg/mL) Interpretation
≤0.25 (S) Susceptible

The absence of resistant strains precludes defining any categories other than “Susceptible”. Strains yielding results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing.

The following interpretive criteria 2 should be used when testing Streptococcus spp including Streptococcus pneumoniae using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

MIC (mcg/mL) Interpretation
≤0.5 (S) Susceptible
1 (I) Intermediate
≥2 (R) Resistant

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 results 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 the drug can be used. This category also provides a buffer zone which 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 procedures. Standardized ceftriaxone powder should provide the following MIC values: 2

*
A bimodal distribution of MICs results at the extremes of the acceptable range should be suspect and control validity should be verified with data from other control strains.
Microorganism ATCC®# MIC (mcg/mL)
Escherichia coli 25922 0.03-0.12
Staphylococcus aureus 29213 1-8*
Pseudomonas aeruginosa 27853 8-32
Haemophilus influenzae 49247 0.06-0.25
Neisseria gonorrhoeae 49226 0.004-0.015
Streptococcus pneumoniae 49619 0.03-0.12

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 3 requires the use of standardized inoculum concentrations. This procedure uses paper discs impregnated with 30 mcg of ceftriaxone to test the susceptibility of microorganisms to ceftriaxone.

Reports from the laboratory providing results of the standard single-disc susceptibility test with a 30 mcg ceftriaxone disc should be interpreted according to the following criteria for aerobic organisms other than Haemophilus spp, Neisseria gonorrhoeae, and Streptococcus spp:

Zone Diameter (mm) Interpretation
≥21 (S) Susceptible
14-20 (I) Intermediate
≤13 (R) Resistant

The following interpretive criteria 3 should be used when testing Haemophilusspecies when using Haemophilus Test Media (HTM).

Zone Diameter (mm) Interpretation
≥26 (S) Susceptible

The absence of resistant strains precludes defining any categories other than “Susceptible”. Strains yielding results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing.

The following interpretive criteria 3 should be used when testing Neisseria gonorrhoeae when using GC agar base and 1% defined growth supplement.

Zone Diameter (mm) Interpretation
≥35 (S) Susceptible

The absence of resistant strains precludes defining any categories other than “Susceptible”. Strains yielding results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing.

The following interpretive criteria 3 should be used when testing Streptococcus spp other than Streptococcus pneumoniae when using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.

Zone Diameter (mm) Interpretation
≥27 (S) Susceptible
25-26 (I) Intermediate
≤24 (R) Resistant

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disc test with the MIC for ceftriaxone.

Disc diffusion interpretive criteria for ceftriaxone discs against Streptococcus 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 ceftriaxone. Streptococcus pneumoniae isolates should not be reported as penicillin (ceftriaxone) resistant or intermediate based solely on an oxacillin zone diameter of ≤19 mm. The ceftriaxone MIC should be determined for those isolates with oxacillin zone diameters ≤19 mm.

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 ceftriaxone disc should provide the following zone diameters in these laboratory test quality control strains: 3

Microorganism ATCC®# Zone Diameter Ranges (mm)
Escherichia coli 25922 29-35
Staphylococcus aureus 25923 22-28
Pseudomonas aeruginosa 27853 17-23
Haemophilus influenzae 49247 31-39
Neisseria gonorrhoeae 49226 39-51
Streptococcus pneumoniae 49619 30-35

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by standardized test methods.4 The MIC values obtained should be interpreted according to the following criteria:

MIC (mcg/mL) Interpretation
≤16 (S) Susceptible
32 (I) Intermediate
≥64 (R) Resistant

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ceftriaxone powder should provide the following MIC values for the indicated standardized anaerobic dilution 4 testing method:

Method Microorganism ATCC®# MIC (mcg/mL)
Agar Bacteroides fragilis 25285 32-128
Bacteroides thetaiotaomicron 29741 64-256
Broth Bacteroides thetaiotaomicron 29741 32-128

ATCC® is a registered trademark of the American Type Culture Collection.

INDICATIONS AND USAGE

Before instituting treatment with Ceftriaxone Injection, USP, appropriate specimens should be obtained for isolation of the causative organism and for determination of its susceptibility to the drug. Therapy may be instituted prior to obtaining results of susceptibility testing.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftriaxone Injection, USP and other antibacterial drugs, Ceftriaxone 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.

Ceftriaxone Injection, USP is indicated for the treatment of the following infections when caused by susceptible organisms:

LOWER RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.

ACUTE BACTERIAL OTITIS MEDIA caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains).

NOTE: In one study lower clinical cure rates were observed with a single dose of ceftriaxone compared to 10 days of oral therapy. In a second study comparable cure rates were observed between single dose ceftriaxone and the comparator. The potentially lower clinical cure rate of ceftriaxone should be balanced against the potential advantages of parenteral therapy.

SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci, Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii,* Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis* or Peptostreptococcus species.

URINARY TRACT INFECTIONS (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae.

UNCOMPLICATED GONORRHEA (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae.

PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae. Ceftriaxone, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and Chlamydia trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added.

BACTERIAL SEPTICEMIA caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae.

BONE AND JOINT INFECTIONS caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species.

INTRA-ABDOMINAL INFECTIONS caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most strains of Clostridium difficile are resistant) or Peptostreptococcus species.

MENINGITIS caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae.Ceftriaxone has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis* and Escherichia coli.*

*Efficacy for this organism in this organ system was studied in fewer than ten infections.

SURGICAL PROPHYLAXIS: The preoperative administration of a single 1 gm dose of ceftriaxone may reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated (e.g., vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous cholecystitis in high-risk patients, such as those over 70 years of age, with acute cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common duct bile stones) and in surgical patients for whom infection at the operative site would present serious risk (e.g., during coronary artery bypass surgery). Although ceftriaxone has been shown to have been as effective as cefazolin in the prevention of infection following coronary artery bypass surgery, no placebo controlled trials have been conducted to evaluate any cephalosporin antibiotic in the prevention of infection following coronary artery bypass surgery.

When administered prior to surgical procedures for which it is indicated, a single 1 gm dose of ceftriaxone provides protection from most infections due to susceptible organisms throughout the course of the procedure.

CONTRAINDICATIONS

Ceftriaxone Injection, USP is contraindicated in patients with known allergy to the cephalosporin class of antibiotics. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

Neonates (≤28 days)

Hyperbilirubinemic neonates, especially prematures, should not be treated with Ceftriaxone Injection, USP. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients.

Ceftriaxone Injection, USP must not be co-administered with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition, in neonates because of the risk of precipitation of ceftriaxone-calcium salt. Cases of fatal reactions with ceftriaxone-calcium precipitates in lung and kidneys in neonates have been described. In some cases the infusion lines and the times of administration of ceftriaxone and calcium-containing solutions differed.

For information regarding all other patients, see WARNINGS.

WARNINGS

Hypersensitivity

BEFORE THERAPY WITH CEFTRIAXONE INJECTION, USP IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY MEASURES.

Interaction with Calcium-Containing Products

There are no reports to date of intravascular or pulmonary precipitations in patients, other than neonates, treated with ceftriaxone and calcium-containing IV solutions. However, the theoretical possibility exists for an interaction between ceftriaxone and IV calcium-containing solutions in patients other than neonates. Therefore, Ceftriaxone Injection, USP and calcium-containing solutions, including continuous calcium-containing infusions such as parenteral nutrition, should not be mixed or co-administered to any patient irrespective of age, even via different infusion lines at different sites. As a further theoretical consideration and based on 5 half-lives of ceftriaxone, Ceftriaxone Injection, USP and IV calcium-containing solutions should not be administered within 48 hours of each other in any patient (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

Clostridium difficile

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Ceftriaxone Injection, USP, 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 Ceftriaxone Injection, USP 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.

Although transient elevations of BUN and serum creatinine have been observed, at the recommended dosages, the nephrotoxic potential of ceftriaxone is similar to that of other cephalosporins.

Ceftriaxone is excreted via both biliary and renal excretion (see CLINICAL PHARMACOLOGY). Therefore, patients with renal failure normally require no adjustment in dosage when usual doses of Ceftriaxone Injection, USP are administered, but concentrations of drug in the serum should be monitored periodically. If evidence of accumulation exists, dosage should be decreased accordingly.

Dosage adjustments should not be necessary in patients with hepatic dysfunction; however, in patients with both hepatic dysfunction and significant renal disease, Ceftriaxone Injection, USP dosage should not exceed 2 gm daily without close monitoring of serum concentrations.

Alterations in prothrombin times have occurred rarely in patients treated with ceftriaxone. Patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during Ceftriaxone Injection, USP treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

Prolonged use of Ceftriaxone Injection, USP may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Ceftriaxone Injection, USP should be prescribed with caution in individuals with a history of gastrointestinal disease, especially colitis.

There have been reports of sonographic abnormalities in the gallbladder of patients treated with ceftriaxone; some of these patients also had symptoms of gallbladder disease.These abnormalities appear on sonography as an echo without acoustical shadowing suggesting sludge or as an echo with acoustical shadowing which may be misinterpreted as gallstones. The chemical nature of the sonographically detected material has been determined to be predominantly a ceftriaxone-calcium salt. The condition appears to be transient and reversible upon discontinuation of ceftriaxone and institution of conservative management.Therefore, Ceftriaxone Injection, USP should be discontinued in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above.

Information for Patients

Patients should be counseled that antibacterial drugs including Ceftriaxone Injection, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Ceftriaxone Injection, USP 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 Ceftriaxone Injection, USP 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.

Carcinogenesis and Mutagenesis and Impairment of Fertility

Carcinogenesis

Considering the maximum duration of treatment and the class of the compound, carcinogenicity studies with ceftriaxone in animals have not been performed. The maximum duration of animal toxicity studies was 6 months.

Mutagenesis

Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies.

Impairment of Fertility

Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of 2 gm/day.

Pregnancy

Teratogenic Effects

Pregnancy Category B.

Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose.

There are, however, no adequate and 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

In rats, in the Segment I (fertility and general reproduction) and Segment III (perinatal and postnatal) studies with intravenously administered ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less

Nursing Mothers

Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone Injection, USP is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Ceftriaxone Injection, USP in neonates, infants and pediatric patients have been established for the dosages described in the DOSAGE AND ADMINISTRATION section. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone Injection, USP should not be administered to hyperbilirubinemic neonates, especially prematures (see CONTRAINDICATIONS).

ADVERSE REACTIONS

Ceftriaxone is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to ceftriaxone therapy or of uncertain etiology, were observed:

LOCAL REACTIONS— pain, induration and tenderness was 1% overall. Phlebitis was reported in <1% after IV administration.

HYPERSENSITIVITY— rash (1.7%). Less frequently reported (<1%) were pruritus, fever or chills.

HEMATOLOGIC— eosinophilia (6%), thrombocytosis (5.1%) and leukopenia (2.1%). Less frequently reported (<1%) were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.

GASTROINTESTINAL— diarrhea (2.7%). Less frequently reported (<1%) were nausea or vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS).

HEPATIC—elevations of SGOT (3.1%) or SGPT (3.3%). Less frequently reported (<1%) were elevations of alkaline phosphatase and bilirubin.

RENAL— elevations of the BUN (1.2%). Less frequently reported (<1%) were elevations of creatinine and the presence of casts in the urine.

CENTRAL NERVOUS SYSTEM— headache or dizziness were reported occasionally (<1%).

GENITOURINARY— moniliasis or vaginitis were reported occasionally (<1%).

MISCELLANEOUS— diaphoresis and flushing were reported occasionally (<1%).

Other rarely observed adverse reactions (<0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, a decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.

Cases of fatal reactions with ceftriaxone-calcium precipitates in lung and kidneys in neonates have been described. In some cases the infusion lines and times of administration of ceftriaxone and calcium-containing solutions differed (see CONTRAINDICATIONS).

OVERDOSAGE

In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic.

DOSAGE AND ADMINISTRATION

Ceftriaxone Injection, USP is administered intravenously.

Ceftriaxone Injection, USP and calcium-containing solutions, including continuous calcium-containing infusions such as parenteral nutrition, should not be mixed or co-administered to any patient irrespective of age, even via different infusion lines at different sites (see CONTRAINDICATIONS and WARNINGS).

Neonates

Hyperbilirubinemic neonates, especially prematures, should not be treated with Ceftriaxone Injection, USP (see CONTRAINDICATIONS).

Pediatric Patients

For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams.

For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams.

In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.

Adults

The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. The total daily dose should not exceed 4 grams.

If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.

For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended.

Generally, Ceftriaxone Injection, USP therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.

When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.

No dosage adjustment is necessary for patients with impairment of renal or hepatic function; however, blood levels should be monitored in patients with severe renal impairment (e.g., dialysis patients) and in patients with both renal and hepatic dysfunctions.

Ceftriaxone Injection, USP should be administered intravenously by infusion over a period of 30 minutes.

DIRECTIONS FOR USE

Ceftriaxone Injection, USP is for intravenous administration using sterile equipment.

Storage

Store in a freezer capable of maintaining a temperature of -20°C/-4°F.

Thawing of Plastic Container

Thaw frozen container at room temperature (25°C/77°F) or under refrigeration (5°C/41°F). [DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION.]

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 21 days under refrigeration (5°C/41°F) or 48 hours at room temperature (25°C/77°F). 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:

1. Suspend container from eyelet support.

2. Remove protector from outlet port at bottom of container.

3. Attach administration set. Refer to complete directions accompanying set.

ANIMAL PHARMACOLOGY

Concretions consisting of the precipitated calcium salt of ceftriaxone have been found in the gallbladder bile of dogs and baboons treated with ceftriaxone.

These appeared as a gritty sediment in dogs that received 100 mg/kg/day for 4 weeks. A similar phenomenon has been observed in baboons but only after a protracted dosing period (6 months) at higher dose levels (335 mg/kg/day or more). The likelihood of this occurrence in humans is considered to be low, since ceftriaxone has a greater plasma half-life in humans, the calcium salt of ceftriaxone is more soluble in human gallbladder bile and the calcium content of human gallbladder bile is relatively low.

HOW SUPPLIED

Ceftriaxone Injection, USP is supplied premixed as a frozen, iso-osmotic, sterile, nonpyrogenic solution of ceftriaxone sodium in a carton of 24 x 50 mL single dose GALAXY containers (PL 2040 plastic). The following strengths are available:

1 gm equivalent of ceftriaxone, iso-osmotic with approximately 1.9 gm Dextrose Hydrous, USP, added (NDC 0338-5002-41).

2 gm equivalent of ceftriaxone, iso-osmotic with approximately 1.2 gm Dextrose Hydrous, USP, added (NDC 0338-5003-41).

NOTE: Store Ceftriaxone Injection, USP in the frozen state at or below -20°C/-4°F. See DIRECTIONS FOR USE:

REFERENCES

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Fifth Edition. NCCLS document M7-A5 (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898, 2000.

2. National Committee for Clinical Laboratory Standards, Supplemental Tables. NCCLS document M100-S10(M7) (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898, 2000.

3. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898, 2000.

4. National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Fourth Edition. NCCLS document M11-A4 (ISBN 1-56238-210-1). NCCLS, Wayne, PA 19087-1898, 1997.

Baxter Healthcare Corporation

Deefield, IL 60015 USA

U.S. Pat. Nos. 4,686,125; 4,779,997

Baxter and GALAXY are trademarks of Baxter International Inc.

07-19-54-517 Rev. November 2007


Ceftriaxone (Ceftriaxone Sodium)
PRODUCT INFO
Product Code 0338-5002 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAVENOUS DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Ceftriaxone Sodium (Ceftriaxone) Active 1 GRAM  In 50 MILLILITER
Dextrose Inactive 1.9 GRAM  In 50 MILLILITER
Sodium Hydroxide Inactive  
Hydrochloric Acid Inactive  
Water Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 0338-5002-41 24 BAG In 1 CARTON contains a BAG
1 50 MILLILITER In 1 BAG This package is contained within the CARTON (0338-5002-41)

Ceftriaxone (Ceftriaxone Sodium)
PRODUCT INFO
Product Code 0338-5003 Dosage Form INJECTION, SOLUTION
Route Of Administration INTRAVENOUS DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Ceftriaxone Sodium (Ceftriaxone) Active 2 GRAM  In 50 MILLILITER
Dextrose Inactive 1.2 GRAM  In 50 MILLILITER
Sodium Hydroxide Inactive  
Hydrochloric Acid Inactive  
Water Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 0338-5003-41 24 BAG In 1 CARTON contains a BAG
1 50 MILLILITER In 1 BAG This package is contained within the CARTON (0338-5003-41)

Revised: 02/2008Baxter Healthcare Corporation

Data are from FDA and U.S. National Library of Medicine.