Rx Drugs Info

ceftriaxone and dextrose (Ceftriaxone sodiuminjection 
[B. Braun Medical Inc.]

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

DESCRIPTION

Ceftriaxone for Injection and Dextrose Injection is a sterile, nonpyrogenic, single use, packaged combination of Ceftriaxone Sodium and Dextrose Injection (diluent) in the DUPLEX sterile container. The DUPLEX Container is a flexible dual chamber container.

The drug chamber is filled with ceftriaxone sodium, a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous administration. Ceftriaxone sodium is (6R,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 C18H16N8Na2O7S3•3.5H2O. It has a calculated molecular weight of 661.60 and the following structural formula:

Chemical Structure

Ceftriaxone sodium is supplied as a dry powder form equivalent to either 1 g or 2 g of ceftriaxone. Ceftriaxone sodium is a white to yellowish-orange crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. The pH of a 1% aqueous solution is approximately 6.7. The color of ceftriaxone sodium solutions ranges from light yellow to amber, depending on the length of storage and concentration.

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

The diluent chamber contains Dextrose Injection. The concentration of Hydrous Dextrose in Water for Injection USP has been adjusted to render the reconstituted drug product iso-osmotic. Dextrose USP has been added to adjust osmolality (approximately 1.87 g and 1.11 g to 1 g and 2 g dosages, respectively). Dextrose Injection is sterile, nonpyrogenic, and contains no bacteriostatic or antimicrobial agents.

Hydrous Dextrose USP has the following structural (molecular) formula:

Chemical Structure

The molecular weight of Hydrous Dextrose USP is 198.17.

After removing the peelable foil strip, activating the seals, and thoroughly mixing, the reconstituted drug product is intended for single intravenous use. When reconstituted, the approximate osmolality for the reconstituted solution for Ceftriaxone for Injection and Dextrose Injection is 290 mOsmol/kg.

The DUPLEX Container is Latex-free, PVC-free, and DEHP-free.

The DUPLEX dual chamber container is made from a specially formulated material. The product (diluent and drug) contact layer is a mixture of thermoplastic rubber and a polypropylene ethylene copolymer that contains no plasticizers. The safety of the container system is supported by USP biological evaluation procedures.

CLINICAL PHARMACOLOGY

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

TABLE 1. Ceftriaxone Plasma Concentrations After Single Dose Administration
  Average Plasma Concentrations (mcg/mL)
Dose/Route 0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 16 hr 24 hr
*
IV doses were infused at a constant rate over 30 minutes.
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 g 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
  Average Urinary Concentrations (mcg/mL)
Dose/Route 0–2 hr 2–4 hr 4–8 hr 8–12 hr 12–24 hr 24–48 hr
0.5 g IV 526 366 142 87 70 15
1 g IV 995 855 293 147 132 32
2 g 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 g 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/g in the gallbladder wall and 62.1 mcg/mL in the concurrent plasma.

Over a 0.15 to 3 g 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 g 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.

TABLE 4. Average Pharmacokinetic Parameters of Ceftriaxone in Humans
Subject Group Elimination Half-Life
(hr)
Plasma Clearance
(L/hr)
Volume of Distribution
(L)
*
Creatinine clearance.
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 criteria2 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 criteria2 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 criteria2 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 values2:

Microorganism ATCC®# MIC (mcg/mL)
*
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.
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 procedure3 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 criteria3 should be used when testing Haemophilus species 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 criteria3 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 criteria3 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 strains3:

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 methods4. 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 dilution4 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

INDICATIONS AND USAGE

Before instituting treatment with Ceftriaxone for Injection and Dextrose Injection, 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 for Injection and Dextrose Injection and other antibacterial drugs, Ceftriaxone for Injection and Dextrose Injection 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 for Injection and Dextrose Injection 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.

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 morganii1, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis1 or Peptostreptococcus species.

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

PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae. Ceftriaxone sodium, 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 sodium has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis1 and Escherichia coli.1


1
Efficacy for this organism in this organ system was studied in fewer than ten infections.

SURGICAL PROPHYLAXIS: The preoperative administration of a single 1 g dose of Ceftriaxone for Injection and Dextrose Injection 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 sodium 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 g dose of Ceftriaxone for Injection and Dextrose Injection provides protection from most infections due to susceptible organisms throughout the course of the procedure.

CONTRAINDICATIONS

Ceftriaxone for Injection and Dextrose Injection is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.

Neonates (≤28 days)

Hyperbilirubinemic neonates, especially prematures, should not be treated with Ceftriaxone for Injection and Dextrose Injection. 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 for Injection and Dextrose Injection 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.

Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn products.

WARNINGS

Hypersensitivity

BEFORE THERAPY WITH CEFTRIAXONE FOR INJECTION AND DEXTROSE INJECTION 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 for Injection and Dextrose Injection 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 for Injection and Dextrose Injection and IV calcium-containing solutions should not be administered within 48 hours of each other in any patient (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

No data are available on potential interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).

Clostridium difficile

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

Although transient elevations of BUN and serum creatinine have been observed, at the recommended dosages, the nephrotoxic potential of ceftriaxone sodium 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 for Injection and Dextrose Injection 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 for Injection and Dextrose Injection dosage should not exceed 2 g daily without close monitoring of serum concentrations.

Alterations in prothrombin times have occurred rarely in patients treated with ceftriaxone sodium. 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 for Injection and Dextrose Injection treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

Prolonged use of Ceftriaxone for Injection and Dextrose Injection 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 for Injection and Dextrose Injection 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 sodium; 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 sodium and institution of conservative management. Therefore, Ceftriaxone for Injection and Dextrose Injection should be discontinued in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above.

As with other dextrose-containing solutions, Ceftriaxone for Injection and Dextrose Injection should be prescribed with caution in patients with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason.

If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result.

Use only if solution is clear and container and seals are intact.

Information for Patients

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

Carcinogenesis, Mutagenesis, 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 g/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 for Injection and Dextrose Injection is administered to a nursing woman.

Pediatric Use

Ceftriaxone for Injection and Dextrose Injection in the DUPLEX® Container is designed to deliver a 1 g or 2 g dose of ceftriaxone. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of ceftriaxone.

Safety and effectiveness of Ceftriaxone for Injection and Dextrose Injection 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 for Injection and Dextrose Injection should not be administered to hyperbilirubinemic neonates, especially prematures (see CONTRAINDICATIONS).

ADVERSE REACTIONS

Ceftriaxone sodium is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to ceftriaxone sodium 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 for Injection and Dextrose Injection is intended for intravenous administration only.

Ceftriaxone for Injection and Dextrose Injection 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 for Injection and Dextrose Injection (see CONTRAINDICATIONS).

PEDIATRIC PATIENTS

Ceftriaxone for Injection and Dextrose Injection in the DUPLEX® Container is designed to deliver a 1 g or 2 g dose of ceftriaxone. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of ceftriaxone.

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 for Injection and Dextrose Injection 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.

DIRECTIONS FOR USE

Ceftriaxone for Injection and Dextrose Injection should be administered intravenously by infusion over a period of 30 minutes.

Vancomycin and fluconazole are physically incompatible with ceftriaxone in admixtures. When either of these drugs is to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.

Ceftriaxone for Injection and Dextrose Injection should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs due to possible incompatibility (see WARNINGS).

After the indicated stability time periods, unused portions of solutions should be discarded.

CAUTION: Do not use plastic containers in series connections. Such use would 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.

NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.

Directions for Use of DUPLEX Drug Delivery System

Patient Labeling and Drug Powder/Diluent Inspection

Diagram 1
 

Diagram 2
 

Reconstitution (Activation)

Diagram 3
 

Administration

Diagram 4
 

Precautions

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 for Injection and Dextrose Injection in the DUPLEX Drug Delivery System is a flexible dual chamber container supplied in two concentrations. After reconstitution, the concentrations are equivalent to 1 g and 2 g ceftriaxone. The diluent chamber contains approximately 50 mL of Dextrose Injection. Dextrose Injection has been adjusted to 3.74% and 2.22% for the 1 g and 2 g doses, respectively, such that the reconstituted solution is iso-osmotic.

Ceftriaxone for Injection and Dextrose Injection is supplied sterile and nonpyrogenic in the DUPLEX Drug Delivery System containers packaged 24 units per case.

NDC Cat. No. Dose Volume
Ceftriaxone for Injection and Dextrose Injection
0264-3153-11 3153-11 1 g 50 mL
Ceftriaxone for Injection and Dextrose Injection
0264-3155-11 3155-11 2 g 50 mL

Store the unactivated unit at 20–25°C (68–77°F). Excursions permitted to 15–30°C (59–86°F).

Rx only

Revised: September 2007

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.

DUPLEX is a registered trademark of B. Braun Medical Inc.

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

U.S. Patent Nos. D388,168, D397,789, D402,366, D407,816, 5,944,709, and 6,165,161.

Made in USA

B. Braun Medical Inc.
Irvine, CA USA 92614-5895

©2007 B. Braun Medical Inc.

Y36-002-639


Ceftriaxone and Dextrose (Ceftriaxone sodium)
PRODUCT INFO
Product Code 0264-3153 Dosage Form INJECTION
Route Of Administration INTRAVENOUS DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Ceftriaxone Sodium (Ceftriaxone) Active 1 GRAM  In 50 MILLILITER
Dextrose Inactive 1.87 GRAM  In 50 MILLILITER
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 0264-3153-11 24 CONTAINER In 1 CASE contains a CONTAINER
1 50 MILLILITER In 1 CONTAINER This package is contained within the CASE (0264-3153-11)

Ceftriaxone and Dextrose (Ceftriaxone sodium)
PRODUCT INFO
Product Code 0264-3155 Dosage Form INJECTION
Route Of Administration INTRAVENOUS DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Ceftriaxone Sodium (Ceftriaxone) Active 2 GRAM  In 50 MILLILITER
Dextrose Inactive 1.11 GRAM  In 50 MILLILITER
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 0264-3155-11 24 CONTAINER In 1 CASE contains a CONTAINER
1 50 MILLILITER In 1 CONTAINER This package is contained within the CASE (0264-3155-11)

Revised: 01/2008B. Braun Medical Inc.

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