Ceftriaxone for Injection USP 1 g

ROCEPHIN - ceftriaxone sodium injection, powder, for solution 
BAXTER HEALTHCARE CORPORATION

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Ceftriaxone for Injection USP 1 g

Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftriaxone sodium and other antibacterial drugs, ceftriaxone for 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 is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular 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-l-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate.

The molecular formula of ceftriaxone sodium is C18H16N8Na2O7S3 . 3.5 H2O. It has a calculated molecular weight of 661.60 and the following structural formula:

Structural Formula

Ceftriaxone for injection 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 for injection solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

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

CLINICAL PHARMACOLOGY:

Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0.5, 1 or 2 g dose and intramuscular (IM) administration of a single 0.5 (250 mg/mL or 350 mg/mL concentrations) or 1 g dose in healthy subjects are presented in Table 1.

TABLE 1 Ceftriaxone Plasma Concentrations After Single Dose Administration
Dose/ RouteAverage Plasma Concentrations (mcg/mL)
0.5 hr1 hr2 hr4 hr6 hr8 hr12 hr16 hr24 hr
0.5 g IV*82594837292315105

0.5 g IM

250 mg/ mL
22333835302616ND5

0.5 g IM

350 mg/mL
20323834312416ND5
1 g IV*1511118867534328189
1 g IM40687668564429NDND
2 g IV*2571921541178974463115
*IV doses were infused at a constant rate over 30 minutes.
ND = Not determined.

Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours postdosing. Multiple IV or IM 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
Dose/ RouteAverage Urinary Concentrations (mcg/mL)
0-2 hr2-4 hr4-8 hr8-12 hr12-24 hr24-48 hr
0.5 g IV526366142877015
0.5 g IM 1154253081279628
1 g IV99585529314713232
1 g IM504628418237NDND
2 g IV2692197675727419840
ND = Not determined.

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 IV75 mg/kg IV
Maximum Plasma Concentrations (mcg/mL)216275
Elimination Half-life (hr)4.64.3
Plasma Clearance (mL/hr/kg)4960
Volume of Distribution (mL/kg)338373
CSF Concentration – inflamed meninges (mcg/mL)5.66.4
Range (mcg/mL)1.3 – 18.51.3 – 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
*
Creatinine clearance
Subject GroupElimination Half-life (hr)

Plasma

Clearance (L/hr)
Volume of Distribution (L)
Healthy Subjects5.8 – 8.70.58 – 1.455.8 – 13.5
Elderly Subjects (mean age, 70.5 yr)8.90.8310.7
Patients with renal impairment
Hemodialysis patients (0-5 mL/ min)*14.70.6513.7
Severe (5-15 mL/ min)15.70.5612.5
Moderate (16-30 mL/min)11.40.7211.8
Mild (31 – 60 mL/ min)12.40.7013.3
Patients with liver disease8.81.113.6

Pharmacokinetics in the Middle Ear Fluid:

In one study, total ceftriaxone concentrations (bound and unbound) were measured in middle ear fluid obtained during the insertion of tympanostomy tubes in 42 pediatric patients with otitis media. Sampling times were from 1 to 50 hours after a single intramuscular injection of 50 mg/kg of ceftriaxone. Mean (± SD) ceftriaxone levels in the middle ear reached a peak of 35 (± 12) mcg/mL at 24 hours, and remained at 19 (± 7) mcg/mL at 48 hours. Based on middle ear fluid ceftriaxone concentrations in the 23 to 25 hour and the 46 to 50 hour sampling time intervals, a half-life of 25 hours was calculated. Ceftriaxone is highly bound to plasma proteins. The extent of binding to proteins in the middle ear fluid is unknown.

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 strain)

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 procedure1. 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 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.
MicroorganismATCC® #

MIC (mcg/mL)

Escherichia coli259220.03 - 0.12
Staphylococcus aureus292131 – 8*
Pseudomonas aeruginosa27853 8 - 32
Haemophilus influenzae49247 0.06 - 0.25
Neisseria gonorrhoeae49226

0.004 - 0.015

Streptococcus pneumoniae49619 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 “Non-susceptible” 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 “Non-susceptible” 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 strains:3

MicroorganismATCC® #Zone Diameter Ranges (mm)
Escherichia coli25922 29 - 35
Staphylococcus aureus25923 22 - 28
Pseudomonas aeruginosa27853 17 - 23
Haemophilus influenzae 49247 31 - 39
Neisseria gonorrhoeae49226 39 - 51
Streptococcus pneumoniae49619 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 dilution4 testing method:

Method Microorganism ATCC® #

MIC (mcg/mL)

AgarBacteroides fragilis25285 32-128
Bacteroides thetaiotaomicron29741 64-256
BrothBacteroides thetaiotaomicron29741 32-128

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

INDICATIONS AND USAGE:

Before instituting treatment with ceftriaxone for 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 other antibacterial drugs, ceftriaxone for 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 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 for injection compared to 10 days of oral therapy. In a second study comparable cure rates were observed between single dose ceftriaxone for injection and the comparator. The potentially lower clinical cure rate of ceftriaxone for injection should be balanced against the potential advantages of parenteral therapy (see CLINICAL STUDIES).

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 for injection, 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 for injection 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 g dose of ceftriaxone for 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 for injection 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 provides protection from most infections due to susceptible organisms throughout the course of the procedure.

CONTRAINDICATIONS:

Ceftriaxone for 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. 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 should not be co-administered with calcium-containing IV solutions, including continuous calcium-containing infusions such as parentral 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-cotaining solutions differed.

For information regarding all other patients, (see WARNINGS).

WARNINGS:

Hypersensitivity:

BEFORE THERAPY WITH CEFTRIAXONE FOR 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 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 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, 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 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 for injection 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 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 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 for injection. 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 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 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 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 for injection; 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 for injection and institution of conservative management. Therefore, ceftriaxone for injection 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 for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., common cold). When ceftriaxone 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 ceftriaxone 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.

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 is administered to a nursing woman.

Pediatric Use: 

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

ADVERSE REACTIONS:

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

LOCAL REACTIONS - pain, induration and tenderness was 1% overall. Phlebitis was reported in <1% after IV administration. The incidence of warmth, tightness or induration was 17% (3/17) after IM administration of 350 mg/mL and 5% (1/20) after IM administration of 250 mg/mL.

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, a decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.

Cases of fatal reactions with calcium-ceftriaxone 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 may be administered intravenously or intramuscularly.

Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone for injection. Particulate formation can result. ceftriaxone for 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 (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 acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE).

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 the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.

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 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:

Intramuscular Administration: Reconstitute ceftriaxone for injection powder with the appropriate diluent (see COMPATIBILITY AND STABILITY ).

Inject diluent into vial, shake vial thoroughly to form solution. Withdraw entire contents of vial into syringe to equal total labeled dose.

After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of ceftriaxone according to the amount of diluent indicated below. If required, more dilute solutions could be utilized. A 350 mg/mL concentration is not recommended for the 250 mg vial since it may not be possible to withdraw the entire contents.

As with all intramuscular preparations, ceftriaxone for injection should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel.

Vial Dosage SizeAmount of Diluent to be Added
250 mg/mL

350 mg/mL

250 mg 0.9 mL

--

500 mg1.8 mL

1.0 mL

1 g3.6 mL2.1 mL
2 g7.2 mL4.2 mL

Intravenous Administration:

Ceftriaxone for injection should be administered intravenously by infusion over a period of 30 minutes. Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. Reconstitute vials with an appropriate IV diluent (see COMPATIBILITY AND STABILITY ).

 

Vial Dosage SizeAmount of Diluent to be Added
250 mg2.4 mL
500 mg4.8 mL
1 g9.6 mL
2 g19.2 mL

After reconstitution, each 1 mL of solution contains approximately 100 mg equivalent of ceftriaxone. Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent.

COMPATIBILITY AND STABILITY:

Ceftriaxone has been shown to be compatible with Flagyl®*IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl®*IV RTU® or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.

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.

Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone for injection. Particulate formation can result.

Ceftriaxone solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (see WARNINGS).

Ceftriaxone for injection sterile powder should be stored at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

Ceftriaxone for injection intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods:


Diluent

Concentration

mg/mL
Storage

Room Temp.

(25°C)

Refrigerated

(4°C)

Sterile Water for Injection

100

250, 350

2 days

24 hours

10 days

3 days

0.9% Sodium Chloride

Solution

100

250, 350

2 days

24 hours

10 days

3 days

5% Dextrose Solution

100

250, 350

2 days

24 hours

10 days

3 days

Bacteriostatic Water

+ 0.9% Benzyl Alcohol

100

250, 350

24 hours

24 hours

10 days

3 days

1% Lidocaine Solution

(without epinephrine)

100

250, 350

24 hours

24 hours

10 days

3 days

Ceftriaxone for injection intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers:

*
Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only.
DiluentStorage
Room Temp. (25°C)Refrigerated (4°C)
Sterile Water2 days10 days
0.9% Sodium Chloride Solution2 days10 days
5% Dextrose Solution2 days10 days
10% Dextrose Solution2 days10 days
5% Dextrose + 0.9% Sodium Chloride Solution*2 daysIncompatible
5% Dextrose + 0.45% Sodium Chloride Solution2 daysIncompatible

The following intravenous ceftriaxone for injection solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).

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

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

Ceftriaxone for injection reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks.

Frozen solutions should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.

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 is supplied as a sterile crystalline powder in glass vials. The following packages are available:

Vials containing 1 g equivalent of ceftriaxone. Box of 10 (NDC 10019-098-01).

CLINICAL STUDIES:  

Clinical Trials in Pediatric Patients With Acute Bacterial Otitis Media:

In two adequate and well controlled U.S. clinical trials a single IM dose of ceftriaxone was compared with a 10 day course of oral antibiotic in pediatric patients between the ages of 3 months and 6 years. The clinical cure rates and statistical outcome appear in the table below:

Clinical Efficacy in Evaluable Population
Study DayCeftriaxone Single DoseComparator – 10 days of Oral Therapy95% Confidence IntervalStatistical Outcome

Study 1 – U.S.

14

28


74% (220/ 296)

58% (167/ 288)

amoxicillin/ clavulanate
82% (247/302)

67% (200/ 297)


(-14.4%, -0.5%)

(-17.5%, -1.2%)

Ceftriaxone is lower than control at study day 14 and 28

Study 2 – U.S.5 14

28


54% (113/ 210)

35% (73/ 206)

TMP-SMZ

60% (124/ 206)

45% (93/ 205)


(-16.4%, 3.6%)

(-19.9%, 0.0%)

Ceftriaxone is equivalent to control at study day 14 and 28.

An open-label bacteriologic study of ceftriaxone without a comparator enrolled 108 pediatric patients, 79 of whom had positive baseline cultures for one or more of the common pathogens. The results of this study are tabulated as follows:

Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by pathogen:

Organism

Study Day 13-15Study Day 30+2
No. AnalyzedNo. Erad. (%)No. AnalyzedNo. Erad. (%)
Streptococcus pneumoniae3832 (84)3525 (71)
Haemophilus influenzae3328 (85)3122 (71)
Moraxella catarrhalis1512 (80)159 (60)

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 Disc Susceptibility Test; 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.
  5. Barnett ED, Teele DW, Klein JO, et al. Comparison of Ceftriaxone and Trimethoprim-Sulfamethoxazole for Acute Otitis Media. Pediatrics. Vol. 99, No.1, January 1997.

*Flagyl and IV RTU are Registered trademarks of G.D.Searle & Co.

Manufactured for: Amerinet Choice

St. Louis, MO 63146

By Lupin Limited

Mumbai 400 098 INDIA

For Product Inquiry 1 800 ANA Drug (1-800-262-3784)

Revised: December, 2007 ID#: 212326 460-594-01

PACKAGE LABEL.PRINCIPLE DISPLAY PANEL

Ceftriaxone for Injection USP Vial Label

Ceftriaxone for Injection USP Vial Label

NDC 10019-098-71

Ceftriaxone

for Injection USP

1 g

For I.M. or I.V. Use

Rx only Single Use Vial

Each vial contains sterile

ceftriaxone sodium USP

equivalent to ceftriaxone 1 g

 Mfd. for Amerinet Choice

by Lupin Limited

Mumbai 400 098 INDIA

For I.M. Administration: Reconstitute with 2.1 mL

1% Lidocaine Hydrochloride Injection (USP) or Sterile

Water for Injection (USP). Each 1 mL of solution contains

approximately 350 mg equivalent of ceftriaxone.

For I.V. Administration: See package insert.

USUAL DOSAGE: See package insert.

Storage Prior to Reconstitution:

Store powder at 20°-25°C (68°-77°F)

[See USP Controlled Room Temperature].

Storage After Reconstitution: See package insert.

PROTECT FROM LIGHT

Code No. MP/DRUGS/28/18/88

460-592-00

(01)00310019098715

Lot No:

Exp:

Ceftrixone for Injection USP Shelf-Pack Label

Ceftrixone for Injection USP Shelf-Pack Label

NDC 10019-098-01

Ceftriaxone for Injection USP

1 g

For Intramuscular or Intravenous Use

Rx only

Each vial contains sterile ceftriaxone sodium USP

equivalent to ceftriaxone 1 g

10 Vials Single Use Vials

Amerinet Choice

Manufactured for Amerinet Choice

St. Louis, MO 63146

by Lupin Limited

Mumbai 400 098 INDIA

Directions for Use:

For I.M. Administration: Reconstitute with 2.1 mL 1 %

Lidocaine Hydrochloride Injection (USP) or Sterile Water

for Injection (USP). Each 1 mL of solution contains

approximately 350 mg equivalent of ceftriaxone.

For I.V. Administration: Reconstitute with 9.6 mL of

an I.V. diluent specified in the accompanying package

insert. Each 1 mL of solution contains approximately

100 mg equivalent of ceftriaxone. Withdraw entire

contents and dilute to the desired concentration with

the appropriate I.V. diluent.

USUAL DOSAGE:

For dosage recommendations and other important

prescribing information, read accompanying insert.

Storage Prior to Reconstitution:

Store powder at 20°-25°C (68°-77°F) [See USP

Controlled Room Temperature].

Storage After Reconstitution: See package insert.

PROTECT FROM LIGHT


ROCEPHIN 
ceftriaxone sodium   injection, powder, for solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)10019-098
Route of AdministrationINTRAVENOUS, INTRAMUSCULARDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
CEFTRIAXONE SODIUM (CEFTRIAXONE) CEFTRIAXONE SODIUM1 g
Inactive Ingredients
Ingredient NameStrength
No Inactive Ingredients Found
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
110019-098-0110 VIAL In 1 BOXcontains a VIAL (10019-098-71)
110019-098-711 VIAL In 1 VIALThis package is contained within the BOX (10019-098-01)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA06512509/30/2003

Labeler - BAXTER HEALTHCARE CORPORATION (005083209)
Registrant - BAXTER HEALTHCARE CORPORATION (005083209)
Establishment
NameAddressID/FEIOperations
LUPIN LIMITED725504448MANUFACTURE
Revised: 12/2009BAXTER HEALTHCARE CORPORATION