Ceftriaxone (Ceftriaxone sodium) for Injection is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration.

Ceftriaxone (Ceftriaxone sodium) sodium is ()-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo--triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-()-(-methyloxime), disodium salt, sesquaterhydrate.

The chemical formula of Ceftriaxone (Ceftriaxone sodium) sodium is CHNNa0S•3.5H0. It has a calculated molecular weight of 661.60 and the following structural formula:

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

Each Pharmacy Bulk Package is supplied as a dry powder in vials containing sterile Ceftriaxone (Ceftriaxone sodium) sodium equivalent to 10 g of Ceftriaxone (Ceftriaxone sodium) and is intended for intravenous infusion only. Ceftriaxone (Ceftriaxone sodium) sodium contains approximately 83 mg (3.6 mEq) of sodium per gram of Ceftriaxone (Ceftriaxone sodium) activity.

This Pharmacy Bulk Package is for use in a pharmacy admixture service; it provides many single doses of Ceftriaxone (Ceftriaxone sodium) for addition to suitable parenteral fluids in the preparation of admixtures for intravenous infusion.

Average plasma concentrations of Ceftriaxone (Ceftriaxone sodium) 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.

*IV doses were infused at a constant rate over 30 minutes.

ND = Not determined.

Ceftriaxone (Ceftriaxone sodium) was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. 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 (Ceftriaxone sodium) above single dose values.

Ceftriaxone (Ceftriaxone sodium) concentrations in urine are shown in Table 2.

ND = Not determined.

Thirty-three percent to 67% of a Ceftriaxone (Ceftriaxone sodium) 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 (Ceftriaxone sodium) , 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 (Ceftriaxone sodium) is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of

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 (Ceftriaxone sodium) 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.

Compared to that in healthy adult subjects, the pharmacokinetics of Ceftriaxone (Ceftriaxone sodium) 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 (Ceftriaxone sodium) dosages up to 2 g per day. Ceftriaxone (Ceftriaxone sodium) was not removed to any significant extent from the plasma by hemodialysis; in six of 26 dialysis patients, the elimination rate of Ceftriaxone (Ceftriaxone sodium) was markedly reduced.

*Creatinine clearance.

The elimination of Ceftriaxone (Ceftriaxone sodium) is not altered when Ceftriaxone (Ceftriaxone sodium) is co-administered with probenecid.

In an study antagonistic effects have been observed with the combination of chloramphenicol and Ceftriaxone (Ceftriaxone sodium) .

Ceftriaxone (Ceftriaxone sodium) has been shown to be active against most strains of the following microorganisms, both and in clinical infections described in the section.

Aerobic gram-negative microorganisms:

Ceftriaxone (Ceftriaxone sodium) is also active against many strains of

NOTE: Many strains of the above organisms that are resistant to multiple antibiotics, e.g., penicillins, cephalosporins, and aminoglycosides, are susceptible to Ceftriaxone (Ceftriaxone sodium) .

Aerobic gram-positive microorganisms:

Viridans group streptococci

NOTE: Methicillin-resistant staphylococci are resistant to cephalosporins, including Ceftriaxone (Ceftriaxone sodium) . Most strains of Group D streptococci and enterococci, eg, are resistant.

Anaerobic microorganisms:

NOTE: Most strains of are resistant.

The following data are available, Ceftriaxone (Ceftriaxone sodium) exhibits minimal inhibitory concentrations (MICs) of 1 mcg/mL or less against most strains of the following microorganisms, however, the safety and effectiveness of Ceftriaxone (Ceftriaxone sodium) in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-negative microorganisms:

Aerobic gram-positive microorganisms:

Anaerobic microorganisms:

The MIC values for aerobic organisms should be interpreted according to the following criteria:

For :

 

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

 

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

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

The following interpretive criteriashould be used when testing on Mueller-Hinton agar with 5% defribrinated sheep blood.

The absence of resistant neisserial 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.

When testing (methicillin-susceptible, MSSA) the following interpretive criteria should be applied:

For staphylococcal infections, a daily dose of 2 to 4 grams should be administered to achieve > 90% target attainment (see).

The following interpretive criteria should be used when testing using Mueller-Hinton broth with 2 to 5% lysed horse blood:

Meningitis:

Non-meningitis infections:

For β-hemolytic streptococci the following interpretive criteria should be used when testing on cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

For the Viridians Group streptococci the following interpretive criteria should be applied:

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 (Ceftriaxone sodium) powder should provide the following MIC values: 

 * 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.

Reports from the laboratory providing results of the standard single-disc susceptibility test with a 30 mcg Ceftriaxone (Ceftriaxone sodium) disc should be interpreted according to the following criteria for aerobic organisms:

 For :

When testing on Haemophilus Test Media (HTM), the following interpretive criteria should be used:

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

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

 For , the following disc diffusion criteria apply:

For (methicillin-susceptible, MSSA), the following interpretive criteria apply:

The following interpretive criteria should be used when testing β-hemolytic streptococci using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO:

  For the Viridians Group streptococci the following criteria apply:

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 (Ceftriaxone sodium) .

Disc diffusion interpretive criteria for Ceftriaxone (Ceftriaxone sodium) discs against 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 (Ceftriaxone sodium) . isolates should not be reported as penicillin (Ceftriaxone (Ceftriaxone sodium) ) resistant or intermediate based solely on an oxacillin zone diameter of 19 mm. The Ceftriaxone (Ceftriaxone sodium) 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 (Ceftriaxone sodium) disc should provide the following zone diameters in these laboratory test quality control strains: 

 

 

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 (Ceftriaxone sodium) powder should provide the following MIC values for the indicated standardized anaerobic dilution testing method:

Before instituting treatment with Ceftriaxone (Ceftriaxone sodium) sodium, 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 (Ceftriaxone sodium) and other antibacterial drugs, Ceftriaxone (Ceftriaxone sodium) 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 (Ceftriaxone sodium) is indicated for the treatment of the following infections when caused by susceptible organisms:

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

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

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

Ceftriaxone (Ceftriaxone sodium) is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.

A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving Ceftriaxone (Ceftriaxone sodium) and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Ceftriaxone (Ceftriaxone sodium) and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom Ceftriaxone (Ceftriaxone sodium) and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates.

 
As with other cephalosporins, anaphylactic reactions with fatal outcome have been reported, even if a patient is not known to be allergic or previously exposed.

Do not use diluents containing
calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute
Ceftriaxone (Ceftriaxone sodium) vials or to further dilute a reconstituted vial for IV administration
because a precipitate can form. Precipitation of Ceftriaxone (Ceftriaxone sodium) -calcium can also
occur when Ceftriaxone (Ceftriaxone sodium) is mixed with calcium-containing solutions in the same
IV administration line. Ceftriaxone (Ceftriaxone sodium) must not be administered simultaneously
with calcium-containing IV solutions, including continuous calcium-containing
infusions such as parenteral nutrition via a Y-site. However, in patients other
than neonates, Ceftriaxone (Ceftriaxone sodium) and calcium-containing solutions may be administered
sequentially of one another if the infusion lines are thoroughly flushed between
infusions with a compatible fluid. studies using adult and neonatal plasma
from umbilical cord blood demonstrated that neonates have an increased risk
of precipitation of Ceftriaxone (Ceftriaxone sodium) -calcium (see ,
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment and surgical evaluation should be instituted as clinically indicated.

Prescribing Ceftriaxone (Ceftriaxone sodium) 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 (Ceftriaxone sodium) is similar to that of other cephalosporins.

Ceftriaxone (Ceftriaxone sodium) is excreted via both biliary and renal excretion (see ). Therefore, patients with renal failure normally require no adjustment in dosage when usual doses of Ceftriaxone (Ceftriaxone sodium) are administered.

Dosage adjustments should not be necessary in patients with hepatic dysfunction: however, in patients with both hepatic dysfunction and signifi cant renal desease, caution should be exercised and the Ceftriaxone (Ceftriaxone sodium) dosage should not exceed 2 g daily.

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

Prolonged use of Ceftriaxone (Ceftriaxone sodium) 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 (Ceftriaxone sodium) should be prescribed with caution in individuals with a history of gastrointestinal disease, especially colitis.

Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported rarely in patients treated with Ceftriaxone (Ceftriaxone sodium) . Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, total parenteral nutrition). A cofactor role of Ceftriaxone (Ceftriaxone sodium) -related biliary precipitation cannot be ruled out.

Patients should be counseled that antibacterial drugs including Ceftriaxone (Ceftriaxone sodium) should only be used to treat bacterial infections. They do not treat viral infections (e.g., common cold). When Ceftriaxone (Ceftriaxone sodium) 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 (Ceftriaxone sodium) 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 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 antibiotic. If this occurs, patients should contact their physician as soon as possible.

Carcinogenesis:
Impairment of Fertility:
Of the total number of subjects in clinical studies of Ceftriaxone (Ceftriaxone sodium) , 32% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics of Ceftriaxone (Ceftriaxone sodium) were only minimally altered in geriatric patients compared to healthy adult subjects and dosage adjustments are not necessary for geriatric patients with Ceftriaxone (Ceftriaxone sodium) dosages up to 2 grams per day (see ).

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

Other rarely observed adverse reactions (

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.

Ceftriaxone (Ceftriaxone sodium) may be administered intravenously or intramuscularly. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for intravenous infusion only. Ceftriaxone (Ceftriaxone sodium) sodium should be administered intravenously by infusion over a period of 30 minutes.

There have been no reports of an interaction between Ceftriaxone (Ceftriaxone sodium) and oral calcium-containing products or interaction between intramuscular Ceftriaxone (Ceftriaxone sodium) and calcium-containing products (IV or oral).

 

Ceftriaxone (Ceftriaxone sodium) is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of Ceftriaxone (Ceftriaxone sodium) -calcium (see ).

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.

If is a suspected pathogen, appropriate antichlamydial coverage should be added, because Ceftriaxone (Ceftriaxone sodium) has no activity against this organism.

Generally, Ceftriaxone (Ceftriaxone sodium) sodium 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 therapy should be continued for at least 10 days.

No dosage adjustment is necessary for patients with impairment of renal or hepatic function.

Ceftriaxone (Ceftriaxone sodium) for Injection USP is supplied as a sterile crystalline powder in Pharmacy Bulk Package as follows:

NOTE: Storage prior to reconstitution: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]