CEFTRIAXONE SODIUM injection, powder, for solution

Ceftriaxone Sodium by

Drug Labeling and Warnings

Ceftriaxone Sodium by is a Prescription medication manufactured, distributed, or labeled by NuCare Pharmceuticals,Inc., NuCare Pharmaceuticals,Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

SPL UNCLASSIFIED SECTION

Rx only

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 bacteria.

DESCRIPTION

Ceftriaxone for injection, USP is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone sodium is (6 R, 7 R)-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, 7 2-( Z)-( O-methyloxime), disodium salt, sesquaterhydrate.

The chemical formula of ceftriaxone sodium is C 18H 16N 8Na 2O 7S 33.5H 2O. It has a calculated molecular weight of 661.60 and the following structural formula:

Ceftriaxone sodium is a white to yellowish 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, concentration and diluent used. Each vial contains ceftriaxone sodium equivalent to 250 mg, 500 mg, 1 gram or 2 grams of ceftriaxone activity. Ceftriaxone sodium 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

* IV doses were infused at a constant rate over 30 minutes.
	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
0.5 g IV *	82	59	48	37	29	23	15	10	5
0.5 g IM 250 mg/mL	22	33	38	35	30	26	16	ND	5
0.5 g IM 350 mg/mL	20	32	38	34	31	24	16	ND	5
1 g IV *	151	111	88	67	53	43	28	18	9
1 g IM	40	68	76	68	56	44	29	ND	ND
2 g lV *	257	192	154	117	89	74	46	31	15
ND = Not determined.

Ceftriaxone 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 above single dose values.

Ceftriaxone concentrations in urine are shown in Table 2.

Table 2. Urinary Concentrations of Ceftriaxone After Single Dose Administration

Dose/Route	Average Urinary Concentrations (mcg/mL)
	0 to 2 hr	2 to 4 hr	4 to 8 hr	8 to 12 hr	12 to 24 hr	24 to 48 hr
0.5 g IV	526	366	142	87	70	15
0.5 g IM	115	425	308	127	96	28
1 g IV	995	855	293	147	132	32
1 g IM	504	628	418	237	ND	ND
2 g IV	2692	1976	757	274	198	40
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 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 to 18.5	1.3 to 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 six of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced.

Table 4. Average Pharmacokinetic Parameters of Ceftriaxone in Humans

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

The elimination of ceftriaxone is not altered when ceftriaxone is co-administered with probenecid.

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.

Interaction with Calcium

Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 grams ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxone-calcium precipitation.

Microbiology

Mechanism of Action

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

Mechanism of Resistance

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

Interaction with Other Antimicrobials

In an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone.

Antibacterial Activity

Ceftriaxone has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE (1) section:

• Gram-negative bacteria
  Acinetobactercalcoaceticus
  Enterobacteraerogenes
  Enterobacter cloacae
  Escherichia coli
  Haemophilusinfluenzae
  Haemophilusparainfluenzae
  Klebsiellaoxytoca
  Klebsiellapneumoniae
  Moraxella catarrhalis
  Morganellamorganii
  Neisseria gonorrhoeae
  Neisseria meningitidis
  Proteus mirabilis
  Proteus vulgaris
  Pseudomonas aeruginosa
  Serratiamarcescens
• Gram-positive bacteria
  Staphylococcus aureus
  Staphylococcus epidermidis
  Streptococcus pneumoniae
  Streptococcus pyogenes
  Viridans group streptococci
• Anaerobic bacteria
  Bacteroidesfragilis
  Clostridium species
  Peptostreptococcus species

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

• Gram-negative bacteria
  Citrobacterdiversus
  Citrobacterfreundii
  Providencia species (including Providenciarettgeri)
  Salmonella species (including Salmonella typhi)
  Shigella species
• Gram-positive bacteria
  Streptococcus agalactiae
• Anaerobic bacteria
  Porphyromonas (Bacteroides) melaninogenicus
  Prevotella (Bacteroides) bivius

Susceptibility Test Methods

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

Dilution techniques: Quantitative methods 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 test method. 1,3 The MIC values should be interpreted according to criteria provided in Table 5.

Diffusion techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. 2,3 This procedure uses paper disks impregnated with 30 mcg ceftriaxone to test the susceptibility of microorganisms to ceftriaxone. The disk diffusion interpretive criteria are provided in Table 5.

Anaerobic techniques: For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by a standardized agar test method. 3,4 The MIC values obtained should be interpreted according to the criteria provided in Table 5.

Table 5. Susceptibility Test Interpretive Criteria for Ceftriaxone.

* Susceptibility interpretive criteria for Enterobacteriaceae are based on a dose of 1 gram IV q 24h. For isolates with intermediate susceptibility, use a dose of 2 grams IV q 24h in patients with normal renal function. † For Haemophilus influenzae, susceptibility interpretive criteria are based on a dose of 2 grams IV every 24 hours in patients with normal renal function. ‡ The current absence of data on resistant isolates precludes defining any category other than ‘Susceptible’. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing. § 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.
Pathogen	Minimum Inhibitory Concentrations (mcg/ml)			Disk Diffusion Zone Diameters (mm)
	(S) Susceptible	(I) Intermediate	(R) Resistant	(S) Susceptible	(I) Intermediate	(R) Resistant
Enterobacteriaceae*	≤ 1	2	≥ 4	≥ 23	20 to 22	≤ 19
Haemophilus; influenzae †, ‡	≤ 2	-	-	≥ 26	-	-
Neisseria gonorrhoeae‡	≤ 0.25	-	-	≥ 35	-	-
Neisseria meningitidis‡	≤ 0.12	-	-	≥ 34	-	-
Streptococcus; pneumoniae § meningitis isolates	≤ 0.5	1	≥ 2	-	-	-
Streptococcus; pneumoniae§ non-meningitis isolates	≤ 1	2	≥ 4	-	-	-
Streptococcus species beta-hemolytic group ‡	≤ 0.5	-	-	≥ 24	-	-
Viridans group streptococci	≤ 1	2	≥ 4	≥ 27	25 to 26	≤ 24
Anaerobic bacteria (agar method)	≤ 1	2	≥ 4	-	-	-

Susceptibility of staphylococci to ceftriaxone may be deduced from testing only penicillin and either cefoxitin or oxacillin.

A report of Susceptible indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration at the site of infection. A report of Intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. 1,2,3,4 Standard ceftriaxone powder should provide the following range of MIC values noted in Table 6. For the diffusion technique using the 30 mcg disk, the criteria in Table 6 should be achieved.

Table 6. Acceptable Quality Control Ranges for Ceftriaxone

QC Strain	Minimum Inhibitory Concentrations (mcg/mL)	Disk Diffusion Zone diameters (mm)
Escherichia coli ATCC 25922	0.03 to 0.12	29 to 35
Staphylococcus aureus ATCC 25923	----------	22 to 28
Staphylococcus aureus ATCC 29213	1 to 8	---------
Haemophilusinfluenzae ATCC 49247	0.06 to 0.25	31 to 39
Neisseria gonorrhoeae ATCC 49226	0.004 to 0.015	39 to 51
Pseudomonas aeruginosa ATCC 27853	8 to 64	17 to 23
Streptococcus pneumoniae ATCC 49619	0.03 to 0.12	30 to 35
Bacteroidesfragilis ATCC 25285 (agar method)	32 to 128	---------
Bacteroidesthetaiotaomicron ATCC 29741 (agar method)	64 to 256	---------

INDICATIONS AND USAGE

Before instituting treatment with ceftriaxone, 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, USP and other antibacterial drugs, ceftriaxone for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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

Lower Respiratory Tract Infections

caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilusinfluenzae, Haemophilusparainfluenzae, Klebsiellapneumoniae, Escherichia coli, Enterobacteraerogenes, Proteus mirabilis or Serratiamarcescens.

Acute Bacterial Otitis Media

caused by Streptococcus pneumoniae, Haemophilusinfluenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains).

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

Skin and Skin Structure Infections

caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci, Escherichia coli, Enterobacter cloacae, Klebsiellaoxytoca, Klebsiellapneumoniae, Proteus mirabilis, Morganellamorganii,1 Pseudomonas aeruginosa, Serratiamarcescens, Acinetobactercalcoaceticus, Bacteroidesfragilis2 or Peptostreptococcus species.

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

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

Urinary Tract Infections (complicated and uncomplicated)

caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganellamorganii or Klebsiellapneumoniae.

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 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, Haemophilusinfluenzae or Klebsiellapneumoniae.

Bone and Joint Infections

caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiellapneumoniae or Enterobacter species.

Intra-abdominal Infections

caused by Escherichia coli, Klebsiellapneumoniae, Bacteroidesfragilis, Clostridium species (Note: most strains of Clostridium difficile are resistant) or Peptostreptococcus species.

Meningitis

caused by Haemophilusinfluenzae, Neisseria meningitidis or Streptococcus pneumoniae. Ceftriaxone has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis3 and Escherichia coli. 4

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

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

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