Ceftriaxone

CEFTRIAXONE- ceftriaxone sodium injection, solution
Baxter Healthcare Corporation

Rx Only

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

DESCRIPTION

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

The chemical formula of ceftriaxone sodium is C18 H16 N8 Na2 O7 S3 •7/2 H2 O. It has a calculated molecular weight of 661.60 and the following structural formula:

Chemical formulation for ceftriaxone sodium
(click image for full-size original)

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

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

Ceftriaxone Injection, USP is supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution premixed in a dextrose diluent. Dextrose, USP has been added to adjust the osmolality (approximately 1.9 g and 1.2 g as dextrose hydrous to the 1 g and 2 g dosages, respectively). The pH may be adjusted with sodium hydroxide and/or hydrochloric acid. Solutions of premixed Ceftriaxone Injection, USP may range from light yellow to amber in color. After thawing, the solution is intended for intravenous use. The pH of thawed solutions may range from 6.0 to 8.0. See HOW SUPPLIED for package description.

The plastic container for the frozen solution is fabricated from a specially designed multilayer plastic, PL 2040. Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers as well as by tissue culture toxicity studies.

CLINICAL PHARMACOLOGY

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

Table 1
*
IV doses were infused at a constant rate over 30 minutes.

Ceftriaxone Plasma Concentrations After Single Dose Administration

Dose/Route

Average Plasma Concentrations (mcg/mL)

0.5 hr

1 hr

2 hr

4 hr

6 hr

8 hr

12 hr

16 hr

24 hr

0.5 gm IV *

82

59

48

37

29

23

15

10

5

1 gm IV *

151

111

88

67

53

43

28

18

9

2 gm IV *

257

192

154

117

89

74

46

31

15

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

Ceftriaxone concentrations in urine are shown in Table 2.

Table 2

Urinary Concentrations of Ceftriaxone After Single Dose Administration

Dose/Route

Average Urinary Concentrations (mcg/mL)

0-2 hr

2-4 hr

4-8 hr

8-12 hr

12-24 hr

24-48 hr

0.5 gm IV

526

366

142

87

70

15

1 gm IV

995

855

293

147

132

32

2 gm IV

2692

1976

757

274

198

40

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

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

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

Table 3

Average Pharmacokinetic Parameters of Ceftriaxone in Pediatric Patients With Meningitis

50 mg/kg IV

75 mg/kg IV

Maximum Plasma Concentrations (mcg/mL)

216

275

Elimination Half-life (hr)

4.6

4.3

Plasma Clearance (mL/hr/kg)

49

60

Volume of Distribution (mL/kg)

338

373

CSF Concentration — inflamed meninges (mcg/mL)

5.6

6.4

Range (mcg/mL)

1.3-18.5

1.3-44

Time after dose (hr)

3.7 (± 1.6)

3.3 (± 1.4)

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

Table 4
*
Creatinine clearance.

Average Pharmacokinetic Parameters of Ceftriaxone in Humans

Subject Group

Elimination Half-life (hr)

Plasma Clearance (L/hr)

Volume of Distribution (L)

Healthy Subjects

5.8-8.7

0.58-1.45

5.8-13.5

Elderly Subjects (mean age, 70.5 yr)

8.9

0.83

10.7

Patients With Renal Impairment

Hemodialysis Patients (0-5 mL/min)*

14.7

0.65

13.7

Severe (5-15 mL/min)

15.7

0.56

12.5

Moderate (16-30 mL/min)

11.4

0.72

11.8

Mild (31-60 mL/min)

12.4

0.70

13.3

Patients With Liver Disease

8.8

1.1

13.6

The elimination of ceftriaxone is not altered when Ceftriaxone Injection, USP is co-administered with probenecid.

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