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, 7^² -(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:

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.