Ceftriaxone Sodium

CEFTRIAXONE SODIUM- ceftriaxone sodium injection, powder, for solution
Qilu Pharmaceutical Co., Ltd.

Rx only

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 bacteria.

DESCRIPTION

Ceftriaxone for injection, USP 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-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 •3.5H₂ O. It has a calculated molecular weight of 661.59 and the following structural formula:

Ceftriaxone for injection, 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. The pH of a 1% aqueous solution is approximately 6.7. The color of Ceftriaxone for injection, USP 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 g or 2 g of ceftriaxone activity.

Ceftriaxone for injection, USP 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/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
* IV doses were infused at a constant rate over 30 minutes.ND = Not determined.
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 IV *	257	192	154	117	89	74	46	31	15

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
ND = Not determined.
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

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

Subject Group	Elimination Half-Life(hr)	Plasma Clearance(L/hr)	Volume of Distribution(L)
* Creatinine clearance.
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 for injection is co-administered with probenecid.