CEFTRIAXONE- ceftriaxone sodium injection, powder, for solution
Xellia Pharmaceuticals USA LLC
|PHARMACY BULK PACKAGENOT FOR DIRECT INFUSION|
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.
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 661.60 and the following structural formula:
Ceftriaxone 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 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 Pharmacy Bulk Package bottles containing sterile ceftriaxone sodium, USP equivalent to 10 grams of ceftriaxone and is intended for intravenous infusion only. Ceftriaxone sodium contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity.
A Pharmacy Bulk Package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion. FURTHER DILUTION IS REQUIRED BEFORE USE. (See DOSAGE AND ADMINISTRATION, and DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE.)
Average plasma concentrations of ceftriaxone following a single 30-minute intravenous infusion of a 0.5, 1 or 2 g dose and intramuscular 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.
|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|
|ND = Not determined.|
|0.5 g Intravenous *||82||59||48||37||29||23||15||10||5|
|0.5 g Intramuscular 250 mg/mL||22||33||38||35||30||26||16||ND||5|
|0.5 g Intramuscular 350 mg/mL||20||32||38||34||31||24||16||ND||5|
|1 g Intravenous *||151||111||88||67||53||43||28||18||9|
|1 g Intramuscular||40||68||76||68||56||44||29||ND||ND|
|2 g Intravenous *||257||192||154||117||89||74||46||31||15|
Ceftriaxone was completely absorbed following intramuscular administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. Multiple intravenous or intramuscular 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.
|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 Intravenous||526||366||142||87||70||15|
|0.5 g Intramuscular||115||425||308||127||96||28|
|1 g Intravenous||995||855||293||147||132||32|
|1 g Intramuscular||504||628||418||237||ND||ND|
|2 g Intravenous||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 intravenous 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 intravenous dose and after a 75 mg/kg intravenous 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 intravenous dose and after a 75 mg/kg intravenous dose are also shown in Table 3.
|50 mg/kgIntravenous||75 mg/kgIntravenous|
|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 6 of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced.
|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.
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