Easy-Ceft 1g: Package Insert and Label Information

EASY-CEFT 1G- ceftriaxone
American Health RX, LLC

CEFTRIAXONE FOR INJECTION, USP

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 (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 C18H16N8Na2O7S3•3.5H2O. It has a calculated molecular weight of 661.60 and the following structural

formula:

Molecular Diagram
(click image for full-size original)

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

Clinical Pharmacology

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

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 g IV*

82

59

48

37

29

23

15

10

5

0.5 g IM

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

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


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
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 Pharmacoklnetlc Parameters of Ceftrlaxone In Pediatric Patients With Meningitis

50 mg/kg IV 75 mg/kg IV
Maximum Concentration (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)

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

*Creatinine clearance

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

Pharmacoklnetlcs In the Middle Ear Fluid:

Pharmacokinetics In the Middle Ear Fluid:

n 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.

Interaction With Calcium

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.

Mechanism of Action:

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:

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.

Susceptibility Testing

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and
associated test methods and quality control standards recognized by FDA
for this drug, please see: https://www.fda.gov/STIC.

Antibacterial Activity

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 section:
• Gram-negative bacteria
Acinetobacter calcoaceticus
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella oxytoca
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Neisseria gonorrhoeae
Neisseria meningitidis
Proteus mirabilis
Proteus vulgaris
Pseudomonas aeruginosa
Serratia marcescens
• Gram-positive bacteria
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pyogenes
Viridans group streptococci
• Anaerobic bacteria
Bacteroides fragilis
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
Citrobacter diversus
Citrobacter freundii
Providencia species (including Providencia rettgen)
Salmonella species (including Salmonella typhi)
Shigella species
• Gram-positive bacteria
Streptococcus agalactiae
• Anaerobic bacteria
Porphyromonas (Bacteroides) melaninogenicus
Prevotefla (Bacteroides) bivius

INDICATIONS AND USAGE

INDICATIONS AND USAGE

Before instituting treatment with Ceftriaxone for Injection, USP, 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:

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