Drug Detail:Rocephin injection (Ceftriaxone (injection) [ sef-trye-ax-one ])
Drug Class: Third generation cephalosporins
Rocephin - Clinical Pharmacology
Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0.5, 1 or 2 gm dose and intramuscular (IM) administration of a single 0.5 (250 mg/mL or 350 mg/mL concentrations) or 1 gm dose in healthy subjects are presented in Table 1.
| Dose/Route | Average Plasma Concentrations (µg/mL) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 0.5 hr | 1 hr | 2 hr | 4 hr | 6 hr | 8 hr | 12 hr | 16 hr | 24 hr | |
| ND = Not determined. | |||||||||
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| 0.5 gm IV* | 82 | 59 | 48 | 37 | 29 | 23 | 15 | 10 | 5 |
| 0.5 gm IM | |||||||||
| 250 mg/mL | 22 | 33 | 38 | 35 | 30 | 26 | 16 | ND | 5 |
| 0.5 gm IM | |||||||||
| 350 mg/mL | 20 | 32 | 38 | 34 | 31 | 24 | 16 | ND | 5 |
| 1 gm IV* | 151 | 111 | 88 | 67 | 53 | 43 | 28 | 18 | 9 |
| 1 gm IM | 40 | 68 | 76 | 68 | 56 | 44 | 29 | ND | ND |
| 2 gm 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 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.
| Dose/Route | Average Urinary Concentrations (µg/mL) | |||||
|---|---|---|---|---|---|---|
| 0-2 hr | 2-4 hr | 4-8 hr | 8-12 hr | 12-24 hr | 24-48 hr | |
| ND = Not determined. | ||||||
| 0.5 gm IV | 526 | 366 | 142 | 87 | 70 | 15 |
| 0.5 gm IM | 115 | 425 | 308 | 127 | 96 | 28 |
| 1 gm IV | 995 | 855 | 293 | 147 | 132 | 32 |
| 1 gm IM | 504 | 628 | 418 | 237 | ND | ND |
| 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 µg/mL in the gallbladder bile, 788 µg/mL in the common duct bile, 898 µg/mL in the cystic duct bile, 78.2 µg/gm in the gallbladder wall and 62.1 µg/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 µg/mL to a value of 85% bound at 300 µg/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.
| 50 mg/kg IV | 75 mg/kg IV | |
|---|---|---|
| Maximum Plasma Concentrations (µg/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 (µg/mL) | 5.6 | 6.4 |
| Range (µg/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 six 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) |
|---|---|---|---|
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| 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 Rocephin is co-administered with probenecid.
Microbiology
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Anaerobic techniques:
For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by a standardized agar test method 3,4. The MIC values obtained should be interpreted according to the criteria provided in Table 5.
| Pathogen | Minimum Inhibitory Concentrations (mcg/ml) | Disk Diffusion Zone Diameters (mm) |
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|---|---|---|---|---|---|---|
| (S) Susceptible | (I) Intermediate | (R) Resistant | (S) Susceptible | (I) Intermediate | (R) Resistant | |
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| Enterobacteriaceae* | ≤ 1 | 2 | ≥4 | ≥ 23 | 20-22 | ≤19 |
| Haemophilus influenzae†,‡ | ≤2 | - | - | ≥26 | - | - |
| Neisseria gonorrhoeae* | ≤ 0.25 | - | - | ≥ 35 | - | - |
| Neisseria meningitidis‡ | ≤ 0.12 | - | - | ≥ 34 | - | - |
| Streptococcus pneumoniae § meningitis isolates | ≤ 0.5 | 1 | ≥ 2 | - | - | - |
| Streptococcus pneumoniae § non-meningitis isolates | ≤1 | 2 | ≥4 | - | - | - |
| Streptococcus species beta-hemolytic group‡ | ≤0.5 | - | - | ≥ 24 | - | - |
| Viridans group streptococci | ≤ 1 | 2 | ≥ 4 | ≥27 | 25-26 | ≤24 |
| Anaerobic bacteria (agar method) | ≤ 1 | 2 | ≥ 4 | - | - | - |
Susceptibility of staphylococci to ceftriaxone may be deduced from testing only penicillin and either cefoxitin or oxacillin.
A report of Susceptible indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration at the site of infection. A report of Intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Quality Control:
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test 1,2,3,4. Standard ceftriaxone powder should provide the following range of MIC values noted in Table 6. For the diffusion technique using the 30 mcg disk, the criteria in Table 6 should be achieved.
| QC Strain | Minimum Inhibitory Concentrations (mcg/mL) | Disk Diffusion Zone diameters (mm) |
|---|---|---|
| Escherichia coli ATCC 25922 | 0.03 - 0.12 | 29 - 35 |
| Staphylococcus aureus ATCC 25923 | ---------- | 22 - 28 |
| Staphylococcus aureus ATCC 29213 | 1 – 8 | --------- |
| Haemophilus influenzae ATCC 49247 | 0.06 - 0.25 | 31 - 39 |
| Neisseria gonorrhoeae ATCC 49226 | 0.004 - 0.015 | 39 - 51 |
| Pseudomonas aeruginosa ATCC 27853 | 8-64 | 17-23 |
| Streptococcus pneumoniae ATCC 49619 | 0.03 - 0.12 | 30 - 35 |
| Bacteroides fragilis ATCC 25285 (agar method) | 32 – 128 | --------- |
| Bacteroides thetaiotaomicron ATCC 29741 (agar method) | 64 – 256 | --------- |
Indications and Usage for Rocephin
Before instituting treatment with Rocephin, 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 Rocephin and other antibacterial drugs, Rocephin 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.
Rocephin is indicated for the treatment of the following infections when caused by susceptible organisms:
LOWER RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.
ACUTE BACTERIAL OTITIS MEDIA caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains).
NOTE: In one study lower clinical cure rates were observed with a single dose of Rocephin compared to 10 days of oral therapy. In a second study comparable cure rates were observed between single dose Rocephin and the comparator. The potentially lower clinical cure rate of Rocephin should be balanced against the potential advantages of parenteral therapy (see CLINICAL STUDIES).
SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci, Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii,1 Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis1 or Peptostreptococcus species.
URINARY TRACT INFECTIONS (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae.
UNCOMPLICATED GONORRHEA (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae.
PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae. Rocephin, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and Chlamydia trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added.
BACTERIAL SEPTICEMIA caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae.
BONE AND JOINT INFECTIONS caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species.
INTRA-ABDOMINAL INFECTIONS caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most strains of Clostridium difficile are resistant) or Peptostreptococcus species.
MENINGITIS caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae. Rocephin has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis1 and Escherichia coli.1
- 1
- Efficacy for this organism in this organ system was studied in fewer than ten infections.
Warnings
Hypersensitivity Reactions
Before therapy with Rocephin is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. This product should be given cautiously to penicillin and other beta-lactam agent-sensitive patients. Antibacterial drugs should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. Serious acute hypersensitivity reactions may require the use of subcutaneous epinephrine and other emergency measures.
As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i.e., anaphylaxis) have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated.
Adverse Reactions/Side Effects
Rocephin is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to Rocephin therapy or of uncertain etiology, were observed:
LOCAL REACTIONS—pain, induration and tenderness was 1% overall. Phlebitis was reported in <1% after IV administration. The incidence of warmth, tightness or induration was 17% (3/17) after IM administration of 350 mg/mL and 5% (1/20) after IM administration of 250 mg/mL.
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS—injection site pain (0.6%).
HYPERSENSITIVITY—rash (1.7%). Less frequently reported (<1%) were pruritus, fever or chills.
INFECTIONS AND INFESTATIONS—genital fungal infection (0.1%).
HEMATOLOGIC—eosinophilia (6%), thrombocytosis (5.1%) and leukopenia (2.1%). Less frequently reported (<1%) were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.
BLOOD AND LYMPHATIC DISORDERS—granulocytopenia (0.9%), coagulopathy (0.4%).
GASTROINTESTINAL—diarrhea/loose stools (2.7%). Less frequently reported (<1%) were nausea or vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS).
HEPATIC—elevations of aspartate aminotransferase (AST) (3.1%) or alanine aminotransferase (ALT) (3.3%). Less frequently reported (<1%) were elevations of alkaline phosphatase and bilirubin.
RENAL—elevations of the BUN (1.2%). Less frequently reported (<1%) were elevations of creatinine and the presence of casts in the urine.
CENTRAL NERVOUS SYSTEM—headache or dizziness were reported occasionally (<1%).
GENITOURINARY—moniliasis or vaginitis were reported occasionally (<1%).
MISCELLANEOUS—diaphoresis and flushing were reported occasionally (<1%).
INVESTIGATIONS—blood creatinine increased (0.6%).
Other rarely observed adverse reactions (<0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, a decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.
Rocephin Dosage and Administration
Rocephin may be administered intravenously or intramuscularly.
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Rocephin vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when Rocephin is mixed with calcium-containing solutions in the same IV administration line. Rocephin must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, Rocephin and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see WARNINGS).
There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).
Compatibility and Stability
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Rocephin vials or to further dilute a reconstituted vial for IV administration. Particulate formation can result.
Ceftriaxone has been shown to be compatible with Flagyl® IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl® IV RTU® (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.
Vancomycin, amsacrine, aminoglycosides, and fluconazole are incompatible with ceftriaxone in admixtures. When any of these drugs are to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.
Rocephin solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (see WARNINGS).
Rocephin sterile powder should be stored at room temperature—77°F (25°C)—or below and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.
Rocephin intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods:
| Storage | |||
|---|---|---|---|
| Diluent | Concentration mg/ml | Room Temp. (25°C) | Refrigerated (4°C) |
| Sterile Water for Injection | 100 250, 350 | 2 days 24 hours | 10 days 3 days |
| 0.9% Sodium Chloride Solution | 100 250, 350 | 2 days 24 hours | 10 days 3 days |
| 5% Dextrose Solution | 100 250, 350 | 2 days 24 hours | 10 days 3 days |
| Bacteriostatic Water + 0.9% Benzyl Alcohol | 100 250, 350 | 24 hours 24 hours | 10 days 3 days |
| 1% Lidocaine Solution (without epinephrine) | 100 250, 350 | 24 hours 24 hours | 10 days 3 days |
Rocephin intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers:
| Storage | ||
|---|---|---|
| Diluent | Room Temp. (25°C) | Refrigerated (4°C) |
|
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| Sterile Water | 2 days | 10 days |
| 0.9% Sodium Chloride Solution | 2 days | 10 days |
| 5% Dextrose Solution | 2 days | 10 days |
| 10% Dextrose Solution | 2 days | 10 days |
| 5% Dextrose + 0.9% Sodium Chloride Solution* | 2 days | Incompatible |
| 5% Dextrose + 0.45% Sodium Chloride Solution | 2 days | Incompatible |
The following intravenous Rocephin solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).
After the indicated stability time periods, unused portions of solutions should be discarded.
NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.
Rocephin reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks.
Frozen solutions of Rocephin should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.
How is Rocephin supplied
Rocephin is supplied as a sterile crystalline powder in glass vials. The following packages are available:
Vials containing 500 mg equivalent of ceftriaxone. Box of 1 (NDC 0004-1963-02) and box of 10 (NDC 0004-1963-01).
Vials containing 1 gm equivalent of ceftriaxone. Box of 1 (NDC 0004-1964-04) and box of 10 (NDC 0004-1964-01).
| ROCEPHIN
ceftriaxone sodium injection, powder, for solution |
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| ROCEPHIN
ceftriaxone sodium injection, powder, for solution |
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| Labeler - Genentech, Inc. (080129000) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| F. Hoffmann-La Roche Ltd | 485244961 | MANUFACTURE(0004-1963, 0004-1964) , ANALYSIS(0004-1963, 0004-1964) | |
