CEFTRIAXONE- ceftriaxone sodium injection, powder, for solution
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CEFTRIAXONE FOR INJECTION safely and effectively. See full prescribing information for CEFTRIAXONE FOR INJECTION.
CEFTRIAXONE FOR INJECTION, USP in ADD-Vantage™ Vial, for intravenous use
Initial U.S. Approval: 1993
RECENT MAJOR CHANGES
Warnings and Precautions, Urolithiasis and post-renal acute renal failure. (5.6) 7/2015
INDICATIONS AND USAGE
Ceftriaxone for Injection is a cephalosporin antibacterial indicated for the treatment of the following infections caused by susceptible isolates of the designated bacteria: Lower Respiratory Tract Infections. (1.1); Acute Bacterial Otitis Media. (1.2); Skin and Skin Structure Infections. (1.3); Complicated and Uncomplicated Urinary Tract Infections. (1.4); Uncomplicated Gonorrhea (cervical/urethral and rectal). (1.5); Pelvic Inflammatory Disease. (1.6); Bacterial Septicemia. (1.7); Bone and Joint Infections. (1.8); Intra-abdominal Infections. (1.9); Meningitis. (1.10); and Surgical Prophylaxis. (1.11).
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.
DOSAGE AND ADMINISTRATION
For intravenous use only over approximately 30 minutes. (2)
Use this formulation of ceftriaxone only in patients who require the entire 1 or 2 gram dose and not any fraction thereof. (2.1)
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
The most common adverse reactions occurring in greater than 2% of patients receiving ceftriaxone include diarrhea, eosinophilia, thrombocytosis, leukopenia, and elevations of SGOT and SGPT. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Hepatic and renal impairment
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
4.1 Anaphylaxis to Ceftriaxone or the Cephalosporin Class of Antibacterials, Penicillins, or Other Betalactam Antibacterials
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.
Ceftriaxone for Injection, USP is indicated for the treatment of the following infections when caused by susceptible bacteria.
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 Ceftriaxone for Injection, USP compared to 10 days of oral therapy. In a second study comparable cure rates were observed between single dose Ceftriaxone for Injection, USP and the comparator. The potentially lower clinical cure rate of Ceftriaxone for Injection, USP should be balanced against the potential advantages of parenteral therapy [see Clinical Studies (14)].
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*, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis* or Peptostreptococcus species.
Complicated and uncomplicated urinary tract infections 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. Ceftriaxone sodium, 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. Ceftriaxone sodium has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis* and Escherichia coli*.
* The efficacy for these organisms in this organ system were studied in fewer than ten infections.
The preoperative administration of a single 1 g dose of Ceftriaxone for Injection, USP may reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated (e.g., vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous cholecystitis in high-risk patients, such as those over 70 years of age, with acute cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common duct bile stones) and in surgical patients for whom infection at the operative site would present serious risk (e.g., during coronary artery bypass surgery). Although ceftriaxone sodium has been shown to have been as effective as cefazolin in the prevention of infection following coronary artery bypass surgery, no placebo-controlled trials have been conducted to evaluate any cephalosporin antibacterial in the prevention of infection following coronary artery bypass surgery.
When administered prior to surgical procedures for which it is indicated, a single 1 g dose of Ceftriaxone for Injection, USP provides protection from most infections due to susceptible organisms throughout the course of the procedure.
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 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 in the ADD-VantageTM Vial is container intended for intravenous infusion only, after dilution with appropriate volume of ADD-Vantage diluent solution.
Ceftriaxone for Injection, USP in the ADD-Vantage Vial container should be used only in patients who require the entire 1 or 2 gram dose and not any fraction thereof. The recommended adult dosages are outlined in Table 1. Ceftriaxone for Injection should be administered intravenously (IV) over approximately 30 minutes.
Generally, Ceftriaxone therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required. When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone 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, ceftriaxone 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 and Precautions (5.2)].
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).
Site and Type of Infection
Total Daily Dose
Usual Adult Dose
1 g to 2 g
once a day or in equally divided doses twice a day
should not exceed 4 g*
1 gram IV once
1/2 to 2 hours before surgery
Skin and Skin Structure Infections
50 to 75 mg per kg
once a day or in equally divided doses every 12 hours
should not exceed 2 g
100 mg per kg
once a day or in equally divided doses every 12 hours
should not exceed 4 g*
Serious Infections other than Meningitis
50 to 75 mg per kg
every 12 hours
should not exceed 2 g
* Patients with hepatic impairment and significant renal impairment should not receive more than 2 grams per day of ceftriaxone.
If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.
For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended. (The above is for informational purposes only. Ceftriaxone in ADD-Vantage vials is not intended for intramuscular use.)
No dosage adjustment is necessary for patients with impairment of renal or hepatic function.
The dosages recommended for adults require no modification in elderly patients, up to 2 gm per day, provided there is no severe renal and hepatic impairment [see Warnings and Precautions (5.7)].
Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone for injection. Ceftriaxone for Injection is contraindicated in premature neonates [see Contraindications (4.2)].
Ceftriaxone is contraindicated in neonates (≤28 days) if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium [see Contraindications (4.2)].
Intravenous doses should be given over 60 minutes in neonates to reduce the risk of bilirubin encephalopathy.
Ceftriaxone for Injection, USP in the ADD-Vantage Vial container is designed to deliver a 1 g or 2 g dose of ceftriaxone. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of ceftriaxone. [see Use in Specific Populations (8.4)]
For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams.
For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended [see Indications and Usage (1.2)]. (The above is for informational purposes only. Ceftriaxone in ADD-Vantage vials is not intended for intramuscular use.)
For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams.
In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.
Ceftriaxone should be administered intravenously by infusion over a period of 30 minutes, except in neonates where administration over 60 minutes is recommended to reduce the risk of bilirubin encephalopathy.
ADD-Vantage Vials for IV use only contain ceftriaxone sodium equivalent to 1 gm or 2 gm Ceftriaxone to be used with 50 mL or 100 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP in the ADD-Vantage Flexible Diluent Container. [see Instructions For Use of the ADD-Vantage™ System (2.6)].
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone for injection. 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.
Solutions of ceftriaxone for injection 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 the possible incompatibility [see Warnings and precautions (5.1)].
Ceftriaxone sodium sterile powder should be stored at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature] 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.
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. ADD-Vantage Vials - Ceftriaxone for Injection Units: [see Instructions For Use of the ADD-Vantage™ System (2.6)].
*Registered trademark of G.D. Searle & Co.
To Open Diluent Container
Peel overwrap at corner and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.
To Assemble Vial and Flexible Diluent Container
(Use Aseptic Technique)
To Reconstitute the Drug
Preparation for Administration: (Use Aseptic Technique)
The ADD-Vantage System is designed to minimize drug waste by allowing the drug and diluent to be mixed at bedside just prior to administration. However, in those rare instances where the admixed unit cannot be administered within the specified time, Ceftriaxone ADD-Vantage units may be safely stored under the following conditions:
0.9% Sodium Chloride Solution
10 mg/mL to 40 mg/mL
5% Dextrose Solution
10 mg/mL to 40 mg/mL
Reconstituted ADD-Vantage units should not be stored in a frozen state (-20°C).
ADD-Vantage™ Vial, single-use container:
Ceftriaxone for Injection is contraindicated in patients with known hypersensitivity to ceftriaxone, any of its excipients or to any other cephalosporin. Patients with previous hypersensitivity reactions to penicillin and other beta lactam antibacterial agents may be at greater risk of hypersensitivity to ceftriaxone [see Warnings and Precautions (5.1)].
Premature neonates: Ceftriaxone for Injection is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).
Hyperbilirubinemic neonates: Hyperbilirubinemic neonates should not be treated with Ceftriaxone for Injection. Ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients.
Neonates Requiring Calcium Containing IV Solutions
Ceftriaxone for Injection is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium [see clinical pharmacology (12.3), Warnings and Precautions (5.2) and Dosage and Administration (2.2)].
Cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids.
In some of these cases, the same intravenous infusion line was used for both Ceftriaxone for Injection and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. There have been no similar reports in patients other than neonates.
Intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated. When lidocaine solution is used as a solvent with ceftriaxone for intramuscular injection, exclude all contraindications to lidocaine. Refer to the prescribing information of lidocaine.
Before therapy with Ceftriaxone for Injection 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.
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone 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, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium. [see Clinical Pharmacology (12.3), Dosage and Administration (2.2), Contraindications (4.2) and Drug Interactions (7.2)].
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on Ceftriaxone for Injection the diagnosis of a cephalosporin associated anemia should be considered and Ceftriaxone for Injection stopped until the etiology is determined.
Ceftriaxone-calcium precipitates in the gallbladder have been observed in patients receiving ceftriaxone. These precipitates appear on sonography as an echo without acoustical shadowing suggesting sludge or as an echo with acoustical shadowing which may be misinterpreted as gallstones. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of gallbladder disease. The condition appears to be reversible upon discontinuation of ceftriaxone sodium and institution of conservative management. Discontinue ceftriaxone sodium in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above.
Ceftriaxone is excreted via both biliary and renal excretion [see Clinical Pharmacology (12.3)]. Therefore, patients with renal failure normally require no adjustment in dosage when usual doses of ceftriaxone are administered.
Dosage adjustments should not be necessary in patients with hepatic dysfunction; however, in patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the ceftriaxone dosage should not exceed 2 gm daily.
Ceftriaxone is not removed by peritoneal- or hemodialysis. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. In patients with both severe renal and hepatic dysfunction, close clinical monitoring for safety and efficacy is advised.
Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported in patients treated with ceftriaxone sodium. Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, total parenteral nutrition). A cofactor role of ceftriaxone-related biliary precipitation cannot be ruled out.
Prescribing Ceftriaxone for Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of ceftriaxone for injection may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Ceftriaxone for injection should be prescribed with caution in individuals with a history of gastrointestinal disease, especially colitis.
Alterations in prothrombin times have occurred in patients treated with ceftriaxone sodium. Monitor prothrombin time during Ceftriaxone for Injection treatment in patients with impaired vitamin K synthesis or low vitamin K stores (eg, chronic hepatic disease and malnutrition). Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.
Concomitant use of ceftriaxone with Vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with ceftriaxone [see Adverse Reactions (6.1)].
In patients treated with Ceftriaxone for Injection the Coombs' test may become positive. Ceftriaxone for Injection, like other antibacterial drugs, may result in positive test results for galactosemia.
Nonenzymatic methods for the glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with Ceftriaxone for Injection should be done enzymatically.
The presence of ceftriaxone may falsely lower estimated blood glucose values obtained with some blood glucose monitoring systems. Please refer to instructions for use for each system. Alternative testing methods should be used if necessary.
The following serious adverse reactions to ceftriaxone are described below and elsewhere in the labeling:
Ceftriaxone is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to ceftriaxone therapy or of uncertain etiology, were observed:
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%).
rash (1.7%). Less frequently reported (<1%) were pruritus, fever or chills.
Infections And Infestations
genital fungal infection (0.1%).
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%).
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 and Precautions (5.3)].
elevations of aspartate aminotransferase (AST) (3.1%) or alanine aminotransferase (ALT) (3.3%). Less frequently reported (<1%) were elevations of alkaline phosphatase and bilirubin.
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%).
moniliasis or vaginitis were reported occasionally (<1%).
diaphoresis and flushing were reported occasionally (<1%).
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.
In addition to the adverse reactions reported during clinical trials, the following adverse experiences have been reported during clinical practice in patients treated with ceftriaxone. Data are generally insufficient to allow an estimate of incidence or to establish causation.
A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom ceftriaxone and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates.
In addition to the adverse reactions listed above that have been observed in patients treated with ceftriaxone, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:
Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced [see Dosage and Administration (2.1)]. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
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. [see Dosage and Administration (2.5)].
Precipitation of ceftriaxone-calcium can occur when Ceftriaxone for Injection is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone for Injection must not be administered simultaneously with calcium-containing IV solutions. Ceftriaxone for Injection and calcium-containing solutions may be administered sequentially. [see Clinical Pharmacology (12.3), Warnings and Precautions (5.2), Contraindications (4.2) and Dosage and Administration (2.2)].
Pregnancy Category B
Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
In rats, in the Segment I (fertility and general reproduction) and Segment III (perinatal and postnatal) studies with intravenously administered ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less.
Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone for Injection is administered to a nursing woman.
Safety and effectiveness of ceftriaxone in neonates, infants and pediatric patients have been established for the dosages described in the DOSAGE AND ADMINISTRATION section. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone should not be administered to hyperbilirubinemic neonates, especially prematures [see Contraindications (4.2)].
Of the total number of subjects in clinical studies of ceftriaxone sodium, 32% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Ceftriaxone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
The pharmacokinetics of ceftriaxone were only minimally altered in geriatric patients compared to healthy adult subjects and dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to 2 grams per day provided there is no severe renal and hepatic impairment [see Clinical Pharmacology (12)].
In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic.
Ceftriaxone for 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, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate.
The chemical formula of ceftriaxone sodium is C18H16N8Na2O7S3•3.5H2O. It has a calculated molecular weight of 661.59 and the following structural formula:
Ceftriaxone sodium is supplied as a dry powder form equivalent to either 1 g or 2 g of ceftriaxone. 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.
Ceftriaxone sodium contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity.
Ceftriaxone is an antibacterial drug [see Microbiology (12.4)].
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 2. Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. Multiple IV 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.
Average Plasma Concentrations (mcg/mL)
0.5 gm IV*
0.5 gm IM
0.5 gm IM
1 gm IV*
1 gm IM
2 gm IV*
ND = Not determined.
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, plasma clearance ranged from 0.58 to 1.45 L/hour, and renal clearance ranged from 0.32 to 0.73 L/hour.
Ceftriaxone is reversibly bound to human plasma proteins and the binding of ceftriaxone decreases with increasing concentration from a value of 95% at plasma concentrations less than 25 mcg/mL to 85% at plasma concentration of 300 mcg/mL. Over a 0.15 to 3 g dose range in healthy adult subjects, the apparent volume of distribution ranged from 5.8 to 13.5 L.
Ceftriaxone crosses the blood placenta barrier.
Ceftriaxone penetrates the inflamed meninges of infants and pediatric patients. The average values of maximum plasma concentration, cerebrospinal fluid (CSF) concentrations, 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.
50 mg/kg IV
75 mg/kg IV
Maximum Plasma Concentrations (mcg/mL)
Elimination Half-life (hr)
Plasma Clearance (mL/hr/kg)
Volume of Distribution (mL/kg)
CSF Concentration-inflamed meninges (mcg/mL)
1.3 to 18.5
1.3 to 44
Time after dose (hr)
3.7 (± 1.6)
3.3 (± 1.4)
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, and 78.2 mcg/g in the gallbladder wall compared to a corresponding concentration of 62.1 mcg/mL in plasma.
Ceftriaxone concentrations in urine are shown in Table 4.
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
0.5 gm IV
0.5 gm IM
1 gm IV
1 gm IM
2 gm IV
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.
The elimination of ceftriaxone is not altered when Ceftriaxone for Injection is co-administered with probenecid.
Average pharmacokinetic parameters of ceftriaxone in healthy subjects, elderly subjects, subjects with renal impairment, and subjects with liver disease are summarized in Table 5. Compared to healthy adult subjects, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction; 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, suggesting that plasma concentrations of ceftriaxone should be monitored in these patients to determine if dosage adjustments are necessary. [see Dosage and Administration (2.1) and Warnings and Precautions (5.5)]
|* Dose ranged from 0.15 to 3 g; ** Creatinine clearance.|
5.8 to 8.7
0.58 to 1.45
5.8 to 13.5
Elderly Subjects (mean age, 70.5 yr)
Patients with Renal Impairment
Severe (5 to 15 mL/min)
Moderate (16 to 30 mL/min)
Mild (31 to 60 mL/min)
Patients with Liver Disease
Pharmacokinetics in the Middle Ear Fluid
In 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.
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
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.
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:
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.
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.
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method 1, 3. The MIC values should be interpreted according to criteria provided in Table 6.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 2, 3. This procedure uses paper disks impregnated with 30 mcg ceftriaxone to test the susceptibility of microorganisms to ceftriaxone. The disk diffusion interpretive criteria are provided in Table 6.
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 6.
|a Susceptibility interpretive criteria for Enterobacteriaceae are based on a dose of 1 gram IV q 24h. For isolates with intermediate susceptibility, use a dose of 2 grams IV q 24h in patients with normal renal function.|
b For Haemophilus influenzae, susceptibility interpretive criteria are based on a dose of 2 grams IV every 24 hours in patients with normal renal function.
c The current absence of data on resistant isolates precludes defining any category other than 'Susceptible'. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing.
d Disc diffusion interpretive criteria for ceftriaxone discs against Streptococcus pneumoniae are not available, however, isolates of pneumococci with oxacillin zone diameters of >20 mm are susceptible (MIC ≤0.06 mcg/mL) to penicillin and can be considered susceptible to ceftriaxone. Streptococcus pneumoniae isolates should not be reported as penicillin (ceftriaxone) resistant or intermediate based solely on an oxacillin zone diameter of ≤19 mm. The ceftriaxone MIC should be determined for those isolates with oxacillin zone diameters ≤19 mm.
Minimum Inhibitory Concentrations
Disk Diffusion Zone Diameters
20 to 22
Haemophilus influenzaeb, c
Streptococcus pneumoniaed meningitis isolates
Streptococcus pneumoniaed non-meningitis isolates
Streptococcus species beta-hemolytic groupc
Viridans group streptococci
25 to 26
Anaerobic bacteria (agar method)
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.
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 7. For the diffusion technique using the 30 mcg disk, the criteria in Table 7 should be achieved.
Minimum Inhibitory Concentrations
Escherichia coli ATCC 25922
0.03 to 0.12
29 to 35
Staphylococcus aureus ATCC 25923
22 to 28
Staphylococcus aureus ATCC 29213
1 to 8
Haemophilus influenzae ATCC 49247
0.06 to 0.25
31 to 39
Neisseria gonorrhoeae ATCC 49226
0.004 to 0.015
39 to 51
Pseudomonas aeruginosa ATCC 27853
8 to 64
17 to 23
Streptococcus pneumoniae ATCC 49619
0.03 to 0.12
30 to 35
Bacteroides fragilis ATCC 25285 (agar method)
32 to 128
Bacteroides thetaiotaomicron ATCC 29741 (agar method)
64 to 256
Considering the maximum duration of treatment and the class of the compound, carcinogenicity studies with ceftriaxone in animals have not been performed. The maximum duration of animal toxicity studies was 6 months.
Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies.
Impairment of Fertility
Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of 2 g/day.
Concretions consisting of the precipitated calcium salt of ceftriaxone have been found in the gallbladder bile of dogs and baboons treated with ceftriaxone.
These appeared as a gritty sediment in dogs that received 100 mg/kg/day for 4 weeks. A similar phenomenon has been observed in baboons but only after a protracted dosing period (6 months) at higher dose levels (335 mg/kg/day or more). The likelihood of this occurrence in humans is considered to be low, since ceftriaxone has a greater plasma half-life in humans, the calcium salt of ceftriaxone is more soluble in human gallbladder bile and the calcium content of human gallbladder bile is relatively low.
Clinical Trials in Pediatric Patients With Acute Bacterial Otitis Media: (The following is for informational purposes only. Ceftriaxone in ADD-Vantage vials is not intended for intramuscular use.) In two adequate and well-controlled US clinical trials a single IM dose of ceftriaxone was compared with a 10 day course of oral antibiotic in pediatric patients between the ages of 3 months and 6 years. The clinical cure rates and statistical outcome appear in the table below:
Study 1 - U.S.
Ceftriaxone is lower than control at study day 14 and 28.
Study 2 - U.S.5
Ceftriaxone is equivalent to control at study day 14 and 28.
An open-label bacteriologic study of ceftriaxone without a comparator enrolled 108 pediatric patients, 79 of whom had positive baseline cultures for one or more of the common pathogens. The results of this study are tabulated as follows:
Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by Pathogen
Ceftriaxone for Injection, USP is supplied as a sterile, white to yellowish orange crystalline powder in ADD-Vantage™ Vials as follows:
Unit of Sale
1 gram/ vial
2 grams/ vial
Ceftriaxone sodium sterile powder should be stored at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature] and protected from light.
Patients should be advised that allergic reactions, including serious allergic reactions could occur and that serious reactions require immediate treatment and discontinuation of ceftriaxone. Patients should report to their health care provider any previous allergic reactions to ceftriaxone, cephalosporins, penicillins, or other similar antibacterials.
Advise patients of neurological adverse reactions that could occur with Ceftriaxone for Injection use. Instruct patients to inform a healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures, for immediate treatment, dosage adjustment, or discontinuation of Ceftriaxone for Injection.
Patients should be advised that diarrhea is a common problem caused by antibacterials, which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact a physician as soon as possible.
Patients should be counseled that antibacterial drugs, including Ceftriaxone for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Ceftriaxone for Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Ceftriaxone for Injection or other antibacterial drugs in the future.