Ceftriaxone

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# Black Box Warning

# Overview
Ceftriaxone is an antibiotic that is FDA approved for the treatment of lower respiratory tract infections, acute bacterial otitis media, skin infections, urinary tract infections, pelvic inflammatory disease, bacterial septicemia, bone and joint infections, intraabdominal infection, meningitis, and surgical prophylaxis. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, pseudomembranous enterocolitis, hemolytic anemia, hypersensitivity reaction, kernicterus, renal failure, and lung injury.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Before instituting treatment with ceftriaxone 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 may be administered intravenously or intramuscularly. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for intravenous infusion only. - Ceftriaxone for injection should be administered intravenously by infusion over a period of 30 minutes.
- Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle 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.
- There have been no reports of an interaction between ceftriaxone and oral calcium- containing products or interactions between intramuscular ceftriaxone and calcium- containing products (IV or oral).
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftriaxone 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:
- 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 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 should be balanced against the potential advantages of parenteral therapy.
- 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.
- 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. 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 has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis- and Escherichia coli.
- Efficacy for this organism in this organ system was studied in fewer than ten infections.
- The preoperative administration of a single 1 g dose of ceftriaxone 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 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 antibiotic 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 provides protection from most infections due to susceptible organisms throughout the course of the procedure.
- The usual adult daily dose is 1 to 2 g given once a day (or in equally divided doses twice a day) depending on the type and severity of infection.
- For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 g, in order to achieve >90% target attainment. The total daily dose should not exceed 4 g.
- If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.
- For preoperative use (surgical prophylaxis), a single dose of 1 g administered intravenously 1/2 to 2 hours before surgery is recommended.
- 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.
- No dosage adjustment is necessary for patients with impairment of renal or hepatic function.
- RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION
- The 10 g bottle should be reconstituted with 95 mL of an appropriate IV diluent in a suitable work area such as a laminar flow hood.
- The resulting solution will contain approximately 100 mg/mL of ceftriaxone.
- The container closure may be penetrated only one time, utilizing a suitable sterile transfer device or dispensing set which allows measured distribution of the contents. (A sterile substance which must be reconstituted prior to use may require a separate closure entry).
- Use of this product is restricted to a suitable work area, such as a laminar flow hood.
- The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum of 4 hours from initial closure entry is permitted to complete fluid transfer operations. If reconstitution is necessary, this time limit should begin with the introduction of solvent or diluent into the Pharmacy Bulk Package.
- Unused portions of solutions held longer than the recommended time periods should be discarded.
- Transfer individual dose to appropriate intravenous solutions as soon as possible following reconstitution of the bulk package. The stability of the solution that has been transferred into a container varies according to diluent, concentration and temperature (see COMPATIBILITY AND STABILITY).
- Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired.
- 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.
- Registered trademark of G.D Searle & Co.
- Vancomycin, amsacrine, aminoglycosides, and fluconazole are physically 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.
- Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone for injection or to further dilute a reconstituted pharmacy bulk package bottle for IV administration. Particulate formation can result.
- Ceftriaxone for injection 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- Acute otitis media
- 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day.
- Bacteremia associated with intravascular line
- (Due to Escherichia coli and Klebsiella species, extended-spectrum beta-lactamase negative) 1 to 2 g IV daily.
- Bacterial endocarditis; Prophylaxis: (high-risk patients; dental, respiratory, or infected skin/skin structure or musculoskeletal tissue procedures) 1 g IV or IM 30 to 60 minutes prior to procedure 
- Bacterial meningitis
- 4 g/day IV divided every 12 to 24 hours; maximum 4 g/day
- Bacterial musculoskeletal infection
- 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day
- Chancroid
- 250 mg IM as a single dose.
- Epididymitis
- 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 10 days.
- Gonorrhea
- Uncomplicated, 250 mg IM as a single dose plus either a single dose of azithromycin 1 g ORALLY or doxycycline 100 mg ORALLY twice daily for 7 days
- Gonorrhea
- Conjunctivitis, 1 g IM as a single dose
- Gonorrhea
- Disseminated, 1 g IV or IM every 24 hours for 24 to 48 hours after improvement begins then switch to appropriate oral therapy to complete at least 1 week of therapy
- Gonorrhea
- Meningitis and endocarditis, 1 to 2 g IV every 12 hours, for 10 to 14 days (meningitis) or at least 4 weeks (endocarditis)
- Infection of skin AND/OR subcutaneous tissue: 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day
- Infectious disease of abdomen: 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day
- Infective endocarditis
- (Native valve, highly penicillin-susceptible streptococci) 2 g IV/IM every 24 hours for 4 weeks
- Infective endocarditis: (native valve, highly penicillin-susceptible streptococci) alternative therapy, 2 g IV/IM every 24 hours AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks
- Infective endocarditis: (native valve, relatively penicillin-resistant streptococci) 2 g IV/IM every 24 hours for 4 weeks AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks.
- Infective endocarditis
- (Prosthetic valve, penicillin-susceptible streptococci) 2 g IV/IM every 24 hours for 6 weeks WITH or WITHOUT gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 2 weeks.
- Infective endocarditis
- (Prosthetic valve, penicillin-resistant streptococci) 2 g IV/IM every 24 hours AND gentamicin sulfate 3 mg/kg IV/IM in 1 dose (preferred) or in 3 equally divided doses for 6 weeks.
- Infective endocarditis: (enterococcal, strains resistant to penicillin, aminoglycoside, and vancomycin (E faecalis)) 2 g IV/IM every 12 hours AND ampicillin sodium 2 g IV every 4 hours for a minimum of 8 weeks.
- Infective endocarditis
- (HACEK microorganisms) 2 g IV/IM every 24 hours for 4 to 6 weeks.
- Infective endocarditis
- (Suspected Bartonella, culture-negative) 2 g IV/IM every 24 hours for 6 weeks AND gentamicin sulfate 1 mg/kg IV/IM every 8 hours for 2 weeks WITH or WITHOUT doxycycline 100 mg IV or ORALLY every 12 hours for 6 weeks.
- Infective proctitis
- 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 7 days
- Lower respiratory tract infection
- 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day
- Lyme disease
- 2 g IV once daily for 14 days (range, 10 to 28 days) for early Lyme disease with acute neurological disease manifested by meningitis or radiculopathy, or patients with seventh-cranial-nerve palsy with CNS involvement; for 14 to 21 days for the initial treatment of hospitalized patients with Lyme carditis; for 14 to 28 days for Lyme arthritis with neurological involvement, including those refractory to oral therapy, or late neurologic Lyme disease.
- Pelvic inflammatory disease
- 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day.
- Pelvic inflammatory disease
- 250 mg IM as a single dose plus doxycycline 100 mg ORALLY twice daily for 14 days, with or without metronidazole 500 mg ORALLY twice daily for 14 days.
- Postoperative infection; Prophylaxis
- 1 g IV 0.5 to 2 hours prior to surgery.
- Septicemia
- 1 to 2 g IV every 24 hours or in divided doses twice a day; maximum 4 g/day.
- Sexually transmitted infectious disease; Prophylaxis - Victim of sexual aggression
- 250 mg IM as a single dose plus metronidazole 2 g ORALLY as a single dose plus either azithromycin 1 g ORALLY as a single dose or doxycycline 100 mg ORALLY twice daily for 7 days.
- Urinary tract infectious disease
- 1 to 2 g IV/IM every 24 hours or in divided doses twice a day; maximum 4 g/day.

### NonGuideline-Supported Use
- Bacteremia associated with intravascular line.
- Bacterial endocarditis; Prophylaxis
- Bacterial endocarditis - Streptococcal infectious disease
- Chancroid
- Epididymitis
- Febrile neutropenia
- Infective endocarditis
- Infective proctitis
- Lyme disease
- Peritonitis.
- Salmonella infection
- Sexually transmitted infectious disease; Prophylaxis - Victim of sexual aggression
- Typhoid fever

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- 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 g.
- 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 g.
- In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 g). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 g 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.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftriaxone in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ceftriaxone in pediatric patients.

# Contraindications
- Ceftriaxone for injection is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.
- Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone for injection. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a possible risk of bilirubin encephalopathy in these patients.
- Ceftriaxone is contraindicated in neonates 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.
- 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.

# Warnings
- 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 OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS 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 other cephalosporins, anaphylactic reactions with fatal outcome have been reported, even if a patient is not known to be allergic or previously exposed.
- Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle 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.
- 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, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.

# Adverse Reactions

## Clinical Trials Experience
- 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 OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS 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 other cephalosporins, anaphylactic reactions with fatal outcome have been reported, even if a patient is not known to be allergic or previously exposed.
- Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone bottles or to further dilute a reconstituted bottle 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.
- 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, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.

## Postmarketing Experience
- 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.
- GASTROINTESTINAL
- Stomatitis and glossitis.
- GENITOURINARY
- Oliguria.
- DERMATOLOGIC
- Exanthema, allergic dermatitis, urticaria, edema. As with many medications, isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis) have been reported.
- In addition to the adverse reactions listed above which have been observed in patients treated with ceftriaxone, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics:
- Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and superinfection.
- Altered Laboratory Tests: Positive direct Coombs' test, false-positive test for urinary glucose, and elevated LDH.
- Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced . If seizures associated with drug therapy occur, the drug should be discontinued.
- Anticonvulsant therapy can be given if clinically indicated.

# Drug Interactions
There is limited information regarding Ceftriaxone Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftriaxone in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Ceftriaxone during labor and delivery.

### Nursing Mothers
- Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone for injection is administered to a nursing woman

### Pediatric Use
- In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone for injection should not be administered to hyperbilirubinemic neonates, especially prematures.

### Geriatic Use
- Of the total number of subjects in clinical studies of ceftriaxone, 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.
- 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 g per day.

### Gender
There is no FDA guidance on the use of Ceftriaxone with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ceftriaxone with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Ceftriaxone in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Ceftriaxone in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ceftriaxone in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ceftriaxone in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

### Monitoring
- Patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during ceftriaxone treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

# IV Compatibility
There is limited information regarding IV Compatibility of Ceftriaxone in the drug label.

# Overdosage
- 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.

# Pharmacology

## Mechanism of Action
Ceftriaxone inhibits bacterial cell wall synthesis by means of binding to the penicillin-binding proteins (PBPs).  Inhibition of PBPs would in turn inhibit the transpeptidation step in peptidoglycan synthesis which is required for bacterial cell walls. Like other cephalosporins, ceftriaxone is bacteriocidal and exhibits time-dependent killing

## Structure
- Ceftriaxone for injection, USP is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone sodium is (6R,7R)-7--8-oxo-3-methyl]]-5-thia-1-azabicyclooct-2-ene-2-carboxylic acid, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate.
- The chemical formula of ceftriaxone sodium is C18H16N8Na2O7S33.5H2O. It has a calculated molecular weight of 661.60 and the following structural formula:
- Ceftriaxone sodium is white or yellowish, 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 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 g of ceftriaxone and is intended for intravenous infusion only.
- Ceftriaxone sodium, USP contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity.
- A Pharmacy Bulk Package is a container of 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.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ceftriaxone in the drug label.

## Pharmacokinetics
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.
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.
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.
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.
The elimination of ceftriaxone is not altered when ceftriaxone is co-administered with probenecid.
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 g 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.

## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ceftriaxone in the drug label.

# Clinical Studies
- Clinical Trials in Pediatric Patients With Acute Bacterial Otitis Media: In two adequate and well-controlled U.S. 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:
- 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:

# How Supplied
- Ceftriaxone for Injection, USP in Pharmacy Bulk Package is supplied as a sterile crystalline powder in glass bottles containing ceftriaxone sodium equivalent to 10g ceftriaxone. NOT FOR DIRECT ADMINISTRATION.

## Storage
- Ceftriaxone for injection sterile powder should be stored at 20 to 25C (68 to 77F)  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.
Ceftriaxone 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:
- The following intravenous ceftriaxone solutions are stable at room temperature (25C) 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.
- Ceftriaxone for injection 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 (-20C) in PVC or polyolefin containers, remains stable for 26 weeks.
- Frozen solutions of ceftriaxone for injection should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Ceftriaxone in the drug label.

# Precautions with Alcohol
- Alcohol-Ceftriaxone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- CEFTRIAXONE

# Look-Alike Drug Names
There is limited information regarding Ceftriaxone Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price