Ceftriaxone

Ceftriaxone for Injection and Dextrose Injection is indicated for the treatment of the following infections when caused by susceptible bacteria. Ceftriaxone for Injection and Dextrose 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 ); Skin and Skin Structure Infections ( 1.2 ); Complicated and Uncomplicated Urinary Tract Infections ( 1.3 ); Pelvic Inflammatory Disease ( 1.4 ); Bacterial Septicemia ( 1.5 ); Bone and Joint Infections ( 1.6 ); Intra-abdominal Infections ( 1.7 ); Meningitis ( 1.8 ); and Surgical Prophylaxis ( 1.9 ). To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftriaxone for Injection and Dextrose Injection and other antibacterial drugs, Ceftriaxone for Injection and Dextrose Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.10 )

1.1 Lower Respiratory Tract Infections 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 .

1.2 Skin and Skin Structure Infections 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 The efficacy for these organisms in this organ system were studied in fewer than ten infections. , Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis or Peptostreptococcus species.

1.3 Complicated and Uncomplicated Urinary Tract Infections Complicated and uncomplicated urinary tract infections caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae .

1.4 Pelvic Inflammatory Disease 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.

1.5 Bacterial Septicemia Bacterial septicemia caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae .

1.6 Bone and Joint Infections Bone and joint infections caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species.

1.7 Intra-abdominal Infections Intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species or Peptostreptococcus species.

1.8 Meningitis 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 , however, the efficacy for these organisms in this organ system were studied in fewer than ten infections.

1.9 Surgical Prophylaxis The preoperative administration of a single 1 g dose of Ceftriaxone for Injection and Dextrose Injection 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.

1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftriaxone for Injection and Dextrose Injection and other antibacterial drugs, Ceftriaxone for Injection and Dextrose 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.

Dual-chamber, single-dose container: 1 g ceftriaxone for injection and 50 mL of 3.74% dextrose injection 2 g ceftriaxone for injection and 50 mL of 2.22% dextrose injection DUPLEX® CONTAINER dual chamber, single-dose container consisting of: 1 g ceftriaxone for injection and 50 mL of 3.74% dextrose injection ( 3 ) 2 g ceftriaxone for injection and 50 mL of 2.22% dextrose injection ( 3 )

Anaphylaxis to ceftriaxone or other cephalosporin class antibacterials, penicillins, or other beta-lactam antibacterials ( 4.1 )

4.1 Anaphylaxis to Ceftriaxone or the Cephalosporin Class of Antibacterials, Penicillins, or Other Beta-lactam Antibacterials Ceftriaxone for Injection and Dextrose Injection is contraindicated in patients who have a history of anaphylaxis to ceftriaxone or the cephalosporin class of antibacterials, penicillins, or other beta-lactam antibacterials [see Warnings and Precautions (5.1) ].

Hypersensitivity reactions: Include anaphylaxis and serious skin reactions. Cross-hypersensitivity may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue the drug. ( 5.1 ) Interaction with Calcium-containing Products: Precipitation can occur. Do not administer simultaneously with calcium-containing IV solutions. ( 5.2 ) Clostridioides difficile -associated diarrhea: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. ( 5.3 ) Neurological Adverse Reactions: Serious neurological adverse reactions have been reported. If neurological adverse reactions occur, discontinue Ceftriaxone for Injection and Dextrose Injection therapy and institute appropriate supportive measures. Make appropriate dosage adjustments in patients with severe renal impairment ( 2.1 , 5.3 ). Hemolytic Anemia: Severe cases of hemolytic anemia, including fatalities in adults and children, have been reported. If anemia is diagnosed, discontinue the drug until the etiology is determined. ( 5.4 )

5.1 Hypersensitivity Reactions to Ceftriaxone, Cephalosporins, Penicillins, or Other Drugs Serious, occasionally fatal, hypersensitivity (anaphylactic) reactions have been reported with ceftriaxone. Before therapy with Ceftriaxone for Injection and Dextrose Injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to ceftriaxone, cephalosporins, penicillins, or other drugs. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterials has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Ceftriaxone for Injection and Dextrose Injection occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures including oxygen, corticosteroids, intravenous fluids, intravenous antihistamines, pressor amines, and airway management, as clinically indicated.

5.2 Interaction with Calcium-containing Products Precipitation of ceftriaxone-calcium can occur when Ceftriaxone for Injection and Dextrose Injection is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone for Injection and Dextrose Injection 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 for Injection and Dextrose Injection and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with 0.9% sodium chloride injection or D5W. 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 Drug Interactions (7.2) ]

5.3 Neurological Adverse Reactions Serious neurological adverse reactions have been reported during postmarketing surveillance with ceftriaxone use. These reactions include encephalopathy (disturbance of consciousness including somnolence, lethargy, and confusion), seizures, myoclonus, and non-convulsive status epilepticus [see Adverse Re actions (6.2) ]. Some cases occurred in patients with severe renal impairment who did not receive appropriate dosage adjustment. However, in other cases, neurological adverse reactions occurred in patients receiving an appropriate dosage adjustment. The neurological adverse reactions were reversible and resolved after discontinuation. If neurological adverse reactions associated with Ceftriaxone for Injection and Dextrose Injection therapy occur, discontinue Ceftriaxone for Injection and Dextrose Injection and institute appropriate supportive measures. Make appropriate dosage adjustments in patients with severe renal impairment [see Dosage and Administration (2.1) ] .

5.4 Clostridioides difficile -associated Diarrhea Clostridioides 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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.5 Hemolytic Anemia 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 and Dextrose Injection, the diagnosis of a cephalosporin associated anemia should be considered and Ceftriaxone for Injection and Dextrose Injection stopped until the etiology is determined.

5.6 Hypersensitivity to Dextrose Products Hypersensitivity reactions, including anaphylaxis, have been reported with administration of dextrose products. These reactions have been reported in patients receiving high concentrations of dextrose (i.e. 50% dextrose) 1 . The reactions have also been reported when corn-derived dextrose solutions were administered to patients with or without a history of hypersensitivity to corn products 2 .

5.7 Gallbladder Pseudolithiasis 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 and institution of conservative management. Discontinue ceftriaxone in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above.

5.8 Urolithiasis and Post-Renal Acute Renal Failure Ceftriaxone-calcium precipitates in the urinary tract have been observed in patients receiving ceftriaxone and may be detected as sonographic abnormalities. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of urolithiasis, and ureteral obstruction and post-renal acute renal failure. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of appropriate management. Ensure adequate hydration in patients receiving ceftriaxone. Discontinue ceftriaxone in patients who develop signs and symptoms suggestive of urolithiasis, oliguria or renal failure and/or the sonographic findings described above.

5.9 Patients with Hepatic and Renal Impairment In patients with both hepatic impairment and significant renal disease, Ceftriaxone for Injection and Dextrose Injection dosage should not exceed 2 g daily. […]

The following serious adverse reactions to ceftriaxone are described below and elsewhere in the labeling: Hypersensitivity reactions [see Warnings and Precautions (5.1) ] Ceftriaxone-calcium precipitates [see Warnings and Precautions (5.2) and Drug Interactions (7.2) ] Neurological Adverse Reactions [see Warnings and Precautions (5.3) ] Clostridioides difficile -associated diarrhea [see Warnings and Precautions (5.4) ] Hemolytic anemia [see Warnings and Precautions (5.5) ] 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. To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-854-6851 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following reactions occurred in less than or equal to 6% of the patients: Local reactions—pain, induration, tenderness, and phlebitis after IV administration. Hypersensitivity—rash, pruritus, fever or chills. Hematologic—eosinophilia, thrombocytosis, leucopenia, anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia, and prolongation of the prothrombin time. Gastrointestinal—diarrhea, nausea or vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.4) ]. Hepatic—elevations of SGOT, SGPT, alkaline phosphatase, bilirubin. Renal—elevations of the BUN, creatinine, and the presence of casts in the urine. Central nervous system—headache or dizziness. Genitourinary—moniliasis or vaginitis. Miscellaneous—diaphoresis and flushing. Ceftriaxone-calcium precipitates—Cases of fatal reactions with ceftriaxone-calcium precipitates in lung and kidneys in neonates have been described. In some cases the infusion lines and times of administration of ceftriaxone and calcium-containing solutions differed [see Warnings and Precautions (5.2) and Drug Interactions (7.2) ]. Other observed adverse reactions—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.

6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of ceftriaxone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal—stomatitis and glossitis. Genitourinary—oliguria, ureteric obstruction, post-renal acute renal failure. Hepatic—hepatitis. Dermatologic—severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis), exanthema, allergic dermatitis, urticaria, and edema. Immunologic—Anaphylaxis (anaphylactic shock, transient leucopenia, neutropenia, agranulocytosis and thrombocytopenia). Neurologic – Encephalopathy, seizures, myoclonus, and non-convulsive status epilepticus [see Warnings and Precautions (5.3) ].

6.3 Cephalosporin-class Adverse Reactions 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 antibacterials: Adverse Reactions: Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including hepatitis, cholestasis, aplastic anemia, hemorrhage, and superinfection. Altered Laboratory Tests: Positive direct Coombs’ test, false-positive test for urinary glucose, and elevated lactic acid dehydrogenase (LDH).

Vancomycin, amsacrine, aminoglycosides, and fluconazole are physically incompatible. ( 7.1 ) Calcium-containing products: precipitation can occur. ( 7.2 )

7.1 Vancomycin, Amsacrine, Aminoglycosides, and Fluconazole Vancomycin, amsacrine, aminoglycosides, and fluconazole are physically incompatible with ceftriaxone in admixtures [see Dosage and Administration (2.3) ].

7.2 Calcium-containing Products Precipitation of ceftriaxone-calcium can occur when Ceftriaxone for Injection and Dextrose Injection is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone for Injection and Dextrose Injection must not be administered simultaneously with calcium-containing IV solutions. Ceftriaxone for Injection and Dextrose Injection and calcium-containing solutions may be administered sequentially. [see Warnings and Precautions (5.2) ]

Hepatic and renal impairment Patients with both hepatic and renal impairment should not receive more than 2 grams of ceftriaxone per day ( 5.8 ) Pediatric Patients Ceftriaxone for Injection and Dextrose Injection in the DUPLEX® 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. ( 2.2 , 8.4 )

8.1 Pregnancy Risk Summary Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use, including Ceftriaxone, in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Ceftriaxone crosses the placenta. In animal reproduction studies, no adverse developmental effects were observed when ceftriaxone was administered to pregnant rats at doses up to approximately 2.8 times the clinical dose of 2 g/day (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Published literature shows that ceftriaxone crosses the placenta. While available studies cannot definitively establish the absence of risk, published data from case-control studies and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Reproductive studies have been performed in mice, rats, and primates at intravenous doses of 625, 586, and 84 mg/kg/day, respectively, without evidence of embryotoxicity, fetotoxicity, or teratogenicity. These doses are approximately 1.5, 2.8, and 0.8 times the clinical dose of 2 g/day based on body surface area comparisons. Ceftriaxone was tested in a Segment III (pre-postnatal) study in rats at intravenous doses of up to 586 mg/kg/day (approximately 2.8 times the clinical dose of 2 g/day based on body surface area comparison). No adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior, and reproductive ability of the offspring.

8.2 Lactation Risk Summary Data from published literature report that ceftriaxone is present in human milk. There are no data on the effects of Ceftriaxone on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ceftriaxone for Injection and Dextrose Injection and any potential adverse effects on the breastfed child from Ceftriaxone for Injection and Dextrose Injection or from the mother’s underlying condition.

8.4 Pediatric Use Ceftriaxone for Injection and Dextrose Injection in the DUPLEX® 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 1 g or 2 g adult dose of ceftriaxone.

8.5 Geriatric Use 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) ]

Ceftriaxone is an antibacterial drug [see Microbiology (12.4) ].