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 morganii1, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis1 or Peptostreptococcus species.

1

The efficacy for these organisms in this organ system were studied in fewer than ten infections.

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 gram 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 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.

2.1 Adult Population

Ceftriaxone for Injection, USP, Pharmacy Bulk Package bag SmartPak® should be used only in patients who require a 1 gram dose and not any fraction thereof.

Ceftriaxone for Injection USP Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than the 1 gram dose of Ceftriaxone.

Ceftriaxone for Injection should be reconstituted with Sterile Water for Injection, USP to a concentration of 100 mg per mL and further diluted in 50 mL of a compatible solution.

The recommended adult dosages are outlined in Table 1. Ceftriaxone for Injection, USP, Pharmacy Bulk Package SmartPak® should be used only in patients who require a 1 gram dose and not any fraction thereof.

Ceftriaxone should be administered intravenously (I.V.) over approximately 30 minutes.

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.

2.2 Pediatric Patients

To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the adult 1 gram dose of ceftriaxone. [see Use in Specific Populations (8.4)]

2.3 Preparation for Use of Ceftriaxone for Injection, USP, Pharmacy Bulk Package bags, SmartPak®

Ceftriaxone for Injection, USP Pharmacy Bulk Package bag SmartPak® should be used only in patients who require a 1 gram dose and not any fraction thereof.

Ceftriaxone for Injection USP, Pharmacy Bulk Package SmartPak® bag should not be used in patients who require less than the 1 gram dose of ceftriaxone.

Directions for Proper Use of a Pharmacy Bulk Package

• NOT FOR DIRECT INFUSION. The Pharmacy Bulk Package is for use in the hospital pharmacy admixture service only in a suitable work area, such as a laminar flow hood. Using aseptic technique, the container closure may be penetrated only one time after reconstitution using a suitable sterile dispensing set or transfer device that allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 4 HOURS from initial reconstitution port closure entry is permitted to complete fluid transfer operations. This time limit should begin with the introduction of the solvent or diluent into the Pharmacy Bulk Package. Discard any unused portion after 4 HOURS. This pharmacy bulk package is not intended to be dispensed as a unit
• PRIOR TO RECONSTITUTION:DO NOT USE THE INNER BAG IF PARTICULATE OR FOREIGN MATTER IS PRESENT, IF THE DRY POWDER IS DARK YELLOW OR BROWN, IF THE SEALS ARE NOT INTACT, OR IF THERE IS ANY OTHER DAMAGE TO THE BAG. IN SUCH CASES, DISCARD THE BAG IMMEDIATELY.
• After initial reconstitution port entry, use entire contents of the Pharmacy Bulk Package promptly. Any unused portion must be discarded after 4 HOURS.
• Gather the following items prior to the reconstitution of the product: Appropriate number of bags of Sterile Water for Injection and, depending upon the method of filling, appropriate sterile tubing and adapters.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Use only if solution is clear.
• Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute Ceftriaxone for Injection SmartPak® Pharmacy Bulk Package or to further dilute a reconstituted solution for intravenous administration. Particulate formation can result.

INSTRUCTION FOR RECONSTITUTION OF THE PHARMACY BULK PACKAGE BAG SmartPak®

The entire contents of the bag and the preparation process (reconstitution and dilution) should be completed within 4 hours of initial entry.

• Document the date and time reconstitution starts in the designated place on the container label. The entire contents of the bag must be used within 4 hours from the time of initial entry.
• Remove the translucent unthreaded cap from the reconstitution (smaller) port and discard it.
• Reconstitute the powder through the reconstitution (smaller) port, using Sterile Water for Injection according to the Table 2 below:

• After reconstitution is complete, remove the transfer needle from the reconstitution port.
• Place the bag on a flat surface of a laminar flow hood and mix for at least 15 minutes by rocking gently from side to side. CAUTION: To avoid possible leakage caused by the heavy weight of the added water, do not shake vigorously or pull strongly on the bag.
• When foam dissipates, visually inspect the bag to verify the solution is clear, colorless to pale yellow and free of particulate matter. DO NOT USE THE INNER BAG IF PARTICULATE OR FOREIGN MATTER IS PRESENT.
• Unscrew the clear threaded cap from the transfer (larger) port and discard it. Attach sterile tubing and filling adapter unit to the transfer port.
• Reconstituted solution can now be transferred using the transfer port and the filling adapter.

It should be noted that the spike placed into the transfer port of the Pharmacy Bulk Package SmartPak® is NEVER removed during this procedure and that the reconstitution port is self-sealing.

4.1 Anaphylaxis to Ceftriaxone or the Cephalosporin Class of Antibacterials, Penicillins or Other Beta-Lactam Antibacterials

Ceftriaxone for Injection, USP 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)].

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, USP 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, USP 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, USP is mixed with calcium-containing solutions in the same intravenous administration line. Ceftriaxone for Injection must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions, such as parenteral nutrition via a Y-site. However, in patients other than neonates, Ceftriaxone for Injection, USP 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 (disturbances of consciousness including somnolence, lethargy, and confusion), seizures, myoclonus, and non-convulsive status epilepticus [see Adverse Reactions (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 associate with Ceftriaxone for Injection therapy occur, discontinue Ceftriaxone for Injection and institute appropriate supportive measures. Make appropriate dosage adjustments in patients with severe renal impairment. [see Dosage and Administration (2.1)].

5.4 ​Clostridium difficile-​associated Diahrrhea

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 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, USP, the diagnosis of a cephalosporin-associated anemia should be considered and Ceftriaxone for Injection, USP stopped until the etiology is determined.

5.6 Gallbladder Sonogram Abnormalities

There have been reports of sonographic abnormalities in the gallbladder of patients treated with ceftriaxone sodium; some of these patients also had symptoms of gallbladder disease. These abnormalities 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 chemical nature of the sonographically detected material has been determined to be predominantly a ceftriaxone-calcium salt. The condition appears to be transient and reversible upon discontinuation of ceftriaxone sodium and institution of conservative management. Therefore, ceftriaxone should be discontinued in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above.

5.7 Patients with Hepatic and Renal Impairment

Hepatic Impairment: In patients with both hepatic and significant renal disease, Ceftriaxone for Injection dosage should not exceed 2 grams daily.

Renal Impairment: This formulation of Ceftriaxone for Injection USP – Pharmacy Bulk Package bags SmartPak® should not be used in renally impaired patients who require less than the 1 gram dose of ceftriaxone. In patients with both hepatic impairment and significant renal disease, Ceftriaxone for Injection dosage should not exceed 2 grams per day.

5.8 Pancreatitis

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.

5.9 Development of Drug-Resistant Bacteria

Prescribing Ceftriaxone for Injection, USP 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. As with other antibacterial drugs, 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.

5.10 Alterations in Prothrombin Time

Alterations in prothrombin times have occurred in patients treated with ceftriaxone sodium. 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 for Injection treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

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 ≤ 6% of the patients:

• Local reactions – pain, induration, tenderness, and phlebitis after intravenous administration.
• Hypersensitivity – rash, pruritus, fever or chills.
• Hematologic – eosinophilia, thrombocytosis, leukopenia, 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.

• Neurologic-Encephalopathy, seizures, myoclonus, and non-convulsive status epilepti us [see ​Warnings and Precautions (5.3)]

• Gastrointestinal – stomatitis and glossitis
• Genitourinary – oliguria
• Dermatologic – exanthema, allergic dermatitis, urticaria, edema

Cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) have been reported.

Anaphylaxis (including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia) has been reported.

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 cholestasis, aplastic anemia, hemorrhage, and superinfection.
• Altered Laboratory Tests: Positive direct Coombs’ test, false-positive test for urinary glucose, and elevated LDH.

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 is mixed with calcium-containing solutions in the same intravenous administration line. Ceftriaxone for Injection, USP must not be administered simultaneously with calcium-containing intravenous solutions. Ceftriaxone for Injection and calcium-containing solutions can be administered sequentially [see Warnings and Precautions (5.2)]

8.1 Pregnancy

8.3 Nursing Mothers

Ceftriaxone is excreted in human breast milk. Caution should be exercised when Ceftriaxone for Injection is administered to a nursing woman.

8.4 Pediatric Use

Ceftriaxone for Injection USP, Pharmacy Bulk Package bag, SmartPak® should not be used in pediatric patients who require less than the 1 gram dose of ceftriaxone. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the adult 1 gram 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 [see Clinical Pharmacology (12)].

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (I.V.) infusion of a 0.5, 1 or 2 g dose in healthy subjects are presented in Table 3. Multiple intravenous 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.

TABLE 3: Ceftriaxone Plasma Concentrations After Single Dose Administration

Over a 0.15 to 3 g dose range in healthy adult subjects, the mean 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.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Animal Pharmacology

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).