CEFTRIAXONE AND DEXTROSE

5 WARNINGS AND PRECAUTIONS 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. 5.10 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. 5.11 Development of Drug-resistant Bacteria Prescribing Ceftriaxone for Injection and Dextrose 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. As with other antibacterial drugs, use of Ceftriaxone for Injection and Dextrose 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. 5.12 Patients with Overt or Known Subclinical Diabetes Mellitus or Carbohydrate Intolerance As with other dextrose-containing solutions, Ceftriaxone for Injection and Dextrose Injection should be prescribed with caution in patients with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason. 5.13 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 and Dextrose Injection treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

6 ADVERSE REACTIONS 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).