Ceftriaxone

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 I.V. solutions ( 5.2 ). Neurological adverse reactions: Serioous neurological adverse reactions have been reported during postmarketing surveillance. If serious adverse reactions occur, discontinue the drug and institute appropriate supportive measures. ( 5.3 ) Clostridium difficile -associated diarrhea: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs ( 5.4 ). 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. ( 5.5 ) 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 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) ] Clostridium difficile -associated diarrhea [see Warnings and Precautions (5.3) ] Hemolytic anemia [see Warnings and Precautions (5.4) ] The most common adverse reactions occurring in >2% of patients receiving ceftriaxone include diarrhea, eosinophilia, thrombocytosis, leukopenia, and elevations of SGOT and SGPT. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Samson Medical Technologies, L.L.C. at 1-877-418-3600 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 ≤ 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. inner bag 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.