FDA label 925a8f84-f856-4f15-967d-2f07b7bc5b24

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 ) • Clostridium difficile -associated diarrhea: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. ( 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 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 and other beta-lactam agents or other drugs. This product should be given cautiously to penicillin and other beta-lactam agent-sensitive patients. Antibacterial drugs 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 all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i.e., anaphylaxis) have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated. 5.2 Interaction with Calcium-containing Products Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial 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. [ see Clinical Pharmacology (12.3) , Dosage and Administration (2.2) , Contraindications (4.2) and Drug Interactions (7.2) ]. 5.3 Clostridium difficile -associated Diarrhea 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. 5.4 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 the diagnosis of a cephalosporin associated anemia should be considered and Ceftriaxone for Injection stopped until the etiology is determined. 5.5 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 sodium and institution of conservative management. Discontinue ceftriaxone sodium in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above. 5.6 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 sodium 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. 5.7 Patients with Hepatic and Renal Impairment Ceftriaxone is excreted via both biliary and renal excretion [ see Clinical Pharmacology (12.3) ]. Therefore, patients with renal failure normally require no adjustment in dosage when usual doses of ceftriaxone are administered. Dosage adjustments should not be necessary in patients with hepatic dysfunction; however, in patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the ceftriaxone dosage should not exceed 2 gm daily. Ceftriaxone is not removed by peritoneal- or hemodialysis. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. In patients with both severe renal and hepatic dysfunction, close clinical monitoring for safety and efficacy is advised. 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 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. Prolonged 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 Patients with Gastrointestinal Disease Ceftriaxone for injection should be prescribed with caution in individuals with a history of gastrointestinal disease, especially colitis. 5.11 Alterations in Prothrombin Time Alterations in prothrombin times have occurred in patients treated with ceftriaxone sodium. Monitor prothrombin time during Ceftriaxone for Injection treatment in patients with impaired vitamin K synthesis or low vitamin K stores (eg, chronic hepatic disease and malnutrition). Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy. Concomitant use of ceftriaxone with Vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with ceftriaxone [ see Adverse Reactions (6.1) ]. 5.12 Information for Patients • Patients should be counseled that antibacterial drugs including ceftriaxone for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). • When ceftriaxone for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Ceftriaxone for injection or other antibacterial drugs in the future. • Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. 5.13 Influence on Diagnostic Tests In patients treated with Ceftriaxone for Injection the Coombs' test may become positive. Ceftriaxone for Injection, like other antibacterial drugs, may result in positive test results for galactosemia. Nonenzymatic methods for the glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with Ceftriaxone for Injection should be done enzymatically. The presence of ceftriaxone may falsely lower estimated blood glucose values obtained with some blood glucose monitoring systems. Please refer to instructions for use for each system. Alternative testing methods should be used if necessary.

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 greater than 2% of patients receiving ceftriaxone include diarrhea, eosinophilia, thrombocytosis, leukopenia, and elevations of SGOT and SGPT. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Ceftriaxone is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to ceftriaxone therapy or of uncertain etiology, were observed: Local Reactions pain, induration and tenderness was 1% overall. Phlebitis was reported in <1% after IV administration. The incidence of warmth, tightness or induration was 17% (3/17) after IM administration of 350 mg/mL and 5% (1/20) after IM administration of 250 mg/mL. General Disorders And Administration Site Conditions injection site pain (0.6%). Hypersensitivity rash (1.7%). Less frequently reported (<1%) were pruritus, fever or chills. Infections And Infestations genital fungal infection (0.1%). Hematologic eosinophilia (6%), thrombocytosis (5.1%) and leukopenia (2.1%). Less frequently reported (<1%) were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time. Blood And Lymphatic Disorders granulocytopenia (0.9%), coagulopathy (0.4%). Gastrointestinal diarrhea/loose stools (2.7%). Less frequently reported (<1%) were nausea or vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [ see Warnings and Precautions (5.3) ]. Hepatic elevations of aspartate aminotransferase (AST) (3.1%) or alanine aminotransferase (ALT) (3.3%). Less frequently reported (<1%) were elevations of alkaline phosphatase and bilirubin. Renal elevations of the BUN (1.2%). Less frequently reported (<1 %) were elevations of creatinine and the presence of casts in the urine. Central Nervous System headache or dizziness were reported occasionally (<1%). Genitourinary moniliasis or vaginitis were reported occasionally (<1%). Miscellaneous diaphoresis and flushing were reported occasionally (<1%). Investigations blood creatinine increased (0.6%). Other rarely observed adverse reactions (<0.1%) include 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 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 – pancreatitis, stomatitis and glossitis. • Genitourinary – oliguria, ureteric obstruction, post-renal acute renal failure • Dermatologic – exanthema, allergic dermatitis, urticaria, edema; acute generalized exanthematous pustulosis (AGEP) and isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis) have been reported. • Hematological Changes: Isolated cases of agranulocytosis (< 500/mm 3 ) have been reported, most of them after 10 days of treatment and following total doses of 20 g or more. • Nervous System Disorders: convulsion • Other, Adverse Reactions: symptomatic precipitation of ceftriaxone calcium salt in the gallbladder, kernicterus, oliguria, and anaphylactic or anaphylactoid reactions. 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 antibiotics: • 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). [ see Warnings and Precautions (5.13) ]. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced [ see Dosage and Administration (2.1) ]. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.