Cefazolin Sodium

5 WARNINGS AND PRECAUTIONS Hypersensitivity 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 ) Clostridioides difficile -associated Diarrhea (CDAD): May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. ( 5.3 ) Prothrombin Activity : May be associated with a fall in prothrombin activity. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated ( 5.5 ) 5.1 Hypersensitivity Reactions to Cefazolin, Cephalosporins, Penicillins, or Other Beta-lactams Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with Cefazolin for Injection and Dextrose Injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefazolin, cephalosporins, penicillins, or carbapenems. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefazolin for Injection and Dextrose Injection occurs, discontinue the drug. 5.2 Seizures in Patients with Renal Impairment Seizures may occur with the administration of Cefazolin for Injection and Dextrose Injection, particularly in patients with renal impairment when the dosage is not reduced appropriately. Discontinue Cefazolin for Injection and Dextrose Injection if seizures occur or make appropriate dosage adjustments in patients with renal impairment [see Dosage and Administration (2.4) ] . Anticonvulsant therapy should be continued in patients with known seizure disorders. 5.3 Clostridioides difficile -associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefazolin, 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 isolates 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 drug 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 drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.4 Hypersensitivity to Dextrose-containing Products Hypersensitivity reactions, including anaphylaxis, have been reported with administration of dextrose-containing 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 5.5 Prothrombin Activity Cefazolin for Injection and Dextrose Injection may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. 5.6 Risk of Development of Drug-resistant Bacteria Prescribing Cefazolin for Injection and Dextrose Injection in the absence of 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 antimicrobials, prolonged use of Cefazolin for Injection and Dextrose Injection may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken. 5.7 Drug/Laboratory Test Interactions Urinary Glucose The administration of cefazolin may result in a false-positive reaction with glucose in the urine when using glucose tests based on Benedict’s copper reduction reaction that determine the amount of reducing substances like glucose in the urine. It is recommended that glucose tests based on enzymatic glucose oxidase be used. Coombs’ Test Positive direct Coombs' tests have been reported during treatment with cefazolin. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' testing of newborns whose mothers have received cephalosporin antibacterial drugs before parturition, it should be recognized that a positive Coombs' test may be due to the drug. 5.8 Patients with Overt or Known Subclinical Diabetes Mellitus or Carbohydrate Intolerance As with other dextrose-containing solutions, Cefazolin 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.

6 ADVERSE REACTIONS The following serious adverse reactions to Cefazolin for Injection and Dextrose Injection are described below and elsewhere in the labeling: Hypersensitivity Reactions to Cefazolin, Cephalosporins, Penicillins, or Other Beta-lactams [see Warnings and Precautions (5.1) ] Seizures in Patients with Renal Impairment [see Warnings and Precautions (5.2) ] Clostridioides difficile -associated Diarrhea [see Warnings and Precautions (5.3) ] Prothrombin Activity [ see Warnings and Precautions (5.5) ] Adult and Pediatric Patients : Most common adverse reactions: gastrointestinal (nausea, vomiting, diarrhea), and allergic reactions (anaphylaxis, urticaria, skin rash). ( 6 ) Pediatric Patients with Perioperative Prophylaxis: The most frequently reported adverse reactions (incidence ≥ 5%) were nausea, infusion site pain, and headache. ( 6 ) 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 adverse reactions were reported from clinical trials: Gastrointestinal: Diarrhea, oral candidiasis (oral thrush), mouth ulcers, vomiting, nausea, stomach cramps, epigastric pain, heartburn, flatus, anorexia and pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.3) ] . Allergic: Anaphylaxis, eosinophilia, urticaria, itching, drug fever, skin rash, Stevens-Johnson syndrome. Hematologic: Neutropenia, leukopenia, thrombocytopenia, thrombocythemia. Hepatic: Transient rise in SGOT, SGPT, and alkaline phosphatase levels has been observed. Reports of hepatitis have been received. Renal: Reports of increased BUN and creatinine levels, as well as renal failure, have been received. Local Reactions: Instances of phlebitis have been reported at site of injection. Some induration has occurred. Other Reactions: Pruritus (including genital, vulvar and anal pruritus, genital moniliasis, and vaginitis). Dizziness, fainting, lightheadedness, confusion, weakness, tiredness, hypotension, somnolence and headache. Adverse Reactions in Pediatric Patients for Perioperative Prophylaxis Two studies (Study 1: NCT 3231228 and Study 2: NCT 01904357) were conducted to assess the safety and pharmacokinetics of a single 30-minute infusion of either 1 gram or 2 grams (based on weight) of Cefazolin for Injection and Dextrose Injection for perioperative prophylaxis in pediatric patients. Study 1 was a multicenter, open-label, non-comparative, parallel group study to evaluate the safety and pharmacokinetics of a single 30-minute infusion of either 1 gram or 2 grams (based on weight) of Cefazolin for Injection and Dextrose Injection for perioperative prophylaxis in 61 pediatric patients 10 to 17 years of age. Thirty-three subjects with a weight of at least 25 kg but less than 60 kg received a single-dose of 1 gram of cefazolin and 28 subjects with a weight of at least 60 kg received a single-dose of 2 grams of cefazolin. The mean age of the safety population was 14 years and ranged from 10 to 17 years. There were no adverse reactions leading to study discontinuation or deaths reported during the study. The most frequently reported adverse reactions were nausea (14.8%), infusion site pain (6.6%), and headache (4.9%). Study 2 was a multicenter, non-comparative study that evaluated the safety and pharmacokinetics of a single 30-minute infusion of either 1 gram or 2 grams (based on weight) of Cefazolin for Injection and Dextrose Injection for perioperative prophylaxis in 12 pediatric patients 10 to 12 years of age. Subjects weighing at least 25 kg to less than 50 kg received a single-dose of 1 gram of Cefazolin for Injection and Dextrose Injection and subjects weighing at least 50 kg to less than 85 kg received a single-dose of 2 grams of Cefazolin for Injection and Dextrose Injection. The safety findings in Study 2 in pediatric patients aged 10 to 12 years old were similar to those observed in adult patients and the pediatric patients aged 10 to 17 years old in Study 1. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of cefazolin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Serum sickness-like reaction Renal and urinary disorders: Acute tubulointerstitial nephritis (ATIN) Skin and subcutaneous tissue disorders: Acute generalized exanthematous pustulosis (AGEP) 6.3 Cephalosporin-class Adverse Reactions In addition to the adverse reactions listed above that have been observed in patients treated with cefazolin, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibacterials: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal impairment, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, a fall in prothrombin activity, hepatic impairment including cholestasis, and pancytopenia.