CEFAZOLIN

Cefazolin in Dextrose Injection is a frozen, premixed, iso-osmotic, sterile, nonpyrogenic, single-dose solution containing either 1 g Cefazolin, USP, equivalent to 1.05 g Cefazolin Sodium, USP per 50 mL, 2 g Cefazolin, USP, equivalent to 2.1 g Cefazolin Sodium, USP per 100 mL or 3 g Cefazolin, USP, equivalent to 3.15 g Cefazolin Sodium, USP per 150 mL Galaxy container (PL 2040 Plastic). Dextrose, USP has been added to adjust osmolality (4 % as dextrose hydrous). The approximate osmolality for Cefazolin in Dextrose Injection is 290 mOsmol/kg. Cefazolin Sodium is a semi-synthetic cephalosporin antibacterial for parenteral administration and has the following IUPAC nomenclature: Sodium (6R,7R)-3-[[(5-methyl-1,3,4- thiadiazol-2-yl)thio]methyl]-8-oxo-7-[2-(1 H -tetrazol-1-yl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylate. Its molecular formula is C 14 H 13 N 8 O 4 S 3 ·Na and its molecular weight is 454.51 (free acid). Cefazolin Sodium USP has the following structural formula: The sodium content is 48 mg/g of cefazolin sodium. The pH of Cefazolin in Dextrose Injection may have been adjusted with sodium bicarbonate, or sodium hydroxide/hydrochloric acid during manufacture. Water for injection, USP is added as drug vehicle. Contains no preservative. The solution is intended for intravenous use after thawing to room temperature. This Galaxy container (PL 2040 Plastic) is fabricated from a specially designed multilayer plastic (PL 2040). Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. However, the suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies. Cefazolin Sodium, USP Structural Formula.jpg

Cefazolin in Dextrose Injection is a cephalosporin antibacterial indicated for: • Treatment of the following infections caused by susceptible isolates of the designated microorganisms in adult and pediatric patients for whom appropriate dosing with this formulation can be achieved : ( 1 ) ο Respiratory tract infections ( 1.1 ); ο Urinary tract infections ( 1.2 ); ο Skin and skin structure infections ( 1.3 ); ο Biliary tract infections ( 1.4 ); ο Bone and joint infections ( 1.5 ); ο Genital infections ( 1.6 ); ο Septicemia ( 1.7 ); ο Endocarditis ( 1.8 ) • Perioperative prophylaxis in adults and pediatric patients aged 10 to 17 years old for whom appropriate dosing with this formulation can be achieved ( 1.9 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin in Dextrose Injection and other antibacterial drugs, Cefazolin in Dextrose Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.10 ). 1.1 Respiratory Tract Infections Cefazolin in Dextrose Injection is indicated for the treatment of respiratory tract infections due to Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus pyogenes in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5 ) and Use in Specific Populations (8.4) ] . Limitations of Use Injectable benzathine penicillin is considered the drug of choice in treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefazolin in Dextrose Injection is effective in the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of cefazolin in the subsequent prevention of rheumatic fever are not available. 1.2 Urinary Tract Infections Cefazolin in Dextrose Injection is indicated for the treatment of urinary tract infections due to Escherichia coli, and Proteus mirabilis in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5 ) and Use in Specific Populations (8.4) ] . 1.3 Skin and Skin Structure Infections Cefazolin in Dextrose Injection is indicated for the treatment of skin and skin structure infections due to S. aureus , S. pyogenes , and Streptococcus agalactiae in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5 ) and Use in Specific Populations (8.4) ] . 1.4 Biliary Tract Infections Cefazolin in Dextrose Injection is indicated for the treatment of biliary infections due to E. coli , various isolates of streptococci, P. mirabilis, and S. aureus in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5 ) and Use in Specific Populations (8.4) ] . 1.5 Bone and Joint Infections Cefazolin in Dextrose Injection is indicated for the treatment of bone and joint infections due to S. aureus in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5 ) and Use in Specific Populations (8.4) ] . 1.6 Genital Infections Cefazolin in Dextrose Injection is indicated for the treatment of genital infections due to E. coli, and P. mirabilis in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5 ) and Use in Specific Populations (8.4) ]. 1.7 Septicemia Cefazolin in Dextrose Injection is indicated for the treatment of septicemia due to S. pneumoniae, S. aureus , P. mirabilis, and E. coli in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5 ) and Use in Specific Populations (8.4) ] . 1.8 Endocarditis Cefazolin in Dextrose Injection is indicated for the treatment of endocarditis due to S. aureus and S. pyogenes in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5 ) and Use in Specific Populations (8.4) ]. 1.9 Perioperative Prophylaxis Cefazolin in Dextrose Injection is indicated for perioperative prophylaxis in adults and pediatric patients aged 10 to 17 years old for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.3 , 2.4 , 2.5 ) and Use in Specific Populations (8.4) ]. The perioperative use of Cefazolin in Dextrose Injection is indicated in adult and pediatric (aged 10 to 17 years old) surgical patients in whom infection at the operative site would present a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty). The prophylactic administration of Cefazolin in Dextrose Injection preoperatively, intraoperatively, and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures which are classified as contaminated or potentially contaminated (e.g., vaginal hysterectomy, and cholecystectomy in high-risk patients such as those older than 70 years, with acute cholecystitis, obstructive jaundice, or common duct bile stones). 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin in Dextrose Injection and other antibacterial drugs, Cefazolin in Dextrose Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

If a dose of Cefazolin in Dextrose Injection is required that does not equal 1 gram, 2 grams or 3 grams, this product is not recommended for use and an alternative formulation of cefazolin should be considered. ( 2.1 ) For intravenous use only administered over approximately 30 minutes. ( 2.1 ) Recommended Dosing Schedule in Adult Patients with CLcr Greater Than or Equal To 55 m L/min. ( 2.1 ) Site and Type of Infection Dose Frequency Moderate to severe infections 500 mg to 1 gram every 6 to 8 hours Mild infections caused by susceptible gram-positive cocci 250 mg to 500 mg every 8 hours Acute, uncomplicated urinary tract infections 1 gram every 12 hours Pneumococcal pneumonia 500 mg every 12 hours Severe, life-threatening infections (e.g., endocarditis, septicemia) In rare instances, doses of up to 12 grams of cefazolin per day have been used 1 gram to 1.5 grams every 6 hours Perioperative prophylaxis less than 120 kg: 1 gram to 2 grams ½ to 1 hour prior to start of surgery greater than or equal to 120 kg: 3 grams 500 mg to 1 gram additional dose during surgery for lengthy procedures 500 mg to 1 gram every 6 to 8 hours for 24 hours postoperatively Recommended Dosing Schedule in Pediatric Patients with CLcr Greater than or Equal to 70 mL/min. ( 2.1 , 2.2 , and 2.3 ) Site and Type of Infection Dose Frequency Moderate to severe infections For the treatment indications ( 1.1 to 1.8 ) 25 to 50 mg per kg divided into 3 or 4 equal doses Severe infections May increase to 100 mg per kg divided into 3 or 4 equal doses Perioperative prophylaxis (10 to 17 years old) less than 50 kg: 1 gram ½ to 1 hour prior to start of surgery greater than or equal to 50 kg: 2 grams 500 mg to 1 g additional dose during surgery for lengthy procedures 500 mg to 1 g every 6 to 8 hours for 24 hours postoperatively • Dosage adjustment is required for adult patients with CLcr that is less than 55 mL/min and pediatric patients with CLcr that is less than 70 mL/min. ( 2.4 and 8.6 ) • See full prescribing information for preparation and administration instructions. ( 2.5 ) 2.1 Important Administration Instructions If a dose of Cefazolin in Dextrose Injection is required that does not equal 1 gram, 2 grams or 3 grams, this product is not recommended for use and an alternative formulation of cefazolin should be considered. Administer Cefazolin in Dextrose Injection intravenously over approximately 30 minutes. 2.2 Dosage for the Treatment of Infections Dosage for the Treatment of Infections in Adults with Creatinine Clearance (CLcr) Equal to 55 mL/min or Greater The recommended adult dosages for the treatment of infections [see Indications and Usage (1.1 to 1.8) ] are outlined in Table 1 below. Administer Cefazolin in Dextrose Injection intravenously over approximately 30 minutes. Table 1: Recommended Dosing Schedule in Adult Patients with CLcr Greater Than or Equal To 55 mL/min. If a dose of Cefazolin in Dextrose Injection is required that does not equal 1 gram, 2 grams, or 3 grams, this product is not recommended for use and an alternative formulation of cefazolin should be considered. Site and Type of Infection Dose Frequency Moderate to severe infections 500 mg to 1 gram every 6 to 8 hours Mild infections caused by susceptible gram-positive cocci 250 mg to 500 mg every 8 hours Acute, uncomplicated urinary tract infections 1 gram every 12 hours Pneumococcal pneumonia 500 mg every 12 hours Severe, life-threatening infections (e.g., endocarditis, septicemia) In rare instances, doses of up to 12 grams of cefazolin per day have been used. 1 gram to 1.5 grams every 6 hours Dosage for the Treatment of Infections in Pediatric Patients with CLcr Equal to 70 mL/min or Greater The recommended pediatric dosages for the treatment of infections [see Indications and Usage (1.1 to 1.8) ] are outlined in Table 2 below. Administer Cefazolin in Dextrose Injection intravenously over approximately 30 minutes. If a dose of Cefazolin in Dextrose Injection is required that does not equal 1 gram, 2 grams, or 3 grams, this product is not recommended for use and an alternative formulation of cefazolin should be considered [see Use in Specific Populations (8.4) ]. Table 2: Recommended Dosage in Pediatric Patients with CLcr 70 mL/min or greater for Treatment of Infections [see Indications and Usage (1.1 to 1.8)] Type of Severity Recommended Total Daily Dosage Mild to moderate infections 25 mg/kg to 50 mg/kg, divided into 3 or 4 equal doses Severe infections May increase to 100 mg/kg, divided into 3 or 4 equal doses 2.3 Dosage for Perioperative Prophylaxis Dosage for Perioperative Prophylaxis in Adults with CLcr Equal to 55 mL/min or Greater To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended dosages are described in Table 3 below. Table 3: Recommended Dosage for Perioperative Prophylaxis in Adults with CLcr of 55 mL/min or Greater Body Weight (kg) Dose Administered (½ hour to 1 hour prior to the start of surgery) Additional Dose During Lengthy Operative Procedures (e.g., 2 hours or more) Dose for 24 Hours Postoperatively Less than 120 kg 1 gram to 2 grams 500 mg to 1 g 500 mg to 1 g every 6 hours to 8 hours Greater than or equal to 120 kg 3 grams If a dose of Cefazolin in Dextrose Injection is required that does not equal 1 gram, 2 grams, or 3 grams, this product is not recommended, and an alternative formulation of cefazolin should be considered. It is important that (i) the preoperative dose be given just prior (1/2 hour to 1 hour) to the start of surgery so that adequate antibacterial concentrations are present in the serum and tissues at the time of initial surgical incision; and (ii) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient concentrations of the antibacterial drug at the anticipated moments of greatest exposure to infective organisms. The perioperative prophylactic administration of cefazolin should usually be discontinued within a 24-hour period after the surgical procedure. In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery. Dosage for Perioperative Prophylaxis in Pediatric Patients Aged 10 to 17 Years Old with CLcr 70 mL/min or Greater To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are described in Table 4 below. Table 4: Recommended Dosage for Perioperative Prophylaxis in Pediatric with CLcr 70 mL/min or greater Aged 10 to 17 years Old If a dose of Cefazolin in Dextrose Injection is required that does not equal 1 gram or 2 grams, this product is not recommended for use and an alternative formulation of cefazolin should be considered. Body Weight (kg) Dose Administered ½ Hour to 1 Hour Prior to the Start of Surgery Additional Dose During Lengthy Operative Procedures (e.g., 2 Hours or More) Dose for 24 Hours Postoperatively Less than 50 kg 1 g 500 mg to 1 g 500 mg to 1 g every 6 hours to 8 hours Greater than or equal to 50 kg 2 g It is important that (i) the preoperative dose be given just prior (1/2 hour to 1 hour) to the start of surgery so that adequate antibacterial concentrations are present in the serum and tissues at the time of initial surgical incision; and (ii) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient concentrations of the antibacterial drug at the anticipated moments of greatest exposure to infective organisms. The administration of Cefazolin in Dextrose Injection for perioperative prophylaxis should usually be discontinued within a 24-hour period after the surgical procedure. In surgery where the occurrence of infection may be particularly devastating the administration of Cefazolin in Dextrose Injection for perioperative prophylaxis may be continued for 3 days to 5 days following the completion of surgery. 2.4 Dosage Recommendations in Adult and Pediatric Patients with Renal Impairment Dosage Recommendations in Adult Patients with CLcr less than 55 mL/min The dosage recommendation for Cefazolin in Dextrose Injection in adult patients with renal impairment (CLcr less than 55 mL/min) is outlined in Table 5 below. Table 5: Dosage Recommendation for Adult Patients with CLcr less than 55 mL/min Creatinine Clearance Dose Frequency 35 to 54 mL/min Recommended dose every 8 hours or longer 11 to 34 mL/min Half of recommended dose If the recommended dose in adult patients with creatinine clearance equal to 35 mL/min or greater is 1 gram, then this product is not recommended for use in patients with creatinine clearance less than 35 mL/min and an alternative formulation of cefazolin should be considered. every 12 hours 10 mL/min or less Half of recommended dose every 18 to 24 hours Dosage Recommendations in Pediatric Patients with CLcr less than 70 mL/min The dosage recommendation for Cefazolin in Dextrose Injection in pediatric patients with renal impairment (CLcr less than 70 mL/min) is outlined in Table 6 below. Table 6: Recommended Dosage in Pediatric Patients with CLcr less than 70 mL/min If a dose of Cefazolin in Dextrose Injection is required that does not equal 1 gram, 2 or 3 grams, this product is not recommended for use and an alternative formulation of cefazolin should be considered. Creatinine Clearance Recommended Dosage 40 to 70 mL/min 60% of the normal daily dose given in equally divided doses every 12 hours 20 to 40 mL/min 25% of the normal daily dose given in equally divided doses every 12 hours 5 to 20 mL/min 10% of the normal daily dose every 24 hours 2.5 Preparation for Use of Cefazolin in Dextrose Injection Thawing of Plastic Container • Thaw frozen container at room temperature 20°C to 25°C (68°F to 77°F) or under refrigeration 2°C to 8°C (36°F to 46°F). Product should not be thawed by immersion in water baths or by microwave irradiation. Do not force thaw. • No further dilution is necessary. • Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired. • Do not add supplementary medication. • The container should be visually inspected. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection the solution remains cloudy or if an insoluble precipitate is noted or if any seals are not intact, the container should be discarded. • The thawed solution is stable for 30 days under refrigeration (5°C/41°F) or 48 hours at 25°C/77°F. Do not refreeze thawed antibacterial drugs. Preparation for Administration • Suspend container from support. • Remove protector from outlet port at bottom of container. • Attach Intravenous administration set to outlet port. Refer to the manufacturer’s instructions accompanying the administration set for complete directions.

Hypersensitivity to cefazolin or other cephalosporin class antibacterial drugs, penicillins, or other beta-lactams ( 4.1 ) 4.1 Hypersensitivity to Cefazolin or the Cephalosporin Class of Antibacterial Drugs, Penicillins, or Other Beta-lactams Cefazolin in Dextrose Injection is contraindicated in patients who have a history of immediate hypersensitivity reactions (e.g., anaphylaxis, serious skin reactions) to cefazolin or the cephalosporin class of antibacterial drugs, penicillins, or other beta-lactams [ see Warnings and Precautions (5.1) ].

The following serious adverse reactions to Cefazolin in 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) ] • 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 Baxter Healthcare at 1-866-888-2472 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 for injection and dextrose injection and 28 subjects with a weight of at least 60 kg received a single dose of 2 grams of cefazolin for injection and dextrose injection. 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) Cardiac disorders: Kounis syndrome 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.

The renal excretion of cefazolin is inhibited by probenecid. Co-administration of probenecid with Cefazolin in Dextrose Injection is not recommended. Probenecid : The renal excretion of cefazolin is inhibited by probenecid. Co-administration of probenecid with Cefazolin in Dextrose Injection is not recommended. ( 7 )