Cefazolin

6 ADVERSE REACTIONS The following serious adverse reactions to cefazolin injection are described below and elsewhere in the labeling: • Hypersensitivity reactions [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 ) 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. Additional pediatric use information is approved for B. Braun Medical Inc.'s CEFAZOLIN FOR INJECTION AND DEXTROSE INJECTION. However, due to B. Braun Medical Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 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, hepatic impairment including cholestasis, and pancytopenia.

4 CONTRAINDICATIONS • 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 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) ].

11 DESCRIPTION Cefazolin injection is a frozen, premixed, iso-osmotic, sterile, nonpyrogenic, single-dose solution containing either 1g Cefazolin, USP, equivalent to 1.05 g Cefazolin Sodium, USP per 50 mL or 2 g Cefazolin, USP, equivalent to 2.10 g Cefazolin Sodium, USP per 100 mL GALAXY container (PL 2040 Plastic). Dextrose, USP has been added to adjust osmolality (4 % as dextrose hydrous). The approximate osmolality for cefazolin 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 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

2 DOSAGE AND ADMINISTRATION If a dose of cefazolin injection is required that does not equal 1 gram or 2 grams, this product is not recommended for use and as an alternative formulation of cefazolin should be considered. ( 2.1 ) For intravenous use only over approximately 30 minutes. ( 2 ) 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 1 gram to 2 grams ½ to 1 hour prior to start of surgery 500 mg to 1 gram 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 2.1 Important Administration Instructions If a dose of cefazolin injection is required that does not equal 1 gram or 2 grams, this product is not recommended for use and as an alternative formulation of cefazolin should be considered. Administer cefazolin 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 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 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. . 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 injection intravenously over approximately 30 minutes. If a dose of cefazolin 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 [ 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 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 1 g 2 g 500 mg to 1 g 500 mg to 1 g every 6 hours to 8 hours If a dose of cefazolin injection is required that does not equal 1 gram or 2 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. Additional pediatric use information is approved for B. Braun Medical Inc.'s CEFAZOLIN FOR INJECTION AND DEXTROSE INJECTION. However, due to B. Braun Medical Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 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 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 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 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 *If a dose of cefazolin 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. 2.5 Preparation for Use of Cefazolin Injection Thawing of Plastic Container • Thaw frozen container at room temperature 20-25°C (68 - 77°F) or under refrigeration 2-8°C (36 - 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.

1 INDICATIONS AND USAGE Cefazolin 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 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 injection and other antibacterial drugs, cefazolin 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 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 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 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 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 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 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 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 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 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 injection is indicated is indicated for perioperative prophylaxis in adults for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.3 , 2.4 , 2.5 ) . The perioperative use of cefazolin injection is indicated in adult 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 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). Additional pediatric use information is approved for B. Braun Medical Inc.'s CEFAZOLIN FOR INJECTION AND DEXTROSE INJECTION. However, due to B. Braun Medical Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefazolin injection and other antibacterial drugs, cefazolin 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.

10 OVERDOSAGE Accidental overdosage resulting in seizures may occur in patients with renal impairment who receive doses greater than the recommended dosage of cefazolin injection [see Warnings and Precautions (5.2) ]. If seizures associated with accidental overdosage occur, discontinue cefazolin injection and give supportive treatment.

7 DRUG INTERACTIONS The renal excretion of cefazolin is inhibited by probenecid. Co-administration of probenecid with cefazolin injection is not recommended. Probenecid: The renal excretion of cefazolin is inhibited by probenecid. Co-administration of probenecid with cefazolin injection is not recommended. ( 7 ) Additional pediatric use information is approved for B. Braun Medical Inc.'s CEFAZOLIN FOR INJECTION AND DEXTROSE INJECTION. However, due to B. Braun Medical Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Cefazolin is an antibacterial drug [ see Microbiology (12.4) ]. 12.2 Pharmacodynamics The pharmacokinetic/pharmacodynamic relationship for cefazolin has not been evaluated in patients. 12.3 Pharmacokinetics Studies have shown that following intravenous administration of cefazolin to normal volunteers, mean serum concentrations peaked at approximately 185 mcg/mL and were approximately 4 mcg/mL at 8 hours for a 1 gram dose. The serum half-life for cefazolin is approximately 1.8 hours following IV administration. In a study of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg), cefazolin serum concentrations at the third hour of approximately 28 mcg/mL. Plasma pharmacokinetic parameters of cefazolin in healthy volunteers (N=12) following a single 15- minute IV infusion of 2 grams of cefazolin injection are summarized in Table 7 . Table 7: Mean (Standard Deviation) Plasma Pharmacokinetic Parameters of Cefazolin in Healthy Volunteers N C max (mcg/mL) T max T max reported as median (range) (h) AUC 0-inf (mcg*h/mL) T 1/2 (h) CL (L/h) V z (L) Single 2 grams Dose as a 15- Minute IV Infusion 12 280.9 (45.9) 0.25 (0.25-0.33) 509.9 (89.3) 2.01 (0.28) 4.03 (0.68) 11.50 (1.53) N= number of subjects observed; C max = maximum plasma concentration; Tmax = time to maximum plasma concentration; AUC 0-inf = area under the plasma concentration-time curve extrapolated to infinity; t 1/2 = apparent plasma terminal elimination half-life; CL = total clearance; V z = volume of distribution Studies in patients hospitalized with infections indicate that cefazolin produces mean peak serum concentrations approximately equivalent to those seen in healthy volunteers. Bile concentrations in patients without obstructive biliary disease can reach or exceed serum concentrations by up to five times; however, in patients with obstructive biliary disease, bile concentrations of cefazolin are considerably lower than serum concentrations (less than 1.0 mcg/mL). In synovial fluid, the cefazolin concentration becomes comparable to that reached in serum at about 4 hours after drug administration. Studies of cord blood show prompt transfer of cefazolin across the placenta. Cefazolin is present in very low concentrations in the milk of nursing mothers. Cefazolin is excreted unchanged in the urine. In the first 6 hours approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours. Additional pediatric use information is approved for B. Braun Medical Inc.'s CEFAZOLIN FOR INJECTION AND DEXTROSE INJECTION. However, due to B. Braun Medical Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 12.4 Microbiology Mechanism of Action Cefazolin is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Resistance Predominant mechanisms of bacterial resistance to cephalosporins include the presence of extended- spectrum beta-lactamases and enzymatic hydrolysis. Antimicrobial Activity Cefazolin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE (1) section. Gram-Positive Bacteria Staphylococcus aureus Staphylococcus epidermidis Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Methicillin-resistant staphylococci are uniformly resistant to cefazolin. Gram-Negative Bacteria Escherichia coli Proteus mirabilis Most isolates of indole positive Proteus ( Proteus vulgaris ), Enterobacter spp., Morganella morganii, Providencia rettgeri, Serratia spp., and Pseudomonas spp. are resistant to cefazolin. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

12.1 Mechanism of Action Cefazolin is an antibacterial drug [ see Microbiology (12.4) ].

12.2 Pharmacodynamics The pharmacokinetic/pharmacodynamic relationship for cefazolin has not been evaluated in patients.

12.3 Pharmacokinetics Studies have shown that following intravenous administration of cefazolin to normal volunteers, mean serum concentrations peaked at approximately 185 mcg/mL and were approximately 4 mcg/mL at 8 hours for a 1 gram dose. The serum half-life for cefazolin is approximately 1.8 hours following IV administration. In a study of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg), cefazolin serum concentrations at the third hour of approximately 28 mcg/mL. Plasma pharmacokinetic parameters of cefazolin in healthy volunteers (N=12) following a single 15- minute IV infusion of 2 grams of cefazolin injection are summarized in Table 7 . Table 7: Mean (Standard Deviation) Plasma Pharmacokinetic Parameters of Cefazolin in Healthy Volunteers N C max (mcg/mL) T max T max reported as median (range) (h) AUC 0-inf (mcg*h/mL) T 1/2 (h) CL (L/h) V z (L) Single 2 grams Dose as a 15- Minute IV Infusion 12 280.9 (45.9) 0.25 (0.25-0.33) 509.9 (89.3) 2.01 (0.28) 4.03 (0.68) 11.50 (1.53) N= number of subjects observed; C max = maximum plasma concentration; Tmax = time to maximum plasma concentration; AUC 0-inf = area under the plasma concentration-time curve extrapolated to infinity; t 1/2 = apparent plasma terminal elimination half-life; CL = total clearance; V z = volume of distribution Studies in patients hospitalized with infections indicate that cefazolin produces mean peak serum concentrations approximately equivalent to those seen in healthy volunteers. Bile concentrations in patients without obstructive biliary disease can reach or exceed serum concentrations by up to five times; however, in patients with obstructive biliary disease, bile concentrations of cefazolin are considerably lower than serum concentrations (less than 1.0 mcg/mL). In synovial fluid, the cefazolin concentration becomes comparable to that reached in serum at about 4 hours after drug administration. Studies of cord blood show prompt transfer of cefazolin across the placenta. Cefazolin is present in very low concentrations in the milk of nursing mothers. Cefazolin is excreted unchanged in the urine. In the first 6 hours approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours. Additional pediatric use information is approved for B. Braun Medical Inc.'s CEFAZOLIN FOR INJECTION AND DEXTROSE INJECTION. However, due to B. Braun Medical Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

20210728

10

3 DOSAGE FORMS AND STRENGTHS Injection: 1 gram cefazolin per 50 mL or 2 gram cefazolin per 100 mL in a single-dose GALAXY Container supplied as a frozen, premixed, iso-osmotic, sterile, nonpyrogenic solution. • 1 gram in 50 mL and 2 grams in 100 mL ( 3 )

Cefazolin Cefazolin Sodium CEFAZOLIN SODIUM CEFAZOLIN ANHYDROUS DEXTROSE SODIUM BICARBONATE WATER HYDROCHLORIC ACID SODIUM HYDROXIDE Cefazolin Cefazolin Sodium CEFAZOLIN SODIUM CEFAZOLIN ANHYDROUS DEXTROSE SODIUM BICARBONATE WATER HYDROCHLORIC ACID SODIUM HYDROXIDE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and Mutagenesis Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of cefazolin injection have not been performed. Impairment of Fertility Fertility studies conducted in rats subcutaneously administered cefazolin at doses of 2000 mg/kg/day (approximately 3 times the maximum recommended human dose based on body surface area comparison) showed no impairment of mating and fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and Mutagenesis Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of cefazolin injection have not been performed. Impairment of Fertility Fertility studies conducted in rats subcutaneously administered cefazolin at doses of 2000 mg/kg/day (approximately 3 times the maximum recommended human dose based on body surface area comparison) showed no impairment of mating and fertility.

NDA207131

Cefazolin

Cefazolin Sodium

0338-3503

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

12.4 Microbiology Mechanism of Action Cefazolin is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Resistance Predominant mechanisms of bacterial resistance to cephalosporins include the presence of extended- spectrum beta-lactamases and enzymatic hydrolysis. Antimicrobial Activity Cefazolin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE (1) section. Gram-Positive Bacteria Staphylococcus aureus Staphylococcus epidermidis Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Methicillin-resistant staphylococci are uniformly resistant to cefazolin. Gram-Negative Bacteria Escherichia coli Proteus mirabilis Most isolates of indole positive Proteus ( Proteus vulgaris ), Enterobacter spp., Morganella morganii, Providencia rettgeri, Serratia spp., and Pseudomonas spp. are resistant to cefazolin. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Container Label NDC 0338-3508-41 Cefazolin Injection, USP 2g / 100 mL (20 mg / mL) GALAXY Single-Dose Container Discard unused portion Code 2G3508 Sterile Nonpyrogenic Iso-osmotic Each 100 mL contains: 2g Cefazolin, USP, equivalent to 2.10g Cefazolin Sodium, USP with approx. 4 g Dextrose Hydrous, USP added to adjust osmolality, and Water for Injection, USP. pH may have been adjusted with sodium bicarbonate, or sodium hydroxide/hydrochloric acid. Dosage: For Intravenous Infusion Only. See prescribing information. Caution: Do not add supplemental medication or additives. Rx only Store at or below -20°C (-4°F). Thaw at room temperature 20-25°C (68 - 77°F) or under refrigeration 2-8°C (36 - 46°F). Product should not be thawed by immersion in water baths or by microwave irradiation. Do not force thaw. Thawed solution is stable for 30 days under refrigeration or 48 hours at room temperature. DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution is stable for 30 days under refrigeration or 48 hours at room temperature. Do not refreeze. Baxter Logo PL 2040 Plastic Baxter and Galaxy are trademarks of Baxter International Inc. Manufactured by Baxter Healthcare Corporation, Deerfield, IL 60015 USA Made in USA 07-34-00-0357 BAR CODE POSITION ONLY UPC-A 303383508416 Carton Label Thaw at room temperature 20-25°C (68 - 77°F) or under refrigeration 2-8°C (36 - 49°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution is stable for 30 days under refrigeration or 48 hours at room temperature. Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. PL 2040 Plastic 07-04-00-0112 Cegazolin Injection, USP 2g / 100 mL (20 mg / mL) Contains 6 units of Single-Dose bags. Each bag contains 100 mL. Iso-osmotic Store at or below -20°C (-4°F). Rx only NDC 0338-3508-41 Code 2G3508 *FOR BAR CODE POSITION ONLY (01) 20303383508410 GALAXY Container Sterile Nonpyrogenic Each 100 mL contains: 2 g Cefazolin, USP, equivalent to 2.10 g Cefazolin Sodium, USP with approx. 4 g Dextrose Hydrous, USP added to adjust osmolality, and Water for Injection, USP. pH may have been adjusted with sodium bicarbonate, or sodium hydroxide/hydrochloric acid. Dosage: For Intravenous Infusion Only. See prescribing information. Caution: Do not add supplemental medication or additives. Baxter Logo Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation , Deerfield, IL 60015 USA Serialized Shipper Label CODE: 2G3508 LOT: XXXXXXXXX EXP: DD MMM YY QTY: QQ SN: ######### CODE: 2G3508 LOT: XXXXXXXXX EXP: DD MMM YY QTY: QQ SN: ######### FOR PLACEMENT ONLY. (01) X XXXXXXX XXXXX X (21) XXXXXXXXX (17) XXXXX (10) XXXXXXXXX FOR PLACEMENT ONLY. (01) X XXXXXXX XXXXX X (21) XXXXXXXXX (17) XXXXX (10) XXXXXXXXX 07-06-77-681 Container Label Baxter Logo Cefazolin Injection, USP 1 g / 50 mL (20 mg / mL) GALAXY Single Dose Container Discard unused portion NDC 0338-3503-41 Code 2G3503 Sterile Nonpyrogenic Iso-osmotic Each 50 mL contains: 1g Cefazolin, USP, equivalent to 1.05g Cefazolin Sodium, USP with approx. 2 g Dextrose Hydrous, USP added to adjust osmolality. pH may have been adjusted with sodium bicarbonate or sodium hydroxide/hydrochloric acid. Usual Dosage: For Intravenous Infusion Only. See prescribing information. Cautions: Do not add supplementary medication or additives. Must not be used in series connections. Check for minute leaks and solution clarity. See prescribing information. Rx only Store at or below -20°C (-4°F). Thaw at room temperature 20-25°C (68 - 77°F) or under refrigeration 2-8°C (36 - 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution is stable for 30 days under refrigeration or 48 hours at room temperature. Do not refreeze. Baxter and Galaxy are registered trademarks of Baxter International Inc. Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in USA PL2040 Plastic 07-34-00-0356 * BAR CODE POSITION ONLY 303383503411 Carton Label Thaw at room temperature 20-25°C (68 - 77°F) or under refrigeration 2-8°C (36 - 41°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution is stable for 30 days under refrigeration or 48 hours at room temperature. Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Baxter and Galaxy are registered trademarks of Baxter International Inc. PL 2040 Plastic 07-04-00-0111 Baxter Logo Cefazolin Injection, USP 12 - 50 mL Single Dose Containers Iso-osmotic Store at or below -20°C/-4°F. Do not refreeze. 1 g / 50 mL (20 mg / mL) Baxter Healthcare Corporation Deerfield, IL 60015 USA NDC 0338-3503-41 Code 2G3503 *FOR BAR CODE POSITION ONLY (01) 20303383503415 GALAXY Container Sterile Nonpyrogenic Each 50 mL contains: 1g Cefazolin, USP, equivalent to 1.05g Cefazolin Sodium, USP with approx. 2 g Dextrose Hydrous, USP added to adjust osmolality. pH may have been adjusted with sodium bicarbonate or sodium hydroxide/hydrochloric acid. Usual Dosage: For Intravenous Infusion Only. See prescribing information. Cautions: Do not add supplementary medications or additives. Must not be used in series connections. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear . Rx only Serialized Shipper Label CODE: 2G3503 LOT: XXXXXXXXX EXP: DD MMM YY QTY: QQ SN: ######### FOR PLACEMENT ONLY. (01) X XXXXXXX XXXXX X (21) XXXXXXXXX (17) XXXXXX (10) XXXXXXXXX 07-06-77-680 Representative Cefazolin Container Label 0338-3508-41 1 of 2 Representative Cefazolin Container Label 0338-3508-41 2 of 2 Representative Cefazolin Carton Label 0338-3508-41 1 of 2 Representative Cefazolin Carton Label 0338-3508-41 2 of 2 Representative Sample of Serialized lbl Representative Cefazolin Container Label 0338-3503-41 1 of 2 Representative Cefazolin Container Label 0338-3503-41 2 of 2 Representative Cefazolin Carton Label 0338-3503-41 1 of 2 Representative Cefazolin Carton Label 0338-3503-41 2 of 2 Representative Cefazolin 1g Shipper Label 0338-3503-41

Baxter and Galaxy are registered trademarks of Baxter International Inc. Any other trademarks, product brands or images appearing herein are the property of their respective owners. Baxter Baxter Healthcare Corporation Deerfield, IL 60015 Made in USA 07-19-03-485

17 PATIENT COUNSELING INFORMATION Serious Allergic Reactions Advise patients that allergic reactions, including serious allergic reactions could occur and that serious reactions require immediate treatment and discontinuation of cefazolin injection. Patients should report to their health care provider any previous allergic reactions to cefazolin, cephalosporins, penicillins, or other similar antibacterials. Seizures Advise patients that seizures could occur with cefazolin injection. Instruct patients to inform a healthcare provider at once of any signs and symptoms of seizures, for immediate treatment, dosage adjustment, or discontinuation of cefazolin injection. Diarrhea Advise patients that diarrhea is a common problem caused by antibacterials, which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, 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 antibacterials. If this occurs, patients should contact a physician as soon as possible. Antibacterial Resistance Patients should be counseled that antibacterial drugs, including cefazolin injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefazolin 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 cefazolin injection or other antibacterial drugs in the future.

15 REFERENCES 1. Czarny D, Prichard PJ, Fennessy M, Lewis S. Anaphylactoid reaction to 50% solution of dextrose. Med J Aust 1980;2:255-258. 2. Guharoy, SR, Barajas M. Probably Anaphylactic Reaction to Corn-Derived Dextrose Solution. Vet Hum Toxicol 1991;33:609-610.

8.5 Geriatric Use Of the 920 subjects who received cefazolin in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [ see Dosage and Administration (2.3) and Warnings and Precautions (5.2) ].

8.2 Lactation Risk Summary Data from published literature report that cefazolin is present in human milk, but is not expected to accumulate in a breastfed infant. There are no data on the effects of cefazolin on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for cefazolin injection and any potential adverse effects on the breastfed child from cefazolin injection or from the mother’s underlying condition.

8.4 Pediatric Use Cefazolin injection is indicated for the treatment of respiratory tract infections, urinary tract infections, skin and skin structure infections, biliary tract infections, bone and joint infections, genital infections, septicemia, and endocarditis in pediatric patients for whom appropriate dosing with this formulation can be achieved [see Indications and Usage (1.1 to 1.8 )] . Safety and effectiveness of cefazolin injection in premature infants and neonates have not been established and is not recommended for use in this age group of pediatric patients. Dosing for cefazolin in pediatric patients younger than one month old has not been established. Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of cefazolin injection, and to avoid unintentional overdose, this product is not recommended for use if a dose of cefazolin injection that does not equal 1 gram or 2 grams is required and an alternative formulation of cefazolin should be considered [see Dosage and Administration (2.2 , 2 , 3 , 2.4 and 2.5) ] . The safety and effectiveness of cefazolin injection for perioperative prophylaxis have not been established in pediatric patients younger than 10 years old. Additional pediatric use information is approved for B. Braun Medical Inc.'s CEFAZOLIN FOR INJECTION AND DEXTROSE INJECTION. However, due to B. Braun Medical Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

8.1 Pregnancy Risk Summary Available data from published prospective cohort studies, case series and case reports over several decades with cephalosporin use, including cefazolin, in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Cefazolin crosses the placenta. Animal reproduction studies with rats, mice and rabbits administered cefazolin during organogenesis at doses 1 to 3 times the maximum recommended human dose (MRHD) did not demonstrate adverse developmental outcomes. In rats subcutaneously administered cefazolin prior to delivery and throughout lactation, there were no adverse effects on offspring at a dose approximately 2 times the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from case-control studies and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Reproduction studies have been performed in rats, mice and rabbits administered cefazolin during organogenesis at doses of 2000, 4000 and 240 mg/kg/day (approximately 1 to 3 times the maximum recommended human dose on a body surface area comparison). There was no evidence of any adverse effects on embryofetal development due to cefazolin. In a peri‑ postnatal study in rats, cefazolin administered subcutaneously up to 1200 mg/kg/day (approximately 2 times the MRHD based on body surface area comparison) to pregnant dams prior to delivery and through lactation caused no adverse effects on offspring.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published prospective cohort studies, case series and case reports over several decades with cephalosporin use, including cefazolin, in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Cefazolin crosses the placenta. Animal reproduction studies with rats, mice and rabbits administered cefazolin during organogenesis at doses 1 to 3 times the maximum recommended human dose (MRHD) did not demonstrate adverse developmental outcomes. In rats subcutaneously administered cefazolin prior to delivery and throughout lactation, there were no adverse effects on offspring at a dose approximately 2 times the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from case-control studies and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Reproduction studies have been performed in rats, mice and rabbits administered cefazolin during organogenesis at doses of 2000, 4000 and 240 mg/kg/day (approximately 1 to 3 times the maximum recommended human dose on a body surface area comparison). There was no evidence of any adverse effects on embryofetal development due to cefazolin. In a peri‑ postnatal study in rats, cefazolin administered subcutaneously up to 1200 mg/kg/day (approximately 2 times the MRHD based on body surface area comparison) to pregnant dams prior to delivery and through lactation caused no adverse effects on offspring. 8.2 Lactation Risk Summary Data from published literature report that cefazolin is present in human milk, but is not expected to accumulate in a breastfed infant. There are no data on the effects of cefazolin on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for cefazolin injection and any potential adverse effects on the breastfed child from cefazolin injection or from the mother’s underlying condition. 8.4 Pediatric Use Cefazolin injection is indicated for the treatment of respiratory tract infections, urinary tract infections, skin and skin structure infections, biliary tract infections, bone and joint infections, genital infections, septicemia, and endocarditis in pediatric patients for whom appropriate dosing with this formulation can be achieved [see Indications and Usage (1.1 to 1.8 )] . Safety and effectiveness of cefazolin injection in premature infants and neonates have not been established and is not recommended for use in this age group of pediatric patients. Dosing for cefazolin in pediatric patients younger than one month old has not been established. Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of cefazolin injection, and to avoid unintentional overdose, this product is not recommended for use if a dose of cefazolin injection that does not equal 1 gram or 2 grams is required and an alternative formulation of cefazolin should be considered [see Dosage and Administration (2.2 , 2 , 3 , 2.4 and 2.5) ] . The safety and effectiveness of cefazolin injection for perioperative prophylaxis have not been established in pediatric patients younger than 10 years old. Additional pediatric use information is approved for B. Braun Medical Inc.'s CEFAZOLIN FOR INJECTION AND DEXTROSE INJECTION. However, due to B. Braun Medical Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Of the 920 subjects who received cefazolin in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [ see Dosage and Administration (2.3) and Warnings and Precautions (5.2) ]. 8.6 Patients with Renal Impairment When cefazolin injection is administered to adult and pediatric patients with low urinary output because of impaired renal function (creatinine clearance less than 55 mL/min and 70 mL/min for adults and pediatric patients, respectively), lower daily dosage is required [see Dosage and Administration (2.4) and Warnings and Precautions (5.2) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Cefazolin injection is supplied as a premixed frozen iso-osmotic solution in 50 mL or 100 mL single-dose GALAXY plastic containers as follows: Code Product Description NDC Number 2G3503 1 gram cefazolin in 50 mL Supplied as 24 bags per carton NDC 0338-3503-41 2G3508 2 grams cefazolin in 100 mL Supplied as 12 bags per carton NDC 0338-3508-41 Store in a freezer capable of maintaining a temperature of -20°C (-4°F) or below [see Dosage and Administration (2.3) ]. Handle frozen product containers with care. Product containers may be fragile in the frozen state.