CEFAZOLIN

Cefazolin for Injection contains cefazolin sodium, a semi-synthetic cephalosporin. It is the sodium salt of 3-{[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-methyl}-8-oxo-7-[2-(1H-tetrazol-1-yl) acetamido]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid. The molecular formula is C 14 H 13 N 8 NaO 4 S 3 and molecular weight is 476.49. Structural Formula: Structural Formula Cefazolin for Injection is supplied as a sterile powder in single-dose vials. The 2 g/vial Cefazolin for Injection contains 2 grams of cefazolin (equivalent to 2.097 g of cefazolin sodium). The 3 g/vial Cefazolin for Injection contains 3 grams of cefazolin (equivalent to 3.144 grams of cefazolin sodium). The 2 g/vial Cefazolin for Injection contains 96 mg of sodium. The 3 g/vial Cefazolin for Injection contains 144 mg of sodium. After reconstitution with sterile water for injection, the drug product solution has a pH of 4.0 to 6.0. Cefazolin for Injection, 2 grams/vial, is intended for intravenous infusion or intravenous bolus injection. Cefazolin for Injection, 2 grams/vial is not for intramuscular administration. Cefazolin for Injection, 3 grams/vial, is intended for intravenous infusion only. Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection or intramuscular administration in adult or pediatric patients [see Dosage and Administration (2.1 , 2.2 , 2.3 )] . Structural Formula

Cefazolin for 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 1 month of age and older for whom appropriate dosing with this formulation can be achieved: Respiratory tract infections ( 1.1 ) Urinary tract infections ( 1.2 ) Skin and skin structure infections ( 1.3 ) Biliary tract infections ( 1.4 ) Bone and joint infections ( 1.5 ) Genital infections ( 1.6 ) Septicemia ( 1.7 ) Endocarditis ( 1.8 ) Perioperative prophylaxis in adult patients ( 1.9 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin for Injection and other antibacterial drugs, Cefazolin for 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 for Injection is indicated for the treatment of respiratory tract infections due to Streptococcus pneumoniae, Klebsiella species, Hemophilus influenzae, Staphylococcus aureus (methicillin-susceptible), and Group A beta-hemolytic streptococciin adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5) ]. Limitations of Use Injectable benzathine penicillin is considered to be the drug of choice in treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefazolin for Injection is indicated for the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of Cefazolin for Injection in the subsequent prevention of rheumatic fever are not available at present. 1.2 Urinary Tract Infections Cefazolin for Injection is indicated for the treatment of urinary tract infections due to Escherichia coli, Proteus mirabilis, and Klebsiella species (spp.) in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5) ]. 1.3 Skin and Skin Structure Infections Cefazolin for Injection is indicated for the treatment of skin and skin structure infections due to S. aureus (methicillin-susceptible) , Group A beta-hemolytic streptococci, and Streptococcus species (spp.) in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5) ]. 1.4 Biliary Tract Infections Cefazolin for Injection is indicated for the treatment of biliary tract infections due to E. coli, various isolates of Streptococcus spp. , P. mirabilis, Klebsiella spp., and S. aureus (methicillin-susceptible ) in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5) ]. 1.5 Bone and Joint Infections Cefazolin for Injection is indicated for the treatment of bone and joint infections due to S. aureus in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5) ]. 1.6 Genital Infections Cefazolin for Injection is indicated for the treatment of genital infections (i.e., prostatitis, epididymitis) due to E. coli, P. mirabilis, and Klebsiella species in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5) ]. 1.7 Septicemia Cefazolin for Injection is indicated for the treatment of septicemia due to S. pneumoniae, S. aureus (methicillin-susceptible), P. mirabilis, E. coli, and Klebsiella species in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5) ]. 1.8 Endocarditis Cefazolin for Injection is indicated for the treatment of endocarditis due to S. aureus (methicillin-susceptible) and Group A beta-hemolytic streptococci in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1 , 2.2 , 2.4 and 2.5) ]. 1.9 Perioperative Prophylaxis Cefazolin for Injection is indicated for perioperative prophylaxis in adults. The prophylactic administration of Cefazolin for 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). The perioperative use of Cefazolin for Injection is indicated in 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 for Injection 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 for Injection may be continued for 3 to 5 days following the completion of surgery. If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism so that appropriate therapy may be instituted [see Dosage and Administration (2.3) ] . 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin for Injection and other antibacterial drugs, Cefazolin for 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.

Cefazolin for Injection, 2 grams/vial: For intravenous infusion ( 2.1 ) For intravenous bolus injection ( 2.1 ) Not for intramuscular administration ( 2.1 ) Cefazolin for Injection, 3 grams/vial: For intravenous infusion only ( 2.1 ) Not for intravenous bolus injection administration or intramuscular administration ( 2.1 ) Recommended Dosage in Adult Patients with CLcr that is greater than or equal to 55 mL/min ( 2.2 ) 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)* 1 gram to 1.5 grams every 6 hours Perioperative prophylaxis 1 gram to 2 grams 1/2 to 1 hour prior to start of surgery 500 mg to 1 gram during surgery for lengthy procedures (e.g., 2 hours or more) 500 mg to 1 gram every 6 to 8 hours for 24 hours postoperatively * In rare instances, doses of up to 12 grams of cefazolin per day have been used. Recommended Dosage in Pediatric Patients with CLcr that is greater than or equal to 70 mL/min ( 2.3 ) Type of Infection Dose Frequency Mild to moderately severe infections 25 mg per kg 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 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 ) See full prescribing information for preparation and administration instructions ( 2.6 ) 2.1 Important Administration Instructions Cefazolin for Injection, 2 grams/vial: Cefazolin for Injection, 2 grams/vial, is for intravenous infusion or intravenous bolus injection in adult and pediatric patients [see Dosage and Administration (2.2 , 2.3 , and 2.6 )] . Not for intramuscular administration. Cefazolin for Injection, 3 grams/vial: Cefazolin for Injection, 3 grams/vial, is for intravenous infusion only in adult and pediatric patients [see Dosage and Administration ( 2.2 , 2.3 , 2.5 , and 2.6 )] . Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection or intramuscular administration [see Dosage and Administration (2.5 , 2.6) ] . 2.2 Recommended Dosage for the Treatment of Infections Recommended Dosage for the Treatment of Infections in Adults with Creatinine Clearance (CLcr) Equal to 55 mL/min or Greater The recommended adult dosages of Cefazolin for Injection for the treatment of infections [see Indications and Usage (1.1 to 1.8) ] are outlined in Table 1 below. Administration instructions are as follows: Cefazolin for Injection, 2 grams/vial is for intravenous infusion or intravenous bolus injection in adult patients [see Dosage and Administration (2.6) ] . Cefazolin for Injection, 3 grams/vial is only for intravenous infusion in adult patients. Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection in adult patients [see Dosage and Administration (2.6) ] . Cefazolin for Injection 2 grams/vial and 3 grams/vial are not for intramuscular injection. Table 1: Recommended Dosage in Adult Patients with CLcr Equal to 55 mL/min or Greater 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)* 1 gram to 1.5 grams every 6 hours * ln rare instances, doses of up to 12 grams of Cefazolin for Injection per day have been used. Recommended Dosage for the Treatment of Infections in Pediatric Patients 1 Month of Age and Older 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. Administration instructions are as follows: Cefazolin for Injection, 2 grams/vial is for intravenous infusion or intravenous bolus injection in pediatric patients [see Dosage and Administration (2.5 , 2.6) ] . Cefazolin for Injection, 3 grams/vial is only for intravenous infusion in pediatric patients. Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection in pediatric patients [see Dosage and Administration (2.6) ] . Cefazolin for Injection 2 grams/vial and 3 grams/vial are not for intramuscular injection. Table 2: Recommended Dosage in Pediatric Patients 1 Month of Age and Older 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 moderately severe 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 Recommended Dosage for Perioperative Prophylactic Use in Adults Recommended 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. Administration instructions are as follows: Cefazolin for Injection, 2 grams/vial is for intravenous infusion or intravenous bolus injection in adult patients [see Dosage and Administration (2.4 , 2.6) ] . Cefazolin for Injection, 3 grams/vial is only for intravenous infusion in adult patients. Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection in adult patients [see Dosage and Administration (2.4 , 2.6) ] . Cefazolin for Injection 2 grams/vial and 3 grams/vial are not for intramuscular injection. Table 3: Recommended Dosage for Perioperative Prophylaxis in Adults with CLcr of 55 mL/min or Greater Dose administered 1/2 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 post-operatively 1 gram to 2 grams 500 mg to 1 gram 500 mg to 1 gram every 6 hours to 8 hours It is important that (1) the preoperative dose be given just (1/2 hour to 1 hour) prior to the start of surgery so that adequate antibacterial levels are present in the serum and tissues at the time of initial surgical incision; and (2) Cefazolin for Injection be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels 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 for Injection may be continued for 3 to 5 days following the completion of surgery. 2.4 Recommended Dosage in Adult and Pediatric Patients with Renal Impairment Recommended Dosage in Adult Patients with CLcr less than 55 mL/min The recommended dosage of Cefazolin for Injection in adult patients with renal impairment (CLcr less than 55 mL/min) is outlined in Table 4 below. Table 4: Recommended Dosage in 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 every 12 hours 10 mL/min or less Half of recommended dose every 18 to 24 hours *All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Recommended Dosage in Pediatric Patients 1 Month of Age and Older with CLcr less than 70 mL/min The recommended dosage of Cefazolin for Injection in pediatric patients 1 month of age and older with renal impairment (CLcr less than 70 mL/min) is outlined in Table 5 below. Table 5: Recommended Dosage in Pediatric Patients 1 Month of Age and Older 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 *All dosage recommendations apply after an initial loading dose. 2.5 Pediatric Dosage Preparation Guide Table 6: Pediatric Dosage Guide 25 mg/kg/day Divided into 3 Doses Weight 25 mg/kg/day Divided into 3 Doses Kg Approximate Single Dose mg/every 8 hours Volume (mL) needed with dilution of 136 mg/mL Dose (mL) from final concentration 40 mg/mL Dose (mL) from final concentration 30 mg/mL Dose (mL) from final concentration 20 mg/mL 4.5 40 mg 0.29 mL 1 1.3 2 9 75 mg 0.55 mL 1.9 2.5 3.8 13.6 115 mg 0.85 mL 2.9 3.8 5.8 18.1 150 mg 1.1 mL 3.8 5 7.5 22.7 190 mg 1.4 mL 4.8 6.3 9.5 Table 7: Pediatric Dosage Guide 25 mg/kg/day Divided into 4 Doses Weight 25 mg/kg/day Divided into 4 Doses Kg Approximate Single Dose mg/every 6 hours Volume (mL) needed with dilution of 136 mg/mL Dose (mL) from final concentration 40 mg/mL Dose (mL) from final concentration 30 mg/mL Dose (mL) from final concentration 20mg/mL 4.5 30 mg 0.22 mL 0.8 1 1.5 9 55 mg 0.40 mL 1.4 1.8 2.8 13.6 85 mg 0.63 mL 2.1 2.8 4.3 18.1 115 mg 0.85 mL 2.9 3.8 5.8 22.7 140 mg 1.03 mL 3.5 4.7 7 Table 8: Pediatric Dosage Guide 50 mg/kg/day Divided into 3 Doses Weight 50 mg/kg/day Divided into 3 Doses Kg Approximate Single Dose mg/every 8 hours Volume (mL) needed with dilution of 136 mg/mL Dose (mL) from final concentration 40 mg/mL Dose (mL) from final concentration 30 mg/mL Dose (mL) from final concentration 20 mg/mL 4.5 75 mg 0.55 mL 1.8 2.5 3.7 9 150 mg 1.10 mL 3.7 5 7.5 13.6 225 mg 1.65 mL 5.6 7.5 11.2 18.1 300 mg 2.21 mL 7.5 10 15 22.7 375 mg 2.76 mL 9.3 12.5 18.7 Table 9: Pediatric Dosage Guide 50 mg/kg/day Divided into 4 Doses Weight 50 mg/kg/day Divided into 4 Doses Kg Approximate Single Dose mg/every 6 hours Volume (mL) needed with dilution of 136 mg/mL Dose (mL) from final concentration 40 mg/mL Dose (mL) from final concentration 30 mg/mL Dose (mL) from final concentration 20 mg/mL 4.5 55 mg 0.40 mL 1.4 1.8 2.8 9 110 mg 0.81 mL 2.8 3.7 5.5 13.6 170 mg 1.25 mL 4.3 5.7 8.5 18.1 225 mg 1.65 mL 5.6 7.5 11.3 22.7 285 mg 2.10 mL 7.1 9.5 14.3 2.6 Preparation of Cefazolin for Injection Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is evident in reconstituted fluids, the drug solutions should be discarded. Reconstituted solutions may range in color from pale yellow to yellow. Reconstitution and Dilution Intravenous Bolus Injection Administration (2g Vial only) For preparation of intravenous bolus injection (2 grams/vial only) use the following steps: Reconstitute Cefazolin for Injection, 2 grams/vial single-dose vials with Sterile Water for Injection according to Table 10 below. Shake well until dissolved. Further dilute vials with an additional 11 mL Sterile Water for Injection and shake well. Inject the solution intravenously slowly, directly, or through tubing for patients receiving parenteral fluids as follows: For 1 g dose, inject the solution intravenously slowly over 3 to 5 minutes and For 2 g dose, inject the solution intravenously slowly over 7 to 11 minutes Table 10: Volume and Concentration for Intravenous Bolus Injection Reconstitution (2 g vial only) Cefazolin for Injection Vial Contents Amount of Sterile Water for Injection for Reconstitution Approximate Reconstituted Concentration Approximate Available Volume 2 grams 5.5 mL 333 mg/mL 6.6 mL Pain associated with intravenous bolus administration has been reported with Cefazolin for Injection. Intermittent or Continuous Intravenous Infusion For intermittent or continuous intravenous infusion, reconstitute Cefazolin for Injection single-dose vials with Sterile Water for Injection according to Table 11 below and shake well . After reconstitution further dilute according to Table 11 using the following diluents: For intermittent or continuous intravenous infusion: Dilute reconstituted Cefazolin for Injection in one of the following solutions: Sodium Chloride Injection, USP 5% Dextrose Injection, USP Discard unused portion. Table 11: Volumes for Reconstitution and Dilution and Final Concentrations for Intermittent or Continuous Intravenous Infusion Cefazolin for Injection Vial Contents Amount of Sterile Water for Injection for Reconstitution Approximate Reconstituted Concentrations Recommended Diluent Volume Approximate Final Concentrations 2 grams 15 mL 136 mg/mL 50 mL or 100 mL 40 mg/mL or 20 mg/mL 3 grams 15 mL 196 mg/mL 100 mL 30 mg/mL Storage of Reconstituted and Diluted Solutions When reconstituted or diluted according to the instructions above, Cefazolin for Injection is stable for 24 hours at room temperature or for 7 days if stored under refrigeration at 2°C to 8°C (36°F to 46°F).

Cefazolin for 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) ]. Hypersensitivity to cefazolin or other cephalosporin class antibacterial drugs, penicillins, or other beta-lactams ( 4 )

The following clinically significant adverse reactions to cefazolin for 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 are gastrointestinal (nausea, vomiting, diarrhea), and allergic reactions (anaphylaxis, skin rash) ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following reactions have been reported: Gastrointestinal: Diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach cramps, anorexia and Clostridioides difficile colitis. Onset of Clostridioides difficile colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.3) ]. Allergic: Anaphylaxis, eosinophilia, itching, drug fever, skin rash, Stevens-Johnson syndrome. Hematologic: Neutropenia, leukopenia, thrombocytopenia, thrombocythemia. Hepatic: Transient rise in serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (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). 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: Erythema multiforme, toxic epidermal necrolysis, renal impairment, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic impairment including cholestasis, and pancytopenia.

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