CEFAZOLIN

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefazolin and other antibacterial drugs, cefazolin 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 is indicated for the treatment of the following infections when caused by susceptible bacteria. Cefazolin for Injection, USP is a cephalosporin antibacterial indicated in the treatment of the following infections caused by susceptible isolates of the designated microorganisms: 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 ); and perioperative prophylaxis ( 1.9 ). 1.1 Respiratory Tract Infections Respiratory tract infections due to Streptococcus pneumoniae , Staphylococcus aureus and Streptococcus pyogenes . Injectable benzathine penicillin is considered the drug of choice in treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefazolin 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 Urinary tract infections due to Escherichia coli and Proteus mirabilis. 1.3 Skin and Skin Structure Infections Skin and skin structure infections due to S. aureus , S. pyogenes , and Streptococcus agalactiae . 1.4 Biliary Tract Infections Biliary infections due to E. coli , various isolates of streptococci, P. mirabilis , and S. aureus . 1.5 Bone and Joint Infections Bone and joint infections due to S. aureus . 1.6 Genital Infections Genital infections due to E. coli and P. mirabilis. 1.7 Septicemia Septicemia due to S. pneumoniae , S. aureus , P. mirabilis, and E. coli. 1.8 Endocarditis Endocarditis due to S. aureus and S. pyogenes. 1.9 Perioperative Prophylaxis The prophylactic administration of cefazolin 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 may also be effective in surgical patients in whom infection at the operative site would present a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty). 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.

2 DOSAGE AND ADMINISTRATION Cefazolin for Injection USP, Pharmacy Bulk Package bag SmartPak ® should not be used in patients who require less than a 250 mg dose of Cefazolin. THIS PHARMACY BULK PACKAGE REQUIRES RECONSTITUTION WITH STERILE WATER FOR INJECTION, USP TO A CONCENTRATION OF 100 mg per mL AND FURTHER DILUTION IN 50 mL OF A COMPATIBLE SOLUTION. THIS IS A PHARMACY BULK PACKAGE - NOT FOR DIRECT INJECTION For intravenous use only over approximately 30 minutes. ( 2 ) THIS IS A PHARMACY BULK PACKAGE NOT FOR DIRECT INJECTION. Cefazolin for Injection USP, Pharmacy Bulk Package bag SmartPak ® should not be used in patients who require less than a 250 mg dose of cefazolin ( 2.1 ) Recommended Dosing Schedule in Adult Patients with CrCl Greater Than or Equal to 55 mL/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)* 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 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. ​Cefazolin for Injection USP, Pharmacy Bulk Package bag SmartPak ® ​ should not be used in patients who require less than a 250 mg dose of cefazolin ( 2.1 ) 2.1 Adult Population Cefazolin for Injection USP, Pharmacy Bulk Package bag SmartPak ® should not be used in patients who require less than a 250 mg dose of Cefazolin. Cefazolin for Injection should be reconstituted with Sterile Water for Injection, USP to a concentration of 100 mg per mL and further diluted in 50 mL of a compatible solution. The recommended adult dosages are outlined in Table 1 . Cefazolin for Injection should be administered intravenously (IV) over approximately 30 minutes. Table 1: Recommended Dosing Schedule in Adult Patients with CrCl Greater Than or Equal to 55 mL/min. *In rare instances, doses up to 12 grams of cefazolin per day have been used. Site and Type of Infection Dose Frequency Moderate to severe infections 500 mg to 1gram 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 2.2 Perioperative Prophylactic Use Cefazolin for Injection USP, Pharmacy Bulk Package bag SmartPak ® should not be used in patients who require less than a 250 mg dose of cefazolin. To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are: 1 gram to 2 grams I.V. administered 1⁄2 hour to 1 hour prior to the start of surgery. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram I.V. during surgery (administration modified depending on the duration of the operative procedure). 500 mg to 1 gram I.V. every 6 to 8 hours for 24 hours postoperatively. It is important that (i) the preoperative dose be given just (1⁄2 to 1 hour) prior 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 may 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 prophylactic administration of cefazolin should usually be discontinued within a 24-hour period after the surgical procedure. In surgery where the occurrence of infection m …

3 DOSAGE FORMS AND STRENGTHS 100 grams Cefazolin for Injection, USP, Pharmacy Bulk Package bag SmartPak ® 300 grams Cefazolin for Injection, USP, Pharmacy Bulk Package bag SmartPak ® THIS IS A PHARMACY BULK PACKAGE – NOT FOR DIRECT INJECTION Pharmacy Bulk Package bags, 100 grams and 300 grams ( 3 ) THIS IS A PHARMACY BULK PACKAGE – NOT FOR DIRECT INJECTION

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 for Injection, USP 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 ) ].

6 ADVERSE REACTIONS The following serious adverse reactions to cefazolin are described below and elsewhere in the labeling: Hypersensitivity reactions [See Warnings and Precautions ( 5.1 ) ] Clostridium difficile -associated diarrhea [see Warnings and Precautions ( 5.3 ) ] Most common adverse reactions: gastrointestinal (nausea, vomiting, diarrhea) and allergic reactions (anaphylaxis, urticaria, skin rash). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Samson Medical Technologies, L.L.C. at 1-877-418-3600 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience 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. As with other cephalosporins, reports of hepatitis have been received. Renal: As with other cephalosporins, 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. 6.2 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.

7 DRUG INTERACTIONS Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood levels. Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood concentrations. ( 7 )

8 USE IN SPECIFIC POPULATIONS Pediatric Use: Cefazolin for Injection USP – Pharmacy Bulk Package bag, SmartPak ® should not be used in pediatric patients who require less than a 250 mg dose of cefazolin. ( 8.4 ) Renal Impairment: Cefazolin for Injection USP – Pharmacy Bulk Package bag SmartPak ® should not be used in renally impaired patients who require less than a 250 mg dose of cefazolin. Lower daily dosage of Cefazolin for Injection is required in patients with impaired renal function (creatinine clearance less than 55 mL/min.) ( 8.6 ) 8.1 Pregnancy Pregnancy Category B . Reproduction studies have been performed in rats, mice, and rabbits at doses of 2000, 4000 and 240 mg/kg/day or 1-3 times the maximum recommended human dose on a body surface area basis. There was no evidence of impaired fertility or harm to the fetus due to cefazolin. 8.2 Labor and Delivery When cefazolin has been administered prior to caesarean section, drug concentrations in cord blood have been approximately one quarter to one third of maternal drug levels. The drug appears to have no adverse effect on the fetus. 8.3 Nursing Mothers Cefazolin is present in very low concentrations in the milk of nursing mothers. Caution should be exercised when cefazolin is administered to a nursing woman. 8.4 Pediatric Use Cefazolin for Injection USP, Pharmacy Bulk Package bag, SmartPak ® should not be used in pediatric patients who require less than a 250 mg adult of cefazolin. 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 Cefazolin for Injection USP, Pharmacy Bulk Package bag, SmartPak ® should not be used in patients with renal impairment who require less than a 250 mg dose of Cefazolin. When cefazolin is administered to patients with low urinary output because of impaired renal function (creatinine clearance less than 55 mL/minute), lower daily dosage is required [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.2 ) ].

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

11 DESCRIPTION Cefazolin for Injection USP, Pharmacy Bulk Package bag SmartPak ® should not be used in patients who require less than a 250 mg dose of cefazolin. Cefazolin for Injection, USP, is a sterile, lyophilized, semisynthetic cephalosporin for intravenous administration. It is the sodium salt of 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-carboxylic acid. Each Pharmacy Bulk Package contains 48 mg (2.1 mEq) of sodium per 1 gram of cefazolin sodium. Cefazolin for Injection, USP, is supplied in 100 grams and 300 grams SmartPak ® Pharmacy Bulk Packages bags equivalent. Each SmartPak ® Pharmacy Bulk Package bag contains cefazolin sodium equivalent to 100 grams or 300 grams of cefazolin. BEFORE ADMINISTRATION, THIS PHARMACY BULK PACKAGE REQUIRES RECONSTITUTION USING STERILE WATER FOR INJECTION, USP TO A CONCENTRATION OF 100 mg per mL AND FURTHER DILUTION IN 50 mL OF A COMPATIBLE SOLUTION AND INFUSED INTRAVENOUSLY. A Pharmacy Bulk Package is a container of a sterile preparation for intravenous use that contains many single doses. The contents are intended for use in a pharmacy admixture service and are restricted to the preparation of admixtures for intravenous infusion. The molecular formula is C 14 H 13 N 8 NaO 4 S 3 . The molecular weight is 476.49. The structural formula is as follows: The pH of the reconstituted solution is between 4 and 6. Structural Formula

16 HOW SUPPLIED/STORAGE AND HANDLING Cefazolin for Injection, USP, is available in the following SmartPak ® Pharmacy Bulk Packages bags: 100 grams * One Pharmacy Bulk Package bag Product No. 1100 NDC 66288-1100-1 300 grams ** One Pharmacy Bulk Package bag Product No. 1300 NDC 66288-1300-1 *Each 100 gram Pharmacy Bulk Package bag contains sterile cefazolin sodium equivalent to 100 grams of cefazolin. **Each 300 gram Pharmacy Bulk Package bag contains sterile cefazolin sodium equivalent to 300 grams of cefazolin. SmartPak ® system components are not made with natural rubber latex. As with other cephalosporins, cefazolin tends to darken depending on storage conditions within the stated recommendations; however, product potency is not adversely affected. Storage Conditions Prior to reconstitution, store dry powder at 20° to 25° C (68° to77° F). [See USP Controlled Room Temperature]. Protect From Light.