CEFAZOLIN

Cefazolin for Injection, USP is a semi-synthetic cephalosporin for parenteral administration. 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. Structural Formula: Cefazolin for Injection, USP is a sterile white or off-white powder or crystalline powder. The sodium contect is 48 mg (2 mEq sodium ion) per 1 gram of cefazolin. cefazolin-structure

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin for Injection, USP and other antibacterial drugs, Cefazolin for Injection, USP 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, USP is indicated for the treatment of the following serious infections due to susceptible organisms. 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 ) Perioperative prophylaxis. ( 1.9 ) 1.1 Respiratory Tract Infections Respiratory tract infections due to Streptococcus pneumoniae , Klebsiella species, H. influenzae , Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), and group A beta-hemolytic streptococci. 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 effective in 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 Urinary tract infections due to Escherichia coli , and Proteus mirabilis , Klebsiella species, and some strains of enterobacter and enterococci. 1.3 Skin and Skin Structure Infections Skin and skin structure infections due to S. aureus (penicillin-sensitive and penicillin-resistant), group A beta-hemolytic streptococci, and other strains of streptococci. 1.4 Biliary Tract Infections Biliary infections due to E. coli , various strains of streptococci, P. mirabilis , Klebsiella species, 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, Klebsiella species, and some strains of enterococci. 1.7 Septicemia Septicemia due to S. pneumoniae, S. aureus (penicillin-sensitive and penicillin-resistant), P. mirabilis , E. coli , and Klebsiella species. 1.8 Endocarditis Endocarditis due to S. aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci. 1.9 Perioperative Prophylaxis 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 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 [ see Dosage and Administration (2.1) ].

For intravenous or intramuscular use. ( 2 ) 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) 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 2.1 Adult Population The recommended adult dosages are outlined in Table 1 . Cefazolin for Injection should be administered intravenously (IV) or intramuscularly (IM). Table 1: Recommended Dosing Schedule in Adult Patients with CrCl Greater Than or Equal to 55 mL/min. 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 2.2 Perioperative Prophylactic Use To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are: 1 gram IV or IM 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 IV or IM during surgery (administration modified depending on the duration of the operative procedure). 500 mg to 1 gram IV or IM every 6 to 8 hours for 24 hours postoperatively. 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 antibiotic levels are present in the serum and tissues at the time of initial surgical incision; and (ii) Cefazolin for Injection be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic 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 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. 2.3 Patients with Renal Impairment Cefazolin for Injection may be used in patients with reduced renal function with the following dosage adjustments outlined in Table 2 . Patients with a creatinine clearance of 55 mL/min. or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min. or serum creatinine of 1.6 to 3.0 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min. or serum creatinine of 3.1 to 4.5 mg % should be given 1/2 the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min. or less or serum creatinine of 4.6 mg % or greater should be given 1/2 the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis: [ see Clinical Pharmacology (12.3) ]. Table 2: Dosage Adjustment for Patients with Renal Impairment Creatinine Clearance Dose Frequency 55 mL/min. or greater full dose normal frequency 35 to 54 mL/min. full dose every 8 hours or longer 11 to 34 mL/min. 1/2 usual dose every 12 hours 10 mL/min. or less 1/2 usual dose every 18 to 24 hours 2.4 Pediatric Population In pediatric patients, a total daily dosage of 25 to 50 mg per kg (approximately 10 to 20 mg per pound) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg per kg (45 mg per pound) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin for injection in these patients is not recommended. Pediatric Dosage Guide Weight 25 mg/kg/Day Divided into 3 Doses 25 mg/kg/Day Divided into 4 Doses Lbs Kg Approximate Single Dose mg/q8h Vol. (mL) needed with dilution of 125 mg/mL Approximate Single Dose mg/q6h Vol. (mL) needed with dilution of 125 mg/mL 10 4.5 40 mg 0.35 mL 30 mg 0.25 mL 20 9 75 mg 0.6 mL 55 mg 0.45 mL 30 13.6 115 mg 0.9 mL 85 mg 0.7 mL 40 18.1 150 mg 1.2 mL 115 mg 0.9 mL 50 22.7 190 mg 1.5 mL 140 mg 1.1 mL Weight 50 mg/kg/Day Divided into 3 Doses 50 mg/kg/Day Divided into 4 Doses Lbs Kg Approximate Single Dose mg/q8h Vol. (mL) needed with dilution of 225 mg/mL Approximate Single Dose mg/q6h Vol. (mL) needed with dilution of 225 mg/mL 10 4.5 75 mg 0.35 mL 55 mg 0.25 mL 20 9 150 mg 0.7 mL 110 mg 0.5 mL 30 13.6 225 mg 1 mL 170 mg 0.75 mL 40 18.1 300 mg 1.35 mL 225 mg 1 mL 50 22.7 375 mg 1.7 mL 285 mg 1.25 mL In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min.), 60 percent of the normal daily dose given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min.), 25 percent of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min.) may be given 10 percent of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose. 2.5 Preparation of Parenteral Solution Parenteral drug products should be SHAKEN WELL when reconstituted, and inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solutions should be discarded. When reconstituted or diluted according to the instructions below, Cefazolin for Injection is stable for 24 hours at room temperature or for 10 days if stored under refrigeration (5°C or 41°F). Reconstituted solutions may range in color from pale yellow to yellow without a change in potency. Single-Dose Vials For IM injection, IV direct (bolus) injection or IV infusion, reconstitute with Sterile Water for Injection according to the following table. SHAKE WELL. Vial Size Amount of Diluent Approximate Concentration Approximate Available Volume 1 g 2.5 mL 330 mg/mL 3 mL 2.6 Intramuscular Administration Reconstitute vials with Sterile Water for Injection according to the dilution table above. Shake well until dissolved. Cefazolin should be injected into a large muscle mass. Pain on injection is infrequent with Cefazolin for Injection. 2.7 Intravenous Administration Direct (bolus) injection: Following reconstitution according to the above table, further dilute vials with approximately 5 mL Sterile Water for Injection. Inject the solution slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below). Intermittent or continuous infusion: Dilute reconstituted Cefazolin for Injection in 50 to 100 mL of 1 of the following solutions: Sodium Chloride Injection, USP 5% or 10% Dextrose Injection, USP 5% Dextrose in Lactated Ringer’s Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP 5% Dextrose and 0.2% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP Invert Sugar 5% or 10% in Sterile Water for Injection Ringer’s Injection, USP 5% Sodium Bicarbonate Injection, USP Prior to administration parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

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 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 reactions have been reported: 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 Apotex Corp. at 1-800-706-5575 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), vomiting, nausea, stomach cramps, anorexia, and pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment [ see Warnings and Precautions (5.3) ]. Nausea and vomiting have been reported rarely. Allergic: Anaphylaxis, eosinophilia, 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: Rare instances of phlebitis have been reported at site of injection. Pain at the site of injection after intramuscular administration has occurred infrequently. Some induration has occurred. Other Reactions: Genital and anal pruritus (including vulvar pruritus, genital moniliasis, and vaginitis). 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.

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 )