Cefazolin for Injection USP (Pfizer Canada) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Cefazolin for Injection USP is indicated in the treatment of the following infections when caused by susceptible strains of the listed organisms:

RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae, Staphylococcus aureus (penicillin-sensitive and penicillin-resistant) and group A beta-haemolytic streptococci.

URINARY TRACT INFECTIONS caused by Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae and some strains of enterobacter and enterococci. See NOTE below.

SKIN AND SOFT TISSUE INFECTIONS caused by Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), group A beta-haemolytic streptococci and other strains of streptococci.

BONE AND JOINT INFECTIONS caused by Staphylococcus aureus.

SEPTICEMIA caused by Streptococcus pneumoniae, Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), Proteus mirabilis, Escherichia coli and Klebsiella pneumoniae. See NOTE below.

ENDOCARDITIS caused by Staphylococcus aureus (penicillin-sensitive and penicillin-resistant) and group A beta-haemolytic streptococci.

Determine susceptibility of the causative organism to cefazolin sodium by performing appropriate culture and susceptibility studies should be performed. (see MICROBIOLOGY for disc susceptibility tests and dilution techniques).

NOTE: Most strains of Enterococci, indole positive Proteus (P.vulgaris), Enterobacter cloacae, Morganella morganii, Providencia rettgeri and methicillin-resistant Staphylococci are resistant. Serratia, Pseudomonas, and Acinetobacter calcoaceticus (formerly Mima and Herellea species) are almost uniformly resistant to cefazolin (see MICROBIOLOGY).

Perioperative Prophylaxis: In patients undergoing potentially contaminated surgical procedures, and in patients in whom infection would pose a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty), the preoperative, intraoperative and postoperative administration of Cefazolin for Injection USP may reduce the incidence of certain post-operative infections.

Identification of the causative organisms should be made by culture should signs of infection occur, so that appropriate therapy may be instituted.

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 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.

CONTRAINDICATIONS

Cefazolin sodium is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

WARNINGS AND PRECAUTIONS

WARNINGS

Cefazolin sodium should be used with caution in penicillin - allergic patients. There is clinical evidence of partial cross-allergenicity of the penicillins and the cephalosporins. There are instances of patients who have had reactions to both penicillins and cephalosporins (including fatal anaphylaxis after parenteral use). Clinical and laboratory evidence of partial cross-allergenicity of the two drug classes exists.

Cefazolin sodium should be administered cautiously and then only when absolutely necessary to any patient who has demonstrated allergy, particularly to drugs. Immediate emergency treatment with epinephrine is indicated for serious anaphylactoid reactions. As indicated, oxygen, intravenous steroids, and airway management, including intubation, should also be employed.

There have been reports of pseudomembranous colitis with the use of cephalosporins. It is, therefore, important to consider its diagnosis in patients who develop diarrhea in association with antibiotic use.

Susceptibility/Resistance

Development of Drug Resistant Bacteria

Prescribing Cefazolin for Injection USP in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug- resistant bacteria.

PRECAUTIONS

General

The overgrowth of non-susceptible organisms may result from the prolonged use of cefazolin sodium. It is essential that the patient be carefully observed. In patients with a history of lower gastrointestinal disease, particularly colitis, cefazolin sodium should be prescribed with caution.

Clinitest^® tablets solution, but not enzyme – based tests such as Clinistix^® and Tes-Tape^® may falsely indicate glucose in the urine of patients on cefazolin.

Positive direct and indirect Coombs’ tests have been reported during treatment with cefazolin. These may also occur in neonates whose mothers received cephalosporins before delivery. The clinical significance of this effect has not been established.

Renal: Caution should be exercised in treating patients with pre-existing renal damage although cefazolin has not shown evidence of nephrotoxicity.

Patients with low urinary output due to impaired renal function should be administered reduced daily dosages of cefazolin. (See Dosage in Patients with Reduced Renal Function.) Blood levels of cefazolin in dialysis patients remain fairly high and should be monitored.

Probenecid may decrease renal tubular secretion of cefazolin when used concurrently with cefazolin sodium, resulting in increased and prolonged cefazolin blood levels.

In beta-haemolytic streptococcal infections, treatment should be continued for at least 10 days, to minimize possible complications associated with the disease.

Special populations

Pregnant Women: The safety of the use of cefazolin sodium during pregnancy has not been established.

Nursing Women: Very low concentrations of cefazolin sodium are found in the milk of nursing mothers. Cefazolin sodium should be administered with caution to a nursing woman.

Children: The safety of the use of cefazolin sodium in prematures and infants under one month of age has not been established.

ADVERSE REACTIONS

The following reactions have been reported:

Gastrointestinal: Diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach cramps, anorexia. During antibiotic treatment symptoms of pseudomembranous colitis can appear. There have been rare reports of nausea and vomiting.

Allergic: Allergic reactions occur infrequently and include: anaphylaxis, eosinophilia, itching, drug fever, skin rash.

Haematologic: Neutropenia, anemia, leukopenia, thrombocythemia, positive direct and indirect antiglobulin (Coombs’) tests.

Hepatic and Renal: Without clinical evidence of renal or hepatic impairment transient increases in AST (SGOT), ALT (SGPT), BUN and alkaline phosphatase levels have been observed. Transient hepatitis and cholestatic jaundice have been reported rarely, as with some penicillins and some other cephalosporins.

Local Reactions: Phlebitis at the site of injection has occurred rarely. Infrequently there is pain at the site of injection following intramuscular injection. Some induration has been reported.

Other Reactions: Vulvar pruritus, genital moniliasis, vaginitis and anal pruritus.

DRUG INTERACTIONS

The renal tubular secretion of cefazolin may be decreased when probenecid is used concurrently, resulting in increased and prolonged cefazolin blood levels.

DOSAGE AND ADMINISTRATION

Dosing considerations

After reconstitution cefazolin sodium may be administered either intramuscularly or intravenously. In both cases total daily dosages are the same.

Recommended Dose and Dosage Adjustment

Adults

Adult Dosage Guide

*This dosage recommendation applies to intramuscular use. The efficacy of cefazolin sodium when administered intravenously at 12-hour intervals has not been established.

Cefazolin sodium has been administered in dosages of 6 g per day in serious infections such as endocarditis.

Treatment should be continued for at least 10 days in beta-haemolytic streptococcal infections to minimize possible complications associated with the disease.

Dosage in Patients with Reduced Renal Function:

After an initial loading dose appropriate to the severity of the infection, the following reduced dosage schedule is recommended:

Dosage Guide for Patients with Renal Impairment

Perioperative Prophylactic Use:

The recommended dosage regimen to prevent postoperative infection in contaminated or potentially contaminated surgery is:

1. a) One gram intravenously or intramuscularly administered ½ hour to 1 hour prior to the start of surgery so that at the time of the initial surgical incision adequate antibiotic levels are present in the serum and tissues.
2. b) For lengthy operative procedures (e.g., 2 hours or more) 0.5 to 1.0 g administered intravenously or intramuscularly during surgery. (Administration should be modified according to the duration of the operative procedure and the time of greatest exposure to infective organisms.)
3. c)

   Postoperatively, 0.5 to 1.0 gram intravenously or intramuscularly every 6 to 8 hours for

   24 hours postoperatively. The prophylactic administration of cefazolin sodium may be continued for 3 to 5 days following the completion of surgery in which the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty).

Children:

A total daily dosage of 25 to 50 mg per kg (approximately 10 to 20 mg per pound) of body weight, divided into three or four equal doses, is effective for most mild to moderately severe infections in children.

For severe infections total daily dosage may be increased to 100 mg per kg (45 mg per pound) of body weight. The use of cefazolin in prematures and in infants under one month is not recommended since the safety for use in these patients has not been established.

Paediatric Dosage Guide - 25 mg/kg/day

* 125 mg/mL concentration may be obtained by reconstituting the 500 mg vial with 3.8 mL of diluent.

Paediatric Dosage Guide - 50 mg/kg/day

* 225 mg/mL concentration may be obtained by reconstituting the 500 mg vial with 2.0 mL of diluent.

Treatment with 60% of the normal daily dose may be administered in divided doses every 12 hours to children with mild to moderate renal impairment (Ccr 0.67-1.17 mL/s). Children with moderate to severe renal impairment (Ccr 0.33-0.87 mL/s) should be given 25 percent of the normal daily dose in equally divided doses every 12 hours, and children with severe renal impairment (Ccr 0.08-0.33 mL/s) should receive 10 percent of the normal daily dose every 24 hours.

All dosage recommendations apply after an initial loading dose.

Administration

Cefazolin sodium may be administered intravenously or intramuscularly after reconstitution.

Intramuscular Administration:

Inject the reconstituted solution into a large muscle mass. Pain on injection of cefazolin sodium occurs infrequently.

Intravenous Administration:

Direct (bolus) injection: Inject the appropriately diluted reconstituted solution slowly over 3 to 5 minutes directly into a vein or through tubing for patients receiving parenteral fluids.

Intermittent or Continuous Infusion: The reconstituted solution can be administered along with primary intravenous fluid management programs in a volume control set or in a separate secondary i.v. bottle.

Reconstitution:

Parenteral Products:

Parenteral drug products should be SHAKEN TO DISSOLVE ALL POWDER when reconstituted and inspected visually for particulate matter prior to administration. The drug solutions should be discarded if particulate matter is evident in reconstituted fluids.

Reconstituted solutions may range in colour from pale yellow to yellow without a change in potency. For intramuscular and direct intravenous injection, the reconstituted solutions should be stored in original containers (Type I USP glass vial and grey bromobutyl rubber stopper).

For Intramuscular Injection:

Single Dose Vials:

Reconstitute according to the table which follows. SHAKE TO DISSOVLE ALL POWDER.

Single Dose Vial Reconstitution Table

For Direct Intravenous (bolus) Injection:

Single Dose Vials:

Reconstitute as directed above. SHAKE TO DISSOLVE ALL POWDER. A minimum of 10 mL of Sterile Water for Injection should be used to dilute the reconstituted solution. The reconstituted solutions should be stored in glass containers.

Pharmacy Bulk Vial:

The Pharmacy Bulk Vial is intended for use in hospitals with recognized IV admixture programs and is restricted to the preparation of admixtures for infusion. It is not for direct infusion.

Pharmacy Bulk Vials should be used for intravenous use only. Add, according to the table below, Sterile Water for Injection or Sodium Chloride Injection. SHAKE TO DISSOLVE ALL POWDER

Pharmacy Bulk Vial Reconstitution Table

The vial is intended for single puncture and multiple dispensing, and the vial contents should be used within 8 hours.

For intermittent or continuous intravenous infusion, reconstituted Cefazolin for Injection USP may be further diluted as follows:

Single Dose Vials:

Reconstitute according to the Single Dose Vial Reconstitution Table above. SHAKE TO DISSOLVE ALL POWDER. Further dilute the reconstituted cefazolin sodium to 50 to 100 mL in one of the following solutions:

Sodium Chloride Injection 0.9%

Dextrose Injection 5% or 10%

Dextrose 5% in Lactated Ringer’s Injection

Dextrose 5% and Sodium Chloride Injection 0.9% (also may be used with Dextrose 5% and Sodium Chloride Injection 0.45% or 0.2%)

Lactated Ringer’s Injection

Ringer’s Injection

Sodium Bicarbonate 5% in Sterile Water for Injection

Pharmacy Bulk Vial:

Reconstitute according to the Pharmacy Bulk Vial Reconstitution Table. SHAKE TO DISSOLVE ALL POWDER. Further dilute aliquots in 50 to 100 mL of Sterile Water for Injection or one of the solutions listed above.

The further diluted solutions above should be used within 24 hours at room temperature or 72 hours under refrigeration from the time of initial puncture.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

There is a lack of experience with acute cefazolin sodium overdosage. Supportive therapy should be instituted according to symptoms in cases of suspected overdosage.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Cefazolin sodium is a cephalosporin antibiotic for parenteral administration. Cefazolin exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. Cefazolin is about 85% bound to serum protein. The peak level in serum is approximately 32-42 mg/mL after an intramuscular (i.m.) injection of 500 mg. Over 80% of injected cefazolin is excreted in the urine during the first 24 hours after i.m. injection; most is excreted during the first 4-6 hours.

Clinical Pharmacology

The blood levels of cefazolin listed on the following tables were determined following intramuscular and intravenous administration.

Serum Concentration (mg/mL) Following Administration:

(Time After Intravenous Injection in Minutes)

(Time After Intramuscular Injection in Hours)

The serum half-life is approximately 1.8 hours following intravenous administration and 2.0 hours after intramuscular administration.

The mean peak serum levels of cefazolin in hospitalized patients are approximately equivalent to those seen in normal volunteers.

Healthy volunteers received a continuous intravenous infusion of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg hourly for the next two hours (approximately 100 mg). A steady serum level of 28 mg/mL was attained at the third hour.

Cefazolin levels in synovial fluid and serum are similar four hours after drug administration. Levels in cord blood are equivalent to 40% of those found in maternal blood.

In patients without obstructive biliary disease, serum levels of cefazolin can be up to five times lower than bile levels of cefazolin. However, bile levels of cefazolin are considerably lower than serum levels in patients with obstructive biliary disease.

Cefazolin is excreted unchanged in the urine. Approximately 60% of the drug is excreted in the first six hours, and this increases to 70%-80% within 24 hours. Peak urine concentrations of approximately 2400 mcg/mL and 4000 mcg/mL are achieved following intramuscular doses of 500 mg and 1 gram, respectively.

STORAGE AND STABILITY

Cefazolin for Injection USP should be stored between 15^oC and 25^oC, protected from light.

Reconstituted vials of cefazolin sodium may be stored for 24 hours at controlled room temperature not exceeding 25^oC, or for 72 hours under refrigeration (2 to 8^oC), protected from light.

SPECIAL HANDLING INSTRUCTIONS

Not applicable

DOSAGE FORMS, COMPOSITION AND PACKAGING

Cefazolin for Injection USP is supplied in clear glass vials as a sterile powder of cefazolin sodium equivalent to 500 mg or 1 g of cefazolin.

Cefazolin for Injection USP is also available as a Pharmacy Bulk Vial containing sterile cefazolin sodium powder equivalent to 10 g of cefazolin.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Cefazolin sodium

Chemical Name: Monosodium (6R, 7R)-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-carboxylate.

Molecular Formula: C₁₄ H₁₃N₈NaO₄S₃

Molecular mass: 476.5

Structural Formula:

Physicochemical properties: Cefazolin sodium is white to off-white practically odourless, solid. The drug is freely soluble in water and very slightly soluble in alcohol. It is practically insoluble in chloroform and ether. The pH is between 4.5 and 6.0, in an aqueous solution containing 100 mg of cefazolin per milliliter. The melting point of cefazolin sodium is between 229 to 231°C with a sign of decomposition.

Product Characteristics

Cefazolin for Injection USP vials contain cefazolin sodium. Each gram of cefazolin sodium contains 48 mg of sodium. Cefazolin for Injection USP contains no preservative.

CLINICAL TRIALS

Not applicable

MICROBIOLOGY

CEFAZOLIN ACTIVITY AGAINST CLINICAL ISOLATES

*Reported as 3.13-6.25μg/mL

+ Reported as ≤ 0.1μg/mL

Disc Susceptibility Tests

The following criteria should be used to interpret tests using a standardized 30 μg cephalosporin- class disc:

Zones of 18 mm or greater indicate that the tested organisms are susceptible and are likely to respond to therapy. Zones of 15 to 17 mm indicate organisms of intermediate susceptibility which may be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic levels are attained. Zones of 14 mm or less are produced by resistant organisms.

The cephalothin disc should not be used for testing susceptibility to other cephalosporins.

Dilution Techniques: If the minimal inhibitory concentration (MIC) for cefazolin is not more than 16 mg/mL, then a bacterial isolate may be considered susceptible. If the MIC is equal to or greater than 64 mg/mL, organisms are considered to be resistant.

The ranges of MIC’s for the control strains were:

E.coli ATCC 25922 1.0-4.0 mg/mL

S.aureus ATCC 25923 0.25-1.0 mg/mL

TOXICOLOGY

Acute Toxicity

Parenteral and oral cefazolin demonstrated low toxicity in rodents, canines and rabbits tested in acute toxicity studies.

ACUTE TOXICITY

Subacute and Chronic Toxicity

Rats and dogs were studied in subacute and chronic parenteral toxicity of cefazolin. Rats were treated for 3 and 6 months subcutaneously and for one month intraperitoneally. The highest doses ranged from 2000 mg/kg per day in the 6 month study to 4000 mg/kg per day in the 1 and 3 month studies. Anemia was the only significant abnormality attributable to s.c. drug administration. In all experiments there was a definite dose-related depression of SGPT levels.

Leukocytosis and hypererythropoiesis accompanied the anemia, which was probably related to hemorrhaging at the injection site.

The lowering of the SGPT was dependent upon both the dose and the duration of treatment. This was not statistically significant at the low doses and was reversible upon withdrawal of the drug.

Equivalent chronic studies in dogs produced similar results: at the higher doses there was a fall in SGPT and frank anemia resulted from high subcutaneous doses. Dogs treated intravenously did not develop the anemia indicating that it was probably associated with hemorrhaging at the site of injection.

Reproduction and Teratology

Rabbits and mice were administered cefazolin in doses of 240 mg/kg/day and 2400 mg/kg/day. No teratologic effects were observed. No adverse effects on mating, fertility, gestation, delivery and lactation were observed in rats administered 2000 mg/kg per day. Baby rats whose mothers were injected with 1200 mg/kg/day of cefazolin prior to delivery and throughout lactation were observed and there was no effect on the birth, or peri- and postnatal development.

Nephrotoxicity

The nephrotoxicity of cefazolin was studied following intravenous injections of rabbits and subcutaneous injections of mice and rats. The mean nephrotoxic intravenous dose in rabbits was between 300 and 400 mg/kg/day. No evidence of renal damage was produced when cefazolin was injected subcutaneously into mice at a dose of 8 g/kg/day for up to 3 days and into rats at a dose of 4 g/kg/day for up to 7 days.

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    Product Monograph – CEFAZOLIN FOR INJECTION, Teva Canada Limited. Date of

    Revision July 30, 2018. Submission Control No: 212089.