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Kefzol® (Cefazolin for Injection, USP) is a sterile, semisynthetic cephalosporin for intramuscular or intravenous administration. It is 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-7- [[1 H -tetrazol-1-yl)acetyl]amino-]-, monosodium salt (6 R - trans ). The sodium content is 48.3 mg/g of cefazolin sodium. Cefazolin for Injection, USP, is supplied in 1 g vials. Each vial contains cefazolin sodium equivalent to 1 g of cefazolin.
The molecular formula is C 14 H 13 N 8 NaO 4 S 3 . The molecular weight is 476.5.
The structural formula is as follows:
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The pH of the reconstituted solution is between 4.5 and 6.
Human Pharmacology --Table 1 demonstrates the blood levels and duration of cefazolin following intramuscular administration.
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Clinical pharmacology studies in patients hospitalized with infections indicate that cefazolin produces mean peak serum levels approximately equivalent to those seen in normal volunteers.
In a study (using normal volunteers) 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 produced a steady serum level at the 3rd hour of approximately 28 mcg/mL. Table 2 shows the average serum concentrations after IV injection of a single 1-g dose; average half-life was 1.4 hours.
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Controlled studies in adult normal volunteers receiving 1 g 4 times a day for 10 days, monitoring CBC, AST (SGOT), ALT (SGPT), bilirubin, alkaline phosphatase, BUN, creatinine, and urinalysis, indicated no clinically significant change attributed to cefazolin.
Cefazolin is excreted unchanged in the urine, primarily by glomerular filtration and, to a lesser degree, by tubular secretion. Following intramuscular injection of 500 mg, 56% to 89% of the administered dose is recovered within 6 hours and 80% to nearly 100% in 24 hours. Cefazolin achieves peak urine concentrations greater than 1,000 mcg/mL and 4,000 mcg/mL respectively following 500-mg and 1-g intramuscular doses.
In patients undergoing peritoneal dialysis (2 L/h), mean serum levels of cefazolin were approximately 10 and 30 mcg/mL after 24 hours' instillation of a dialyzing solution containing 50 mcg/mL and 150 mcg/mL respectively. Mean peak levels were 29 mcg/mL (range 13 to 44 mcg/mL) with 50 mcg/mL (3 patients) and 72 mcg/mL (range 26 to 142 mcg/mL) with 150 mcg/mL (6 patients). Intraperitoneal administration of cefazolin is usually well tolerated.
When cefazolin is administered to patients with unobstructed biliary tracts, high concentrations well over serum levels occur in the gallbladder tissue and bile. In the presence of obstruction, however, concentration of the antibiotic is considerably lower in bile than in serum.
Cefazolin readily crosses an inflamed synovial membrane, and the concentration of the antibiotic achieved in the joint space is comparable to levels measured in the serum.
Cefazolin readily crosses the placental barrier into the cord blood and amniotic fluid. It is present in very low concentrations in the milk of nursing mothers.
Microbiology In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell-wall synthesis. Kefzol is active against the following organisms in vitro and in clinical infections:
Staphylococcus aureus (including penicillinase-producing strains)
Staphylococcus epidermidis
Methicillin-resistant staphylococci are uniformly resistant to cefazolin
Group A (beta)-hemolytic streptococci and other strains of streptococci (many strains of enterococci are resistant)
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Most strains of indole positive Proteus (Proteus vulgaris), Enterobacter cloacae, Morganella morganii , and Providencia rettgeri are resistant. Serratia, Pseudomonas , and Acinetobacter calcoaceticus (formerly Mima , and Herellea sp) are almost uniformly resistant to cefazolin.
Disk Susceptibility Tests --Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure * has been recommended for use with disks for testing susceptibility to cefazolin. With this procedure, a report from the laboratory of "susceptible" indicates that the infecting organism is likely to respond to therapy. A report of "resistant" indicates that the infecting organism is not likely to respond to therapy. A report of "moderately susceptible" suggests that the organism would be susceptible if high dosage is used or if the infection were confined to tissues and fluids (eg, urine) in which high antibiotic levels are attained.
For gram-positive isolates, a zone of 18 mm is indicative of a cefazolin-susceptible organism when tested with either the cephalosporin-class disk (30 mcg cephalothin) or the cefazolin disk (30 mcg cefazolin).
Gram-negative organisms should be tested with the cefazolin disk (using the above criteria) because cefazolin has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found to be resistant when tested with the cephalothin disk. When using the cephalothin disk, gram-negative organisms with zone diameters >/= 18 mm may be considered susceptible to cefazolin; however, organisms with zone diameters less than 18 mm are not necessarily resistant or moderately susceptible to cefazolin.
The cefazolin disk should not be used for testing susceptibility to other cephalosporins.
Dilution Techniques --A bacterial isolate should be considered susceptible if the minimal inhibitory concentration (MIC) for cefazolin is </= 16 mcg/mL. Organisms are considered resistant if the MIC is >/= 64 mcg/mL.
Kefzol is indicated in the treatment of the following serious infections due to susceptible organisms:
Respiratory tract infections due to S. pneumoniae , Klebsiella sp, H. influenzae , S. aureus (including penicillinase-producing strains), and group A (beta)-hemolytic streptococci.
Injectable penicillin G benzathine is considered to be the drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever.
Kefzol is effective in the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of Kefzol in the subsequent prevention of rheumatic fever are not available at present.
Genitourinary tract infections due to E. coli , P. mirabilis , Klebsiella sp, and some strains of Enterobacter and enterococci.
Skin and skin structure infections due to S. aureus (including penicillinase-producing strains) and group A (beta)-hemolytic streptococci and other strains of streptococci.
Biliary tract infections due to E. coli , various strains of streptococci, P. mirabilis , Klebsiella sp, and S. aureus .
Bone and joint infections due to S. aureus .
Septicemia due to S. pneumoniae , S. aureus (penicillin-susceptible and penicillin-resistant), P. mirabilis , E. coli , and Klebsiella sp.
Endocarditis due to S. aureus (penicillin-susceptible and penicillin-resistant) and group A (beta)-hemolytic streptococci.
Appropriate culture and susceptible studies should be performed to determine susceptibility of the causative organism to Kefzol.
PERIOPERATIVE PROPHYLAXIS: The prophylactic administration of Kefzol preoperatively, intraoperatively and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures that are classified as contaminated or potentially contaminated (e.g., vaginal hysterectomy, and cholecystectomy in high-risk patients such as those over 70 years of age, who have acute cholecystitis, obstructive jaundice or common-bile-duct stones).
The perioperative use of Kefzol 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).
The prophylactic administration of Kefzol should usually be discontinued within a 24-hour period after the surgical procedure. For surgery in which the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of Kefzol may be continued for 3 to 5 days following the completion of surgery. If there are signs of infection, specimens for culture should be obtained for the identification of the causative organism so that appropriate therapy may be instituted. (See DOSAGE AND ADMINISTRATION.)
Kefzol is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
BEFORE CEFAZOLIN THERAPY IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS AND PENICILLIN. CEPHALOSPORIN C DERIVATIVES SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS.
SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.
There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and the cephalosporins. Patients have been reported to have had severe reactions (including anaphylaxis) to both drugs.
Antibiotics, including Kefzol, should be administered cautiously to any patient who has demonstrated some form of allergy, particularly to drugs.
Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics (including macrolides, semisynthetic penicillins, and cephalosporins); therefore, it is important to consider its diagnosis in patients who develop diarrhea in association with the use of antibiotics. Such colitis may range in severity from mild to life threatening.
Treatment with broad-spectrum antibiotics alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis
Usage in Infants --Safety for use in prematures and infants under 1 month of age has not been established.
General --If an allergic reaction to Kefzol occurs, the drug should be discontinued and the patient treated with the usual agents (eg, epinephrine or other pressor amines, antihistamines, or corticosteroids).
Prolonged use of Kefzol may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
When Kefzol is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required (see DOSAGE AND ADMINISTRATION).
Drug Interactions --Used concurrently, probenecid may decrease renal tubular secretion of cephalosporins, resulting in increased and more prolonged cephalosporin blood levels.
Drug/Laboratory Test Interactions --A false positive reaction for glucose in the urine may occur with Benedict' solution, Fehling' solution, or Clinitest® tablets, but not with enzyme-based tests such as Clinistix® and Tes-Tape®. (Glucose Enzymatic Test Strip, USP, Lilly).
Positive direct and indirect antiglobulin (Coombs') tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery.
Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
Carcinogenesis, Mutagenesis, Impairment of Fertility --Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of cefazolin have not been performed. Studies performed in rats have revealed no evidence of impaired fertility.
Pregnancy: Teratogenic Effects: Pregnancy Category B --Reproduction studies have been performed in rats given doses of 500 mg or 1 g of cefazolin/kg and have revealed no harm to the fetus due to Kefzol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery --When cefazolin has been administered prior to cesarean section, drug levels in cord blood have been measured to be approximately one fourth to one third of maternal drug levels. The drug appears to have no adverse effect on the fetus.
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.
The following reactions have been reported:
Hypersensitivity --Drug fever, skin rash, vulvar pruritus, eosinophilia, and anaphylaxis have occurred.
Blood --Neutropenia, leukopenia, thrombocythemia, and positive direct and indirect Coombs' tests have occurred.
Renal --Transient rise in BUN levels has been observed without clinical evidence of renal impairment. Interstitial nephritis and other renal disorders have been reported rarely. Most patients experiencing these reactions have been seriously ill and were receiving multiple drug therapies. The role of Kefzol in the development of nephropathies has not been determined.
Hepatic --Transient rise in AST, ALT, and alkaline phosphatase levels has been observed rarely. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely.
Gastrointestinal --Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. Nausea and vomiting have been reported rarely. Anorexia, diarrhea, and oral candidiasis (oral thrush) have been reported.
Other --Pain on intramuscular injection, sometimes with induration, has occurred infrequently. Phlebitis at the site of injection has been noted. Other reactions have included genital and anal pruritus, genital moniliasis, and vaginitis.
Signs and Symptoms --Toxic signs and symptoms following an overdose of cefazolin may include pain, inflammation, and phlebitis at the injection site.
The administration of inappropriately large doses of parenteral cephalosporins may cause dizziness, paresthesias, and headaches. Seizures may occur following overdosage with some cephalosporins, particularly in patients with renal impairment in whom accumulation is likely to occur.
Laboratory abnormalities that may occur after an overdose include elevations in creatinine, BUN, liver enzymes and bilirubin, a positive Coombs' test, thrombocytosis, thrombocytopenia, eosinophilia, leukopenia, and prolongation of the prothrombin time.
Treatment --To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR) . In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
If seizures occur, the drug should be discontinued promptly; anticonvulsant therapy may be administered if clinically indicated. Protect the patient' airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient' vital signs, blood gases, serum electrolytes, etc.
In cases of severe overdosage, especially in a patient with renal failure, combined hemodialysis and hemoperfusion may be considered if response to more conservative therapy fails. However, no data supporting such therapy are available.
Kefzol may be administered intramuscularly or intravenously after reconstitution. Total daily dosages are the same for either route of administration.
Intramuscular Administration --Reconstitute 1-g vial as directed by Table 3 with Sterile Water for Injection. Shake well until dissolved. Kefzol should be injected into a large muscle mass. Pain on injection is infrequent with Kefzol.
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Intravenous Administration --Kefzol may be administered by intravenous injection or by continuous or intermittent infusion.
Intermittent intravenous infusion : Kefzol can be administered along with primary intravenous fluid management programs in a volume control set or in a separate, secondary IV bottle. Reconstituted 1 g of Kefzol may be diluted in 50 to 100 mL of 1 of the following intravenous solutions: 0.9% Sodium Chloride Injection, 5% or 10% Dextrose Injection, 5% Dextrose in Lactated Ringer' Injection, 5% Dextrose and 0.9% Sodium Chloride Injection (also may be used with 5% Dextrose and 0.45% or 0.2% Sodium Chloride Injection), Lactated Ringer' Injection, 5% or 10% Invert Sugar in Sterile Water for Injection, Ringer' Injection, Normosol®-M in D5-W, Ionosol® B with Dextrose 5%, or Plasma-Lyte® with 5% Dextrose.
Intravenous injection (Administer solution directly into vein or through tubing): Dilute the reconstituted 1 g of Kefzol in a minimum of 10 mL of Sterile Water for Injection. Inject solution slowly over 3 to 5 minutes. Do not inject in less than 3 minutes.
Dosage --The usual adult dosages are given in Table 4.
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Dosage Adjustment for Patients With Reduced Renal Function --Kefzol may be used in patients with reduced renal function with the following dosage adjustments: Patients with a creatinine clearance >/= 55 mL/min or a serum creatinine </= 1.5 mg% 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 one half the usual dose every 12 hours. Patients with creatinine clearance rates of </= 10 mL/min or serum creatinine >/= 4.6 mg% should be given one half 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. For information about peritoneal dialysis, see CLINICAL PHARMACOLOGY ( Human Pharmacology ).
Perioperative Prophylactic Use --To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended doses are as follows:
It is important that (1) the preoperative dose be given just prior (one half to 1 hour) to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of the initial surgical incision and (2) if exposure to infectious organisms is likely, Kefzol be administered at appropriate intervals during surgery in order that sufficient levels of antibiotic be present when needed.
In surgery in which infection may be particularly devastating (eg, open-heart surgery and prosthetic arthroplasty), the prophylactic administration of Kefzol may be continued for 3 to 5 days following the completion of surgery.
In children, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg/lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections (Table 5). Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections.
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In children with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60% of the normal daily dosage given in divided doses every 12 hours should be sufficient. In children with moderate impairment (creatinine clearance of 40 to 20 mL/min), 25% of the normal daily dosage given in divided doses every 12 hours should be sufficient. In children with severe impairment (creatinine clearance of 20 to 5 mL/min), 10% of the normal daily dosage given every 24 hours should be adequate. All dosage recommendations apply after an initial loading dose is administered.
Since safety for use in premature infants and in infants under 1 month of age has not been established, the use of Kefzol in these patients is not recommended.
In those situations in which the drug and diluent have been mixed, but not immediately administered to the patient, the admixture may be stored under the following conditions:
Vials --Reconstituted Kefzol diluted in Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection is stable for 24 hours at room temperature and for 10 days if stored under refrigeration, 2° to 8°C (36° to 46°F).
Solutions of Kefzol in Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection that are frozen immediately after reconstitution in the original vials are stable for as long as 12 weeks if stored at -20°C. Once thawed, these solutions are stable for 24 hours at room temperature or for 10 days if stored under refrigeration, 2° to 8°C (36° to 46°F). If the product is warmed, care should be taken to avoid heating it after the thawing is complete. Once thawed, the solution should not be refrozen.
Secondary Diluents --Solutions of Kefzol for infusion in 10% Dextrose Injection, 5% Dextrose in Lactated Ringer' Injection, 5% Dextrose and 0.9% Sodium Chloride Injection (also may be used with 5% Dextrose and 0.45% or 0.2% Sodium Chloride Injection), Lactated Ringer' Injection, 5% or 10% Invert Sugar in Sterile Water for Injection, Ringer' Injection, Normosol®-M in D5-W, Ionosol®-B with Dextrose 5%, or Plasma-Lyte with 5% Dextrose should be used within 24 hours after dilution if stored at room temperature or within 96 hours if stored under refrigeration, 2° to 8°C (36° to 46°F). (DO NOT FREEZE KEFZOL DILUTED WITH THE ABOVE DILUENTS.)
Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.
KEFZOL® (Cefazolin for Injection, USP), is available as follows:
1 g, * 10-mL size (No. 768)--(Traypak † of 25) NDC 0002-1498-25
Also available:
10 g, * 100-mL size (No. 7014)--(1s) NDC 0002-7014-01
1 g * (No. 7266)--(Traypak of 25) NDC 0002-7266-25
The above ADD-Vantage Vials are to be used only with Abbott Laboratories' 50-mL or 100-mL Flexible Diluent Containers containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
Instructions for use of the ADD-Vantage Vials are enclosed in the package.
Prior to reconstitution, store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] and protect from light.
Literature revised January 15, 1999
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Manufactured for ELI LILLY AND COMPANY Indianapolis, IN 46285, USA by BMH Limited Philadelphia, PA 19101 |
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