Zinacef (Cefuroxime Sodium)

ZINACEF®

Glaxo Wellcome

Cefuroxime Sodium

Antibiotic

Action And Clinical Pharmacology: In vitro studies demonstrate that the bactericidal action of cefuroxime, a cephalosporin antibiotic, results from inhibition of bacterial cell wall synthesis by inhibiting the transpeptidase and carboxypeptidase enzymes. Cefuroxime is active against the following organisms in vitro:

Gram-positive: S. pyogenes, S. viridans and S. pneumoniae. S. aureus, both penicillin sensitive and beta-lactamase producing. Clostridia. Some strains of methicillin resistant staphylococci have been found to be resistant to cefuroxime. Most strains of S. faecalis are resistant.

Gram-negative: E. coli (including beta-lactamase producing strains), Klebsiella, Enterobacter, H. influenzae, P. mirabilis, Salmonella, Shigella species, N. gonorrhoeae and N. meningitides. Cefuroxime is ineffective against P. aeruginosa and exhibits poor activity against P. vulgaris, B. fragilis, M. morganii, Enterobacter species, Citrobacter species, and many Serratia species.

Cefuroxime is poorly absorbed orally; following a 1 g dose, serum levels of less than 1.2 g/mL were observed and only between 1 and 1.3% of the administered dose was excreted in the urine. Cefuroxime is used by the i.m. or i.v. routes.

Deep i.m. injection of 750 mg of cefuroxime sodium in the lateral side of the thigh, attained peak blood levels of 35 to 40 g/mL, after 30 to 40 minutes. Serum cefuroxime concentrations greater than 12.5 g/mL were maintained for approximately 3 hours, greater than 8 g/mL for approximately 3.5 hours, and 6.25 g/mL for approximately 4 hours, after a 750 mg i.m. dose.

An i.v. dose of cefuroxime resulted in biliary levels which varied considerably between 1.3 and 26 g/mL. Biliary levels appear to be lowest in patients with a non-functioning gallbladder.

Following 750 mg i.m. to 6 women in labor, average concentrations of cefuroxime in amniotic fluid were 18.6 g/mL. This was similar to those in maternal serum where average peak maternal serum concentrations of 19.2 g/mL were attained after 1.2 hours. In umbilical cord blood, the average peaks were 33% of those in the mothers.

Cefuroxime 750 mg and 1.5 g resulted in blood levels of 73 g/mL and 151 g/mL, respectively, 5 minutes after the beginning of the injection.

I.V. infusion of 750 mg over a 30 minute period resulted in a serum level of 51 g/mL at the end of the infusion. I.V. administration of 1.5 g over a 20 minute period, resulted in a concentration of 146 g/mL at the end of the infusion.

Following i.v. administration, more than 95% of cefuroxime is excreted unmetabolized via the kidneys with excretion evenly divided between glomerular filtration and tubular secretion. Approximately 90% of the administered dose was recovered in the urine within 6 hours of i.m. injection, and over 96% after 24 hours.

About 33% of cefuroxime is bound to serum protein. Volume of distribution after a 750 mg i.m. dose is approximately 15 L which increases to about 23 L when the dose of cefuroxime is doubled. The mean half-life of a 750 mg i.m. dose is about 80 minutes. The half-life of cefuroxime after i.v. injection is approximately 65 minutes. Probenecid 500 mg given orally 2 hours before and 1 hour after cefuroxime delayed renal excretion and increased the serum half-life from approximately 76 minutes to 101 minutes.

Renal Impairment: In severe renal impairment (oliguria), the half-life increases to approximately 16 hours.

Susceptibility plate test: With the Bauer-Kirby-Sherris-Turck method of disc susceptibility testing, a disc containing 30 g cefuroxime should give a zone of inhibition of at least 20 mm for a microorganism to be considered susceptible to cefuroxime.

Indications And Clinical Uses: For the treatment of patients with infections caused by susceptible strains of the designated organisms in the following diseases:

Lower Respiratory Tract Infections: Pneumonia caused by S. pneumoniae, H. influenzae including ampicillin-resistant strains, Klebsiella species, S. aureus including ampicillin-resistant (but not methicillin-resistant) strains, S. pyogenes, and E. coli.

Urinary Tract Infections: Caused by E. coli and Klebsiella species.

Soft Tissue Infections: Caused by S. aureus including ampicillin-resistant (but not methicillin-resistant) strains, S. pyogenes, E. coli, Klebsiella species.

Meningitis: Caused by S. aureus including ampicillin-resistant (but not methicillin-resistant) strains, S. pneumoniae, H. influenzae, and N. meningitidis.

Gonorrhea: Caused by N. gonorrhoeae including ampicillin-resistant strains.

Bone and Joint Infections: Caused by S. aureus (penicillinase and non-penicillinase producing strains).

Specimens for bacteriologic culture should be obtained prior to therapy in order to identify the causative organisms and to determine their susceptibility to cefuroxime. Therapy may be instituted before results of susceptibility testing are known. However, modification of the treatment may be required once these results become available.

Prevention: The pre-operative prophylactic administration of cefuroxime may prevent the growth of susceptible disease-causing bacteria and thereby may reduce the incidence of certain post-operative infections: in patients undergoing surgical procedures (e.g. vaginal hysterectomy) that are classified as clean contaminated or potentially contaminated; in patients undergoing open heart surgery in whom infections at the operative site would present a serious risk.

If signs of infection occur postoperatively, specimens for culture should be obtained for identification of causative organism and appropriate antimicrobial therapy should be instituted.

Contra-Indications: Patients who have shown Type I hypersensitivity to cefuroxime or the cephalosporin group of antibiotics. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Before therapy with cefuroxime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins or other drugs. Cefuroxime should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. There is some clinical and laboratory evidence of partial cross allergenicity of the cephalosporins and penicillins.

If an allergic reaction to cefuroxime occurs, treatment should be discontinued and standard agents (e.g., epinephrine, antihistamines, corticosteroids) administered as necessary.

Pseudomembranous colitis has been reported to be associated with treatment of cefuroxime (and other broad-spectrum antibiotics). Therefore, it is important to consider its diagnosis in patients administered cefuroxime who develop diarrhea. Treatment with broad-spectrum antibiotics, including cefuroxime, alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by C. difficile is one primary cause of antibiotic-associated colitis. Mild cases of colitis may respond to drug discontinuance alone. Moderate to severe cases should be managed with fluid, electrolyte, and protein supplementation as indicated. When the colitis is not relieved by discontinuance of cefuroxime administration or when it is severe, consideration should be given to the administration of vancomycin or other suitable therapy. Other possible causes of colitis should also be considered.

Precautions: Cefuroxime should be administered with caution to individuals with a history of gastrointestinal disease, particularly colitis.

Patients with markedly impaired renal function (i.e. creatinine clearance of 20 mL/min/1.73 mor less) should be placed on the special dosage schedule for cefuroxime recommended under Dosage. Normal dosages in these individuals are likely to produce excessive serum concentrations of cefuroxime.

The concomitant administration of aminoglycosides and some cephalosporins has caused nephrotoxicity. Although transient elevations of BUN and serum creatinine have been observed in clinical studies, there is no evidence that cefuroxime, when administered alone, is significantly nephrotoxic.

Studies suggest that the concurrent use of potent diuretics, such as furosemide and ethacrynic acid, may increase the risk of renal toxicity with cephalosporins.

Prolonged treatment with cefuroxime may result in the overgrowth of nonsusceptible organisms, including species originally sensitive to the drug. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Should an organism become resistant during antibiotic therapy, another antibiotic should be substituted.

As with other therapeutic regimens used in the treatment of meningitis, mild-to-moderate hearing loss has been reported in a few pediatric patients treated with cefuroxime. Persistence of positive CSF cultures of H. influenzae at 18 to 36 hours has also been noted with cefuroxime.

Pregnancy: The safety of cefuroxime in the treatment of infections during pregnancy has not been established. If the administration of cefuroxime is considered to be necessary, its use requires that the potential benefits be weighed against possible hazards to the patient and to the fetus. Animal studies have shown cefuroxime to affect bone calcification in the fetus and to show maternal toxicity in the rabbit.

Lactation: Cefuroxime is excreted in human milk in low concentrations (0.5 mg/L). The clinical significance of this is unknown, therefore, caution should be exercised when cefuroxime is administered to a nursing mother.

Geriatrics: The elimination of cefuroxime may be reduced due to impairment of renal function (see Dosage, Impaired Renal Function).

Laboratory Tests: Cefuroxime may interfere with Benedict’s and Fehling’s tests for glycosuria depending on copper reduction but not with enzyme based tests for glycosuria. It may cause false negative reactions in the ferricyanide test, and thus it is recommended that either the glucose oxidase or hexokinase methods be used to determine blood/plasma glucose levels in patients receiving cefuroxime. Cefuroxime does not interfere with the assay of serum and urine creatinine by the alkaline picrate method.

Adverse Reactions: Hypersensitivity: rash and eosinophilia. Anaphylaxis, urticaria, pruritus, interstitial nephritis and drug fever have also been observed with cephalosporin therapy. As with other cephalosporins, there have been rare reports of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis (exanthematic necrolysis).

Local Reactions: thrombophlebitis, stiffness at the site of injection, and inflammatory reactions at the site of injection. Some degree of pain, after i.m. injections when using water as the diluent, has been observed.

Blood: increased erythrocyte sedimentation rate and decreased hemoglobin, eosinophilia, leukopenia, neutropenia and thrombocytopenia. Cephalosporins as a class tend to be absorbed onto the surface of red cell membranes and react with antibodies directed against the drug to produce a positive Coombs’ test (which can interfere with the cross-matching of blood) and very rarely hemolytic anemia.

Renal: increases in BUN and serum creatinine.

Hepatic: transient increases in serum bilirubin, transaminases and alkaline phosphatase.

Others: drowsiness, loose stools, faint feeling, sweating, palpitations and Candida intertrigo.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage of cefuroxime can cause cerebral irritation leading to convulsions. Other than general supportive treatment, no specific antidote is known. Excessive serum levels of cefuroxime can be reduced by dialysis. For treatment of hypersensitivity reactions, see Warnings. tag_DosageDosage

Dosage And Administration: Cefuroxime may be administered i.v. or i.m. after reconstitution.

Dosage and route of administration should be determined by severity of infection, susceptibility of the causative organism(s), and condition of the patient. The i.v. route is preferable for patients with severe or life-threatening infections.

The usual duration of treatment is 5 to 14 days. For b-hemolytic Streptococcal infections, therapy should be continued for at least 10 days.

Adults: For most infections the usual recommended dosage is 750 mg every 8 hours (2.25 g/day) and may be administered either i.m. or i.v.

For severe or life-threatening infections or for infections of the lower respiratory tract, caused by Gram-negative organisms, 1.5 g i.v. every 8 hours (4.5 g/day) is recommended.

For treatment of bacterial meningitis a dosage of 3 g i.v. every 8 hours (9 g/day) should be employed.

Uncomplicated gonorrhea in both males and females should be treated with a single i.m. dose of 1.5 g, in 2 equally divided injections (one in each buttock), accompanied by a single oral dose of 1 g probenecid.

For bone and joint infections, a dosage of 1.5 g i.v. every 8 hours (4.5 g/day) is recommended. In clinical trials, surgical intervention was performed when indicated as an adjunct to cefuroxime therapy. A course of oral antibiotics was administered when appropriate following the completion of parenteral administration of cefuroxime.

Children: Infants and children (1 month to 12 years): 30 to 100 mg/kg/day divided in 3 or 4 equally divided doses. A dose of 60 mg/kg/day is appropriate for most infections. In cases of bacterial meningitis*, a dosage of 200 to 240 mg/kg/day i.v. in 3 or 4 equally divided doses should be employed.

For bone and joint infections, a dosage between 70 to 150 mg/kg/day administered i.v. every 8 hours is recommended. In clinical trials a course of oral antibiotics was administered to children following the completion of parenteral administration of cefuroxime.

Doses in excess of the maximum adult dose should not be used in infants and children.

Neonates (up to 1 month): In the first few weeks of life, the serum half-life of cefuroxime can be 3 to 5 times that in adults. Infections in neonates should be treated with dosages in the range of 30 to 100 mg/kg/day in 2 or 3 equally divided doses.

For bacterial meningitis* a dosage of 100 mg/kg/day i.v. in 2 or 3 equally divided doses should be employed.

*Delayed sterilization of cerebral spinal fluid has been reported in a few children treated with cefuroxime for bacterial meningitis. Hearing impairment has occasionally occurred as a complication of meningitis in children treated with cefuroxime.

Prevention: Clean contaminated or potentially contaminated surgical procedures: The recommended dose is 1.5 g of cefuroxime administered i.v. just prior to surgery.

This may be supplemented with 750 mg administered i.m. or i.v. at 8 and 16 hours when surgery is prolonged.

In general, prophylactic administration is usually not required after the end of surgical procedures, however, intra-operative administrations should be considered if the surgical procedure is lengthy.

In many surgical procedures, continuing prophylactic administration of any antibiotic does not appear to be associated with a reduced incidence of subsequent infection, but will increase the possibility of adverse reactions and the development of bacterial resistance.

Open Heart Surgery: The recommended dosage is 1.5 g of cefuroxime administered i.v. at the induction of anesthesia and every 12 hours thereafter for 48 hours.

Impaired Renal Function: For patients with markedly impaired renal function a reduced dosage of cefuroxime must be employed.

For adults with severe infections who require doses higher than those recommended, serum levels of cefuroxime should be monitored and dosage adjusted accordingly.

Studies in children with renal impairment are not sufficient to recommend specific dosages. If it is necessary to administer cefuroxime to a child with such impairment, consideration should be given to modifying the frequency of drug administration consistent with the recommendations for adults with renal impairment.

When only serum creatinine levels are known, the following formulae may be used to estimate creatinine clearance. The serum creatinine must represent a steady state of renal function. Males: Creatinine clearance (mL/min) = weight (kg) x (140-age) / 72 x serum creatinine (mg/dL)

Creatinine clearance (mL/s) = weight (kg) x (140-age) / 49 x serum creatinine (mmol/L)

Females: 0.85 x male value.

For patients on hemodialysis, a further 750 mg dose of cefuroxime should be administered at the end of each dialysis treatment.

Administration: I.M.: Cefuroxime should be injected into a large muscle mass to minimize pain. As the preparation is in suspension form, a 21-gauge needle should be used.

I.V.: Cefuroxime may be administered i.v. either by a bolus injection or by a short i.v. infusion over a period of approximately 30 minutes.

For continuous i.v. infusions, a solution of cefuroxime (1.5 g dissolved in 16 mL of Water for Injection) may be added to a suitable bottle containing an appropriate i.v. infusion fluid in the amount calculated to give the desired antibiotic dose.

Reconstitution: I.M.: Reconstitute with Sterile Water for Injection.

The reconstituted solution may be further diluted with Sodium Chloride Injection BP 0.9% w/v, 5% w/v Dextrose Injection BP or Compound Sodium Lactate Injection BP (Hartmann’s Solution).

For short i.v. infusion, 1.5 g of cefuroxime is dissolved in 49 mL of Sterile Water for Injection, resulting in an approximate volume of 50 mL (i.e. 30 mg/mL).

7.5 g Pharmacy Bulk Vial: The availability of the pharmacy bulk vial is restricted to hospitals with a recognized i.v. admixture program. Zinacef for injection does not contain any preservatives. The Pharmacy Bulk Vial is intended for multiple dispensing for i.v. use only, employing a single puncture. Reconstitute with 77 mL Sterile Water for Injection. Following reconstitution with Sterile Water for Injection, the solution should be dispensed for further dilution within 8 hours. Any unused portion of the reconstituted solution should be discarded. Shake well until dissolved.

Storage: Reconstituted suspension for i.m. injection and reconstituted solution for i.v. injection should be used within 6 hours if kept below 25°C or 48 hours if stored under refrigeration.

The further diluted solutions for i.v. infusion should be used within 12 hours if kept below 25°C or 36 hours if stored under refrigeration in the dark. Some increase in color intensity may occur on storage.

Note: The pH of 2.74% w/v Sodium Bicarbonate Injection BP considerably affects the color of the solution; therefore, this solution is not recommended for the dilution of cefuroxime. However, if required, for patients receiving Sodium Bicarbonate Injection by infusion, the cefuroxime dose may be introduced into the tube of the set.

Incompatibility: Cefuroxime should not be mixed in the syringe with aminoglycoside antibiotics (e.g. gentamicin sulfate, tobramycin sulfate, amikacin sulfate) because of potential interaction.

Availability And Storage: Each 17 mL vial for i.m. or i.v. injection contains: cefuroxime sodium powder equivalent to cefuroxime 750 mg. Packs of 10.

Each 26 mL vial for i.v. injection contains: cefuroxime sodium powder equivalent to cefuroxime 1.5 g. Packs of 10.

Pharmacy Bulk Vial: Each vial contains: cefuroxime sodium powder equivalent to cefuroxime 7.5 g. Vials of 127 mL, packs of 6.

The dry powder in vials should be stored below 25°C and protected from light. Gluten- and tartrazine-free.

ZINACEF® Glaxo Wellcome Cefuroxime Sodium Antibiotic

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