Cefobid injection

PHARMACY BULK PACKAGE
NOT FOR DIRECT INFUSION

High serum and bile levels of Cefobid are attained after a single dose of the drug. Table 1 demonstrates the serum concentrations of Cefobid in normal volunteers following either a single 15-minute constant rate intravenous infusion of 1, 2, 3 or 4 grams of the drug, or a single intramuscular injection of 1 or 2 grams of the drug.

The mean serum half-life of Cefobid is approximately 2.0 hours, independent of the route of administration.

In vitro studies with human serum indicate that the degree of Cefobid reversible protein binding varies with the serum concentration from 93% at 25 mcg/mL of Cefobid to 90% at 250 mcg/mL and 82% at 500 mcg/mL.

Cefobid achieves therapeutic concentrations in the following body tissues and fluids:

Cefobid is excreted mainly in the bile. Maximum bile concentrations are generally obtained between one and three hours following drug administration and exceed concurrent serum concentrations by up to 100 times. Reported biliary concentrations of Cefobid range from 66 mcg/mL at 30 minutes to as high as 6000 mcg/mL at 3 hours after an intravenous bolus injection of 2 grams.

Following a single intramuscular or intravenous dose, the urinary recovery of Cefobid over a 12-hour period averages 20–30%. No significant quantity of metabolites has been found in the urine. Urinary concentrations greater than 2200 mcg/mL have been obtained following a 15-minute infusion of a 2 g dose. After an IM injection of 2 g, peak urine concentrations of almost 1000 mcg/mL have been obtained, and therapeutic levels are maintained for 12 hours.

Repeated administration of Cefobid at 12-hour intervals does not result in accumulation of the drug in normal subjects. Peak serum concentrations, areas under the curve (AUC's), and serum half-lives in patients with severe renal insufficiency are not significantly different from those in normal volunteers. In patients with hepatic dysfunction, the serum half-life is prolonged and urinary excretion is increased. In patients with combined renal and hepatic insufficiencies, Cefobid may accumulate in the serum.

Cefobid has been used in pediatrics, but the safety and effectiveness in children have not been established. The half-life of Cefobid in serum is 6–10 hours in low birth-weight neonates.

Microbiology

Cefobid is active in vitro against a wide range of aerobic and anaerobic, gram-positive and gram-negative pathogens. The bactericidal action of Cefobid results from the inhibition of bacterial cell wall synthesis. Cefobid has a high degree of stability in the presence of beta-lactamases produced by most gram-negative pathogens. Cefobid is usually active against organisms which are resistant to other beta-lactam antibiotics because of beta lactamase production. Cefobid is usually active against the following organisms in vitro and in clinical infections:

• Staphylococcus aureus, penicillinase and non-penicillinase producing strains
• Staphylococcus epidermidis
• Streptococcus pneumoniae (formerly Diplococcus pneumoniae)
• Streptococcus pyogenes (Group A beta-hemolytic streptococci)
• Streptococcus agalactiae (Group B beta-hemolytic streptococci)
• Enterococcus (Streptococcus faecalis, S. faecium and S. durans)

• Escherichia coli
• Klebsiella species (including K. pneumoniae)
• Enterobacter species
• Citrobacter species
• Haemophilus influenzae
• Proteus mirabilis
• Proteus vulgaris
• Morganella morganii (formerly Proteus morganii)
• Providencia stuartii
• Providencia rettgeri (formerly Proteus rettgeri)
• Serratia marcescens
• Pseudomonas aeruginosa
• Pseudomonas species
• Some strains of Acinetobacter calcoaceticus
• Neisseria gonorrhoeae

• Gram-positive cocci (including Peptococcus and Peptostreptococcus)
• Clostridium species
• Bacteroides fragilis
• Other Bacteroides species

Cefobid is also active in vitro against a wide variety of other pathogens although the clinical significance is unknown. These organisms include: Salmonella and Shigella species,Serratia liquefaciens, N. meningitidis, Bordetella pertussis, Yersinia enterocolitica, Clostridium difficile, Fusobacterium species, Eubacterium species and beta-lactamase producing strains of H. influenzae and N. gonorrhoeae.

Cefobid is contraindicated in patients with known allergy to the cephalosporin-class of antibiotics.

In clinical studies the following adverse effects were observed and were considered to be related to Cefobid therapy or of uncertain etiology:

Hypersensitivity

As with all cephalosporins, hypersensitivity manifested by skin reactions (1 patient in 45), drug fever (1 in 260), or a change in Coombs' test (1 in 60) has been reported. These reactions are more likely to occur in patients with a history of allergies, particularly to penicillin.

Hematology

As with other beta-lactam antibiotics, reversible neutropenia may occur with prolonged administration. Slight decreases in neutrophil count (1 patient in 50) have been reported. Decreased hemoglobins (1 in 20) or hematocrits (1 in 20) have been reported, which is consistent with published literature on other cephalosporins. Transient eosinophilia has occurred in 1 patient in 10.

Hepatic

Of 1285 patients treated with cefoperazone in clinical trials, one patient with a history of liver disease developed significantly elevated liver function enzymes during Cefobid therapy. Clinical signs and symptoms of nonspecific hepatitis accompanied these increases. After Cefobid therapy was discontinued, the patient's enzymes returned to pre-treatment levels and the symptomatology resolved. As with other antibiotics that achieve high bile levels, mild transient elevations of liver function enzymes have been observed in 5–10% of the patients receiving Cefobid therapy. The relevance of these findings, which were not accompanied by overt signs or symptoms of hepatic dysfunction, has not been established.

Gastrointestinal

Diarrhea or loose stools has been reported in 1 in 30 patients. Most of these experiences have been mild or moderate in severity and self-limiting in nature. In all cases, these symptoms responded to symptomatic therapy or ceased when cefoperazone therapy was stopped. Nausea and vomiting have been reported rarely.

Symptoms of pseudomembranous colitis can appear during or for several weeks subsequent to antibiotic therapy (see WARNINGS).

Renal Function Tests

Transient elevations of the BUN (1 in 16) and serum creatinine (1 in 48) have been noted.

Local Reactions

Cefobid is well tolerated following intramuscular administration. Occasionally, transient pain (1 in 140) may follow administration by this route. When Cefobid is administered by intravenous infusion some patients may develop phlebitis (1 in 120) at the infusion site.

The 10 gram vial should be reconstituted with 95 mL of sterile water for injection in two separate aliquots in a suitable work area such as a laminar flow hood. Add 45 mL of solution, shake to dissolve and add 50 mL, shake for final solution. The resulting solution will contain 100 mg/mL of cefoperazone. This closure may be penetrated only one time after reconstitution, if needed, using a suitable sterile transfer device or dispensing set which allows measured dispensing of the contents.

Discard unused solution within 24 hours of initial entry.

Although after reconstitution of the Pharmacy Bulk Package, no significant loss of potency occurs for 24 hours at room temperature and for 5 days if refrigerated, transfer individual dose to appropriate intravenous infusion solutions as soon as possible following reconstitution of the bulk package. Discard unused portions of solution held longer than these recommended periods at room temperature or under refrigeration. The stability of the solution which has been transferred into a container varies according to diluent and concentration. (See STORAGE AND STABILITY.)

The 10 gram vials may be further diluted with the parenteral diluents listed under Table 2.

Vehicles for Intravenous Infusion

The parenteral diluents and approximate concentrations of Cefobid that provide stable solutions are presented under STORAGE AND STABILITY.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Consult your pharmacist.

How to use Cefobid Solution, Reconstituted (Recon Soln)

Consult your pharmacist.