Each vial contains: 

Cefoperazone (as sodium salt) .......................................................................... 500 mg, 1 g, or 2 g

Treatment of the following systemic and/or local infections caused by cefoperazone-susceptible microorganisms: 

Upper and Lower respiratory tract infections, e.g. pneumonia, acute and chronic bronchitis.

Upper and Lower urinary tract infections, e.g. pyelonephritis, urethritis.

Peritonitis, cholecystitis, cholangitis, and other intraabdominal infections.

Septicemia.

Skin and Soft tissue infections, e.g. cellulitis.

Bone and Joint infections, e.g. osteomyelitis.

Pelvic infections, such as endometritis and other infections of the genital tract including gonorrhea, in combination with other broad spectrum antibiotics, if necessary and prophylaxis of postoperative infections in connection with abdominal surgery, gynecological, cardiac and vascular as well as orthopedic surgery.

National and international recommendations for proper use of antimicrobial substances have to be considered when using CEFOZON 2 g vials.

Dosage: 

Adults: 

The usual adult daily dose is 2-4 g, divided in two equal doses every 12 hours; in severe infections, the dose may be increased to 8 g daily in divided doses. Even daily doses of up to 16 g (2 x 8 g) have been tolerated without complications.

The recommended dosage for uncomplicated gonococcal urethritis is 500 mg I.M. as a single dose.

For perioperative prophylaxis, 1-2 g CEFOZON should be administered I.V. approximately 0.5-1.5 hrs prior to the start of surgery. The dose may be repeated every 12 hours. Prophylactic administration should be restricted to a maximum of 72 hours.

Infants and Children (1 month-11 years): 

The recommended dosage in infants and children is 50-200 mg/kg body weight/day in divided doses every 8-12 hours. The maximum dose should not exceed 12 grams/day.

Use in renal dysfunction: 

Daily doses of 2x1 g or 2x2 g CEFOZON may be administered irrespective of the degree of renal dysfunction.

For patients whose glomerular filtration rate is less than 18 ml/min or whose serum creatinine level is greater than 3.5 mg/ dl, the maximum dosage is 4 g per day.

Serum half-life of cefoperazone is slightly reduced during hemodialysis. Dosage should be adjusted according to dialysis requirements.

Use in patients with hepatic dysfunction or coexisting renal and hepatic dysfunction: 

In patients with hepatic dysfunction and/or biliary obstruction, serum half-life is usually prolonged and renal excretion of cefoperazone is increased.

Dosage adjustment may be necessary in cases of severe biliary obstruction, severe hepatic dysfunction or coexisting renal dysfunction.

In patients with both severe renal and hepatic disease, plasma concentrations of cefoperazone should be monitored regularly and dosage adjusted as necessary. In these patients, the dosage should not exceed 2 g daily without close monitoring of serum concentrations. (see also Warnings and Precautions).

Elderly patients: 

There are no special data available on pharmacokinetic parameters in elderly patients.

Duration of treatment: 

The duration of treatment depends on the course of the disease. CEFOZON therapy should be continued for at least 3 days after the patient's temperature has returned to normal.

Combination therapy: 

In patients with severe, life-threatening infections, combination therapy with CEFOZON and an aminoglycoside may be indicated. Because of physical incompatibility, the two drugs must not be mixed nor injected at the same time or at the same site. The solutions should be prepared shortly before injection. (see also Drug Interactions and Incompatibilities).

In case of a combination therapy with aminoglycosides, renal function must be carefully monitored (see also Warnings and Precautions). In these cases also the contraindications of the aminoglycoside have to be considered.

Administration: 

Intermittent I.V. Infusion, I.V. Injection, I.M. Injection.

Instruction for Administration: 

Intravenous Administration: 

Vials of CEFOZON sterile powder may be initially reconstituted with a minimum of 2.8 ml per gram of cefoperazone of any compatible reconstituting solution appropriate for intravenous administration listed below in Table 1.

In case of reconstitution, the use of 5 ml compatible solution per gram of CEFOZON is recommended.

Table 1: Solutions for Initial Reconstitution: 

Table 2: Vehicles for Intravenous Infusion: 

For Intermittent Intravenous Infusion:

Each 1 or 2 g vial of CEFOZON should be dissolved in 20-100 ml of a compatible, sterile intravenous solution and infused over a period of 15 minutes to one hour. If sterile water for injection is the preferred diluent, no more than 20 ml should be added to the vials.

For Continous Intravenous Infusion:

Each gram of CEFOZON should be dissolved in either 5 ml of sterile water for injection or bacteriostatic water for injection and the solution added to an appropriate diluents.

For Direct Intravenous Injection:

The maximum dose of CEFOZON should be two grams per administration for adults and 50 mg/kg per administration for children. The drug should be dissolved in an appropriate diluent to give a final concentration of 100 mg/ml and administered over a period of no less than 3-5 minutes.

Intramuscular Administration: 

Sterile water for injection or Bacteriostatic water for injection may be used to prepare CEFOZON for intramuscular injection.

There is sufficient excess present to allow for withdrawal and administration of the stated volumes.

The drug should be given by deep intramuscular injection into large muscle mass of the gluteus maximum or anterior thigh.

Compatibility: 

The following parentral diluents are comabatible with CEFOZON: Approximate Conc. 

Bacteriostatic water for injection. 300 mg/ml.

5% Dextrose injection. 2 mg to 50 mg/ml.

5% Dextrose and Lactated Ringer’s injection. 2 mg to 50 mg/ml.

5% Dextrose and 0.9 Sodium Chloride injection. 2 mg to 50 mg/ml.

5% Dextrose and 0.2% Sodium Chloride injection. 2 mg to 50 mg/ml.

10% Dextrose injection. 2 mg to 50 mg/ml.

Lactated Ringer’s injection. 2 mg/ml.

0.5% Lidocaine hydrochloride injection. 300 mg/ml.

0.9% Sodium Chloride injection. 2 mg to 300 mg/ml.

Normosol M and 5% Dextrose injection. 2 mg to 50 mg/ml.

Normosol R 2 mg to 50 mg/ml.

Sterile water for injection. 300 mg/ml.

Reconstituted CEFOZON solution may be stored in glass or plastic syringes or in glass or flexible plastic parenteral solution containers.

Frozen samples should be thawed at room temperature before use.After thawing, unused portions should be discarded. Do not freeze.

Hypersensitivity to cefoperazone, to other cephalosporins or to any of the excipients.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other beta-lactam medicinal products.

CEFOZON is contraindicated in patients in whom administration of vitamin K is contraindicated (especially patients with tendency to hemorrhages).

Hypersensitivity: 

Special caution is required to determine any other type of previous hypersensitivity reactions to penicillin or to other beta-lactam medicinal products because patients hypersensitive to these medicines may be hypersensitive to CEFOZON as well (cross-allergy).

Before therapy with CEFOZON is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins or other drugs. CEFOZON should be given cautiously to penicillin sensitive patients. Antibiotics should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs.

If an allergic reaction occurs, the drug should be discontinued and the appropriate therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

Use in Hepatic Dysfunction: 

Cefoperazone is extensively excreted in bile. The serum half-life of cefoperazone is usually prolonged and urinary excretion of the drug increased in patients with hepatic diseases and/or biliary obstruction. Even with severe hepatic dysfunction, therapeutic concentrations of cefoperazone are obtained in bile and only a 2 to 4 fold increase in half-life seen (see Dosage and Administration).

General: 

As with other antibiotics, Vitamin K deficiency or blood coagulation disorders have occurred in a few patients treated with cefoperazone. The mechanism may possibly be related to the suppression of gut flora which normally synthesize this vitamin. Those at risk include patients with poor diet, malabsorption states (e.g. cystic fibrosis) and patients on prolonged intravenous alimentation regimens. Additional factors increasing the risk of hemorrhages and resulting conditions include malignancies, hepatic and/or renal dysfunction, old age, thrombocytopenia, concomitant diseases inducing or increasing hemorrhagic tendencies (e.g. hemophilia, gastrointestinal ulcers), long-term antibiotic treatment. Therefore, prothrombin time (Quick’s test) should be monitored regularly (every 2-3 days) during the course of therapy. If Quick’s time is reduced, administration of vitamin K (10 mg/week) is indicated; in some cases, prophylactic administration of vitamin K may be useful.

As with other antibiotics, overgrowth of nonsusceptible organisms may occur during prolonged use of cefoperazone. Patients should be observed carefully during treatment. If resistance or selection of organisms occurs, a different antibiotic should be used.

As with any potent systemic agent, it is advisable to check periodically for organ system dysfunction during extended therapy; this includes renal, hepatic, and hematopoietic systems. This is particularly important when treating infants.

Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including cefoperazone, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

In case of severe and persisting diarrhoea, CEFOZON therapy should be discontinued immediately and appropriate treatment initiated (e.g. oral vancomycin, 4 x 250 mg). Peristalsis-inhibiting drugs are contraindicated.

CEFOZON should be administered with caution in patients with a history of enterocolitis.

During and up to 5 days after CEFOZON therapy, alcohol consumption and administration of drugs containing alcohol must be avoided (see also Drug Interactions).

Although there is no evidence that cefoperazone alone has a nephrotoxic potential, renal function should be monitored if the drug is administered in conjunction with aminoglycosides (see also Dosage and Administration).

Usage in Infancy: 

Cefoperazone has been effectively used in infants. It has not been extensively studied in premature infants and neonates. In neonates with kernicterus, cefoperazone does not displace bilirubin from plasma protein binding sites.

CEFOZON contains sodium. This has to be taken into consideration by patients on a controlled sodium diet.

Special Precautions for Disposal and Other handling: 

For single use only. Only clear solutions should be used immediately after reconstitution.

The following solutions can be used for reconstitution: 

Sterile water for injection.

5% dextrose with or without lactated Ringer’s solution, or with 0.9% or 0.2% sodium chloride.

10% dextrose solution.

Lactated Ringer’s solution.

0.9% sodium chloride solution.

Incompatibilities 

CEFOZON is only compatible with the solutions mentioned in  Special precautions for Disposal and Other handling.

CEFOZON is incompatible with aminoglycosides; the two drugs must not be mixed nor injected at the same time or at the same site. The solutions should be prepared shortly before injection. The reconstituted solution is chemically and physically stable at 15°C to 25° C for 24 hours, or 5 days in a temperature (2^°C - 8^°C) or for 21 days under the condition to be stored in refrigerator under -10^°C to -20^°C.

Antabuse-like reactions (flushing, sweating, headache and tachycardia) have been observed when alcohol was ingested during and as late as the fifth day after administration of cefoperazone. A similar reaction has also been reported with other cephalosporins. Therefore, alcohol consumption should be avoided during and up to 5 days after CEFOZON therapy.

For patients requiring oral or parenteral artificial feeding, solutions containing ethanol should be avoided. (see also Warnings and Precautions).

If high doses of heparin and oral anticoagulants are administered in conjunction with cefoperazone, coagulation parameters should be monitored frequently and regularly. This also applies to concomitant administration of substances affecting thrombocyte function.

Since nephrotoxic reactions have occurred with concomitant administration of aminoglycosides and cephalosporins, renal function should be monitored in such cases. In case of a combination therapy with an aminoglycoside antibiotic, the two drugs must not be injected together because of physical incompatibility (see also Dosage and Administration, Warnings and Precautions and Incompatibilities).

Although no impairment of renal function has been observed with concomitant administration of cefoperazone and furosemide, it should be borne in mind that renal function may be impaired due to co-administration of cephalosporins and strongly-acting saluretics.

Drug Laboratory Test Interactions: 

A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution.

Pregnancy: 

Reproduction studies have been performed in mice, rats and monkeys at doses up to 10 times the human dose and have revealed no evidence of impaired fertility and did not show any teratological findings. However, since there are no adequate and well-controlled studies in pregnant women and animal reproduction studies are not always predictive of human response, CEFOZON should be used during pregnancy only in life-threatening situations.

Lactation: 

Since small quantities of cefoperazone are excreted in human milk, CEFOZON should not be used during lactation period.

CEFOZON has no or negligible influence on the ability to drive and to use machines.

For the classification of frequencies of side effects, the following categories are used: Very Common: (≥1/10); Common: (≥1/100 and <1/10); Uncommon: (≥1/1000 and <1/100); Rare: (≥ 1 /10,000 and <1/1000); Very Rare: (<1/10,000); Not known (cannot be estimated from the available data).

Blood and Lymphatic system disorders: 

Very common: Decreased haemoglobin, decreased haematocrit, eosinophilia.

Common: Neutropenia¹, decreased neutrophil count, positive Coombs Direct Test, thrombocytopenia.

Not common: Hypoprothrombinaemia.

Immune system disorders²: 

Common: Hypersensitivity.

Not Known: Anaphylactoid reaction (including shock).

Vascular disorders: 

Common: Infusion site phlebitis.

Not Known: Shock, haemorrhage.

Gastrointestinal disorders: 

Common: Diarrhoea.

Uncommon: Vomiting, nausea.

Not Known: Pseudomembranous colitis.

Hepatobiliary disorders³: 

Common: Increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, jaundice.

Skin and Subcutaneous tissue disorders: 

Common: Pruritus, urticaria, maculopapular rash.

Not Known: Stevens Johnson Syndrome, Toxic epidermal necrolysis.

Renal and Urinary disorders: 

Not Known: Increased (transient) BUN and serum creatinine.

General disorders and Administration site conditions: 

Common: Administration site pain.

Uncommon: Drug fever.

Not Known: Headache, sensation of cold.

¹ Associated with prolonged administration, reversible.

² More likely to occur in patients with a history of allergies, particularly to penicillin.

³ Mostly mild or moderate in severity.

Limited information is available on the acute toxicity of cefoperazone in humans. Overdose of the drug would be expected to produce manifestations that are principally extensions of the adverse reactions reported with the drug in section Undesirable Effects. The fact that high cerebral spinal fluid concentrations of beta-lactam antibiotics may cause neurologic effects and the potential for seizures should be considered.

Since cefoperazone is removed from the circulation by hemodialysis, this procedure may enhance the elimination of the drug from the body, should overdose occur in some patients with impaired renal function.

Pharmacodynamic properties: 

Pharmacotherapeutic group: Cephalosporins.

Mechanism of action: CEFOZON is a semisynthetic broad-spectrum cephalosporin with a bactericidal action, which results from the inhibition of bacterial cell wall synthesis. Like all cephalosporins, cefoperazone selectively blocks peptidoglycan synthesis by binding to cell receptors (penicillin binding proteins) and inhibiting the transpeptidase reaction.

Cefoperazone is in vitro active against a wide variety of clinically significant organisms, and is resistant to degradation by many beta-lactamases.

Cefoperazone has rapid bactericidal activity, which is concentration-dependent, against susceptible Gram-positive and Gram-negative organisms in vitro. In infected animal models, AUC/MIC and C_max/MIC were the PK/PD drivers for efficacy.

Mechanism of resistance: 

Bacterial resistance to cefoperazone may be due to one or more of the following mechanisms: 

Hydrolysis by beta-lactamases. Cefoperazone may be efficiently hydrolyzed by certain of the extended-spectrum beta-Iactamases (ESBLs) and by the chromosomally-encoded (AmpC) enzyme that may be induced or stably depressed in certain aerobic Gram-negative bacterial species.

Reduced affinity of penicillin-binding proteins for cefoperazone, e.g. PBP2A in methicillin-resistant Staphylococcus aureus.

Outer membrane impermeability, which restricts access of cefoperazone to penicillin-binding proteins in Gram­-negative organisms. Bacterial efflux pumps.

Sensitivity of microorganisms: 

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species: 

Aerobic gram-positive organisms: Staphylococcus aureus (methicillin-susceptible), Staphylococcus epidermidis (rnethicilIin-susceptible), Streptococcus pneumoniae (formerly Diplococcus pneumoniae), Streptococcus pyogenes (Group A beta-hemolytic streptococci), Streptococcus agalactiae (Group B beta-hemolytic streptococci), Beta-hemolytic streptococci.

Aerobic gram-negative organisms: 

Citrobacter spp., Haemophilus influenzae (ß-Lactamase positive and negative strains), Escherichia coli, Klebsiella pneumoniae, Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae, Neisseria meningitides, Proteus mirabilis, Providencia rettgeri (formerly Proteus rettgeri), Providencia spp., Pseudomonas aeruginosa, Salmonella spp., Shigella spp., Serratia spp. (including S. marcescens), Yersinia enterocoluica.

Anaerobic gram-positive microorganisms: 

Clostridium spp. (except for Clostridium difficile), Eubacterium spp., Lactobacillus spp., Peptococcus spp., Peptostreptococcus spp..

Anaerobic gram-negative microorganisms: 

Bacteroides fragilis, Bacteroides spp., Fusobacterium spp., Veillonella spp..

Species for which acquired resistance may be a problem: 

Aerobic gram-positive microorganisms: 

Enterococcus spp., Streptococcus pneumoniae (penicillin-resistant).

Aerobic gram-negative microorganisms: 

Acinetobacter spp., Bordetella pertussis, Citrobacter freundii, Enterobacter spp., Klebsiella Oxytoca, Proteus penneri, Proteus vulgaris, Proteus spp..

Inherently resistant microorganisms: 

Aerobic gram-positive microorganisms: 

Enterococcus spp., Listeria monocytogenes, Staphylococcus aureus (methicillin-resistant), coagulase negative Staphylococci (methicillin-resistant).

Aerobic gram-negative microorganisms: 

Stenotrophomonas maltophilia.

Pharmacokinetic properties: 

Distribution: Both after intravenous and intramuscular administration, a dose-proportional increase in plasma concentrations is seen; peak plasma levels are reached within 1-2 hours after intramuscular administration. Plasma protein binding of cefoperazone is 90%, the volume of distribution is 0.15 l/kg body weight. Therapeutic concentrations are reached in e.g. cerebrospinal fluid (especially in patients with inflamed meninges), peritoneal fluid, sputum, bile, urine, tonsils, sinus mucous membrane, cardiac muscle, lungs, gallbladder wall, kidneys, prostate, testis, uterus, fallopian tubes, bones. Cefoperazone crosses the placental barrier, therapeutic concentrations being reached in umbilical cord blood and amniotic fluid.

Biotransformation and Elimination: Independent of the route of administration, the mean serum half-life is approximately 2 hours. Most part of cefoperazone is excreted in the bile (maximum bile concentrations are reached within 1-3 hours after administration), 20-30% by the urine in individuals with normal renal function; less than 1% of cefoperazone is metabolised. Due to its extensive biliary excretion, there are no essential changes of the pharmacokinetics in patients with renal impairment. In patients with hepatic insufficiency and/or biliary obstruction, however, serum half-life may be prolonged and relative excretion by the urine is increased.

Store at a temperature below 25^°C .

CEFOZON 500 mg Vials:  Box containing 1 vial + 1 solvent ampoule.

CEFOZON 1 g Vials:  Box containing 1 vial + 2 solvent ampoules.

CEFOZON 2 g Vials:  Box containing 1 vial + 1 (10 ml) solvent ampoule.