Cebanex (Powder) Instructions for Use

Marketing Authorization Holder

MD Trade, LLC (Russia)

ATC Code

J01DD62 (Cefoperazone and beta-lactamase inhibitor)

Active Substances

Sulbactam (Rec.INN registered by WHO)

Cefoperazone (Rec.INN registered by WHO)

Dosage Forms

	Cebanex	Powder for preparation of solution for intravenous and intramuscular injections 1 g+1 g: vial 1 or 50 pcs.
		Powder for preparation of solution for intravenous and intramuscular injections 500 mg+500 mg: vial 1 or 50 pcs.

Dosage Form, Packaging, and Composition

Vials (1) – cardboard packs.
Vials (50) – cardboard packs.

Vials (1) – cardboard packs.
Vials (50) – cardboard packs.

Clinical-Pharmacological Group

Third generation cephalosporin with beta-lactamase inhibitor

Pharmacotherapeutic Group

Antibiotic, cephalosporin + beta-lactamase inhibitor

Pharmacological Action

The antibacterial component of cefoperazone + sulbactam is Cefoperazone – a third-generation cephalosporin antibiotic that acts on susceptible microorganisms during their active reproduction by inhibiting the biosynthesis of mucopeptide in the cell wall. Sulbactam does not possess clinically significant antibacterial activity (except for Neisseriaceae and Acinetobacter), but is an irreversible inhibitor of most major beta-lactamases produced by beta-lactam-resistant microorganisms. Sulbactam binds to some penicillin-binding proteins, resulting in the combination of cefoperazone and sulbactam often having a more pronounced effect on susceptible strains than Cefoperazone alone.

The combination of cefoperazone with sulbactam is active against all microorganisms susceptible to cefoperazone. Furthermore, it exhibits synergy against various microorganisms, primarily: Haemophilus influenzae, Bacteroides species, Staphylococcus species, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Cefoperazone + Sulbactam is active in vitro against a wide range of the following clinically significant microorganisms:

Gram-positive microorganisms

Staphylococcus aureus (penicillinase-producing and non-producing), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococcus), Streptococcus agalactiae (group B beta-hemolytic streptococcus), most other strains of beta-hemolytic streptococci, Streptococcus faecalis (enterococci).

Gram-negative microorganisms

Escherichia coli, Klebsiella species, Enterobacter species, Citrobacter species, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia species, Serratia species (including Serratia marcescens). Salmonella species and Shigella species, Pseudomonas aeruginosa and some other Pseudomonas species, Acinetobacter calcoaceticus. Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.

Anaerobic microorganisms

Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides species and Fusobacterium species).

Gram-positive and gram-negative cocci (including Peptococcus species, Peptostreptococcus species and Veillonella species).

Gram-positive bacilli (including Clostridium species, Eubacterium species and Lactobacillus species).

Pharmacokinetics

Both Sulbactam and Cefoperazone are well distributed in various tissues and fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, and others.

The maximum concentrations of sulbactam and cefoperazone after intravenous administration of 2 g of cefoperazone sulbactam (1 g sulbactam, 1 g cefoperazone) over 5 minutes average 130.2 µg/ml and 236.8 µg/ml, respectively. This reflects a higher volume of distribution for sulbactam (Vd 18.0-27.6 L) compared to that of cefoperazone (V_d = 10.2-11.3 L).

Approximately 84% of sulbactam and 25% of cefoperazone are excreted by the kidneys. The remaining portion of cefoperazone is excreted primarily in the bile. With parenteral administration of the drug, the half-life of sulbactam averages about 1 hour, and that of cefoperazone is 1.7 hours. Serum concentration is proportional to the administered dose.

No significant changes in the pharmacokinetics of either component of cefoperazone + sulbactam are noted upon repeated use.

No accumulation is observed when the drug is administered every 8-12 hours.

Pharmacokinetics in hepatic impairment

Cefoperazone is actively excreted in the bile. The half-life of cefoperazone is usually prolonged, and the renal excretion of the drug increases in patients suffering from liver diseases and/or biliary obstruction. Even with severe hepatic impairment, a therapeutic concentration of cefoperazone is achieved in the bile, and the half-life increases only 2-4 times.

Pharmacokinetics in renal impairment

In patients with varying degrees of renal impairment receiving Cefoperazone + Sulbactam, a high correlation was found between the total body clearance of sulbactam and the estimated creatinine clearance. In patients with end-stage renal disease, a significant prolongation of the half-life of sulbactam was detected (averaging 6.9 hours and 9.7 hours in various studies). Hemodialysis causes significant changes in the half-life, total body clearance, and volume of distribution of sulbactam.

Pharmacokinetics in the elderly

In elderly individuals with renal failure and impaired liver function, an increase in the duration of the half-life, a decrease in clearance, and an increase in the volume of distribution for both sulbactam and cefoperazone are observed. The pharmacokinetics of sulbactam correlates with the degree of renal impairment, and the pharmacokinetics of cefoperazone correlates with the degree of hepatic impairment.

Pharmacokinetics in children

In children, there are no significant differences in the pharmacokinetics of the components of cefoperazone + sulbactam compared to adults. The half-life of sulbactam in children ranges from 0.91 to 1.42 hours, and that of cefoperazone ranges from 1.44 to 1.88 hours.

Indications

Cefoperazone + Sulbactam is indicated for the treatment of the following infections caused by susceptible microorganisms

• Infections of the upper and lower respiratory tract;
• Urinary tract infections;
• Peritonitis, cholecystitis, cholangitis and other intra-abdominal infections;
• Sepsis;
• Meningitis;
• Skin and soft tissue infections;
• Bone and joint infections;
• Inflammatory diseases of the pelvic organs, endometritis, gonorrhea and other infections of the genitourinary tract.

ICD codes

Dosage Regimen

Intravenously and intramuscularly.

Use in adults

In adults, Cefoperazone + Sulbactam is recommended to be used in the following daily doses

The daily dose should be divided into equal parts and administered every 12 hours.

In severe or refractory infections, the daily dose of cefoperazone + sulbactam can be increased to 8 g (with a ratio of the main components of 1:1, i.e., 4 g of cefoperazone and 4 g of sulbactam). If it is necessary to administer more than 8 g (with a ratio of the main components of 1:1), the dose increase is achieved by additional administration of cefoperazone. The dose should be divided into equal parts and administered every 12 hours.

The recommended maximum daily dose of sulbactam is 4 g.

Use in renal impairment

Patients with a creatinine clearance of 15-30 ml/min should receive a maximum of 1 g of sulbactam every 12 hours (maximum daily dose of sulbactam is 2 g), patients with a creatinine clearance of less than 15 ml/min should receive a maximum of 500 mg of sulbactam every 12 hours (maximum daily dose of sulbactam is 1 g). In severe infections, additional administration of cefoperazone may be required.

The pharmacokinetics of sulbactam are significantly altered by hemodialysis. The half-life of cefoperazone from the blood serum decreases somewhat during hemodialysis. Therefore, administration of the drug should be carried out after dialysis. In patients with hepatic impairment and concomitant renal impairment, if regular monitoring of serum cefoperazone concentration is not performed, the maximum daily dose should not exceed 2 g (see the “Special Instructions” section).

Use in children

In children, Cefoperazone + Sulbactam is recommended to be used in the following daily doses

The dose should be divided into equal parts and administered every 6-12 hours.

In severe or refractory infections, the daily dose of cefoperazone + sulbactam can be increased to 160 mg/kg/day (with a ratio of the main components of 1:1, i.e., 80 mg/kg/day of cefoperazone and 80 mg/kg/day of sulbactam). If it is necessary to administer more than 160 mg/kg/day (with a ratio of the main components of 1:1), the dose increase is achieved by additional administration of cefoperazone. The dose should be divided into equal parts and administered every 6-12 hours.

Use in newborns

In newborns during the first week of life, the drug should be administered every 12 hours.

The maximum daily dose of sulbactam in children should not exceed 80 mg/kg/day.

Method of preparation of solutions for parenteral administration

Solution preparation

Intramuscular administration

Water for injections can be used to prepare the solution for intramuscular administration (see table above).

For convenience of administration, a solution of the drug with a cefoperazone concentration of 250 mg/ml or more can also be prepared. In this case, the solution is prepared in two stages, using first water for injections and then 2% lidocaine hydrochloride solution (see below) as solvents, since lidocaine hydrochloride solution cannot be used directly for initial dissolution.

Preparation of solution using lidocaine. Initially, the powder is dissolved in 1.3 ml of sterile water for injections, and then 0.4 ml of 2% lidocaine hydrochloride solution is added. The total volume of solvent is 1.7 ml. The final solution will contain about 250 mg of cefoperazone and about 250 mg of sulbactam per 1 ml of 0.5% lidocaine hydrochloride solution.

Intravenous administration

To prepare a solution for infusion, 1 g (0.5 g + 0.5 g) of cefoperazone + sulbactam is dissolved in an initial volume (approximately 3.4 ml) of one of the following infusion solutions: 5% glucose (dextrose) solution, 5% glucose in saline solution, 5% glucose in 0.225% sodium chloride solution, 0.9% sodium chloride solution or sterile water for injections, and then diluted to 20 ml with the same solution.

Preparation of solution using Ringer’s lactate. Since Ringer’s lactate is not suitable for initial dilution, the solution is prepared in two stages: first, sterile water for injections is used (see table above), and then the resulting solution is diluted with Ringer’s lactate solution to a sulbactam concentration of 5 mg/ml (2 ml of the initial solution is diluted in 50 ml of Ringer’s lactate solution or 4 ml in 100 ml of Ringer’s lactate solution).

Infusion is carried out over 15-60 minutes.

For intravenous injection, the contents of each vial should be dissolved in 3.4 ml of one of the solvents described in the preparation of the infusion solution (see above) and administered over at least 3 minutes.

Adverse Reactions

The drug is generally well tolerated. The following reactions have been noted:

Cardiovascular system decreased blood pressure.

Gastrointestinal tract diarrhea, nausea, vomiting, pseudomembranous colitis.

Allergic reactions maculopapular rash, urticaria, as well as itching, Stevens-Johnson syndrome, anaphylactic shock. The risk of reactions is higher in patients with a history of allergic reactions.

Hematopoietic system decreased neutrophil count; with prolonged treatment – reversible neutropenia, decreased hemoglobin and hematocrit levels, transient eosinophilia, thrombocytopenia, leukopenia, hypoprothrombinemia, bleeding (due to vitamin K deficiency).

Local reactions the drug is well tolerated with intramuscular administration. Sometimes after intramuscular injection, transient pain and burning at the injection site are observed. With intravenous administration through a catheter, phlebitis may develop at the injection site.

Laboratory Parameters transient increase in liver transaminases – aspartate aminotransferase, ALT, alkaline phosphatase and bilirubin in blood serum, hematuria, hypercreatininemia. In some patients, a false-positive Coombs test was observed during treatment. When using Benedict’s or Fehling’s solution, a false-positive reaction for glucose in urine may be observed.

Other headache, fever, chills, vasculitis.

Contraindications

• Allergy to penicillins, Sulbactam, Cefoperazone or any other beta-lactam antibiotics.

With caution: in severe impairment of liver and kidney function; with colitis (including in the anamnesis); in premature newborns.

Use in Pregnancy and Lactation

During pregnancy, the drug should be used only if the expected benefit to the mother outweighs the potential risk to the fetus.

If the drug is taken during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in severe liver dysfunction.

Use in Renal Impairment

Use with caution in severe renal impairment.

Pediatric Use

The maximum daily dose of sulbactam in children should not exceed 80 mg/kg/day.

Special Precautions

Cases of hypersensitivity reactions have been described in patients receiving beta-lactam antibiotics, including cephalosporins; the risk of developing these reactions is higher in patients with a history of hypersensitivity reactions. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be prescribed.

In anaphylactic reactions, emergency administration of epinephrine is necessary. Oxygen, intravenous glucocorticosteroids, and airway patency, including intubation, should be provided as indicated.

Dosage adjustment may be required in cases of severe biliary obstruction, severe liver dysfunction, and renal impairment combined with any of the above conditions.

In patients with impaired liver function and concomitant renal impairment, serum concentrations of cefoperazone should be monitored and its dose adjusted if necessary.

During treatment with cefoperazone, as with other antibiotics, vitamin K deficiency has rarely developed. The probable cause is the suppression of normal intestinal flora, which synthesizes this vitamin. Patients at risk include those with poor nutrition, malabsorption (e.g., in cystic fibrosis), and those on long-term intravenous artificial nutrition. In such cases, as well as in patients receiving anticoagulants, prothrombin time should be monitored and vitamin K should be prescribed if indicated.

During prolonged treatment with cefoperazone + sulbactam, as with other antibiotics, overgrowth of non-susceptible microorganisms may be observed. During long-term therapy, it is recommended to periodically monitor the parameters of the function of internal organs, including kidneys, liver and the hematopoietic system. This is especially important for newborns, primarily premature ones, and young children.

When used concomitantly with aminoglycosides, renal function should be monitored.

Overdose

Symptoms neurological disorders, including seizures.

Treatment symptomatic.

In case of overdose in patients with impaired renal function, hemodialysis may facilitate the removal of the drug from the body.

Drug Interactions

Aminoglycosides

Cefoperazone + sulbactam and aminoglycoside solutions should not be mixed due to pharmaceutical incompatibility between them. If combination therapy with cefoperazone + sulbactam and an aminoglycoside is carried out, the two drugs are administered by sequential infusions using separate secondary catheters, and the primary catheter is flushed between drug administrations. The intervals between the administration of cefoperazone + sulbactam and the aminoglycoside during the day should be as long as possible.

Alcohol

Reactions characterized by flushing, sweating, headache, and tachycardia have been reported when alcohol was consumed during treatment with cefoperazone and within 5 days after its administration; therefore, patients should be warned about the possibility of their occurrence when consuming alcoholic beverages while being treated with cefoperazone + sulbactam. In patients requiring artificial nutrition (oral or parenteral), the use of solutions containing ethanol should be avoided.

Ringer’s solution, 2% lidocaine hydrochloride solution

Cefoperazone + sulbactam solution is incompatible with Ringer’s solution and 2% lidocaine hydrochloride solution upon direct mixing. Compatibility is achieved as a result of two-step preparation: initially, Cefoperazone + Sulbactam is dissolved in water for injections, and then Ringer’s solution or 2% lidocaine hydrochloride solution is added.

Storage Conditions

Store in a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children. List B.

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.