Expiration date: 07/2025

Composition and form of issue:

Powder for preparation of solution for injection. 1 flask contains:

sulbactam 1 g

cefoperazone 1 g

in the ratio 1:1 

in clear, colourless glass vials type 1 with halobutyl rubber caps and Teflon coated aluminum foil 2 g in a box 1 vial.

instruction for use

APPROVED FC MH RF 15.11.2001, St. No. 16.

Description. White powder.

Composition. In vials with the ratio of the main components 1:1 contains 1000 mg + 1000 mg powder of the sulbactam and cefoperazone, respectively.

Pharmacological properties.

Pharmacodynamics. The antibacterial component of sulbactam / cefoperazone is cefoperazone — cefalosporin of the third generation, which acts on sensitive microorganisms during their active reproduction by inhibiting the biosynthesis of mucopeptide of the cell wall. Sulbactam has no clinically significant antibacterial activity (except Neisseriaceae and Acinetobacter). Studies have shown that it is an irreversible inhibitor of most major beta-lactamases, which are produced by microorganisms resistant to beta-lactam antibiotics.

The ability of sulbactam to prevent destruction of penicillins and cephalosporins by resistant microorganisms was confirmed in studies using resistant strains in respect of which sulbactam had expressed synergy with penicillins and cephalosporins. Sulbactam is also associated with some penicillin binding proteins, so sulbactam/cefoperazone often has a more pronounced effect on sensitive strains than one cefoperazone.

The combination of sulbactam and cefoperazone is active against all microorganisms sensitive to cefoperazone. In addition, it has a synergy with respect to various microorganisms, especially: Haemophilus influenzae, Bacteroides species, Staphylococcu species, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Sulbactam / cefoperazone is active in vitro against a wide range of clinically relevant microorganisms:

Gram-positive microorganisms

Staphylococcus aureus( producing and non-producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (beta-hemolytic Streptococcus group a), Streptococcus agalactiae (beta-hemolytic Streptococcus group B), most other strains of beta - hemolytic Streptococcus, many strains of Streptococcus faecalis (Enterococcus).

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 S. marcescens), Salmonella and Shigella species, Pseudomonas aerosa and several others 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, Peptostreptococcus and Veillonella species).

Gram-positive wands (including Clostridium, Eubacterium, 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, etc.

Cmax of sulbactam and cefoperazone after I/V administration of 2 g of sulbactam/cefoperazone (1 g of sulbactam, 1 g of cefoperazone) for 5 min averaged 130, 2 and 236, 8 µg/ml, respectively. This reflects a higher volume of distribution of sulbactam (Vd = 18, 0-27, 6 l) compared to that of cefoperazone (Vd = 10, 2-11, 3 l).

Data on the presence of any pharmacokinetic interaction between sulbactam and cefoperazone when the introduction of sulbactam/cefoperazone no.

Approximately 84% of the dose of sulbactam and 25% of the dose of cefoperazone with the introduction of sulbactam/cefoperazone is excreted by the kidneys. The rest of cefoperazone is excreted mainly with bile. Parenteral sulbactam/cefoperazone T1/2 of sulbactam averages about 1 hour, cefoperazone — 1, 7 h. Serum concentration is proportional to the administered dose.

If you re-use significant changes in the pharmacokinetics of both components of sulbactam/cefoperazone is not marked. When the drug is administered every 8 to 12 h accumulation was not observed.

Application in violation of liver function

Cefoperazone is actively excreted in the bile. T1/2 cefoperazone usually extends, and excretion of the drug in the urine increases in patients suffering from liver diseases and / or biliary obstruction. Even with severe hepatic impairment in bile, the therapeutic concentration of cefoperazone is achieved, and T1/2 increases 2-4 times.

Application in violation of kidney function

In patients with varying degrees of renal dysfunction, receiving sulbactam/cefoperazone, revealed a high correlation between the total clearance of sulbactam from the body and the calculated Cl creatinine. In patients with end-stage renal failure showed a significant lengthening of T 1/2 sulbactam (average of 6, 9 and 9, 7 h in different studies). Hemodialysis caused significant changes T1 / 2, the total clearance of the body and the volume of distribution of sulbactam.

Use in the elderly

Pharmacokinetics of sulbactam / cefoperazone was studied in elderly people with renal insufficiency and impaired liver function. Compared with healthy volunteers showed an increase in the duration of T1/2, a decrease in clearance and increase in the volume of distribution of both sulbactam and cefoperazone. The pharmacokinetics of sulbactam correlated with the degree of renal dysfunction, and the pharmacokinetics of cefoperazone — with the degree of liver dysfunction.

Use in children

Studies in children showed no significant changes in the pharmacokinetics of sulbactam/cefoperazone compared with those in adults. The average T1 / 2 sulbactam in children ranged from 0, 91 to 1, 42 h, cefoperazone - from 1, 44 to 1, 88 h. 

Indications for use. Sulperazone is indicated for the treatment of the following infections caused by sensitive microorganisms:

• infections of the upper and lower respiratory tract
  
• infections of the upper and lower urinary tract
  
• peritonitis, cholecystitis, cholangitis and other intra-abdominal infections
  
• septicaemia
  
• meningitis
  
• skin and soft tissue infections
  
• bone and joint infections
  
• inflammatory diseases of the pelvic organs, endometritis, gonorrhoea and other infections of the genitourinary tract.
  

Dosage and administration. Application in adults. Sulbactam / cefoperazone is recommended in the following daily doses (see table. One):

Table 1

Ratio	Sulbactam / cefoperazone (g)	Sulbactam, dose (g)	Cefoperazone, dose (g)
1:1	2, 0-4, 0	1, 0-2, 0	1, 0-2, 0

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

In severe or refractory infections, the daily dose of sulbactam / cefoperazone can be increased to 8 g at a ratio of the main components of 1:1 (i.e. 4 g cefoperazone). Patients receiving sulbactam / cefoperazone in a ratio of 1:1 may require 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.

Application in violation of kidney function. In patients With CL creatinine 15 -30 ml/min, the maximum dose of sulbactam is 1 g every 12 h (the maximum daily dose of sulbactam 2 g), and in patients with Cl creatinine less than 15 ml / min the maximum dose of sulbactam is 500 mg every 12 h (the maximum daily dose of sulbactam 1 g). In severe infections may require additional administration of cefoperazone.

The pharmacokinetics of sulbactam is significantly altered during hemodialysis. T1 / 2 serum cefoperazone decreases slightly during hemodialysis. Therefore, the introduction of the drug should be planned after dialysis.

Use in children. In children, sulbactam / cefoperazone is recommended in the following daily doses (see table. Two):

Table 2

Ratio	Sulbactam / cefoperazone (g)	Sulbactam, dose (g)	Cefoperazone, dose (g)
1:1	40-80	20-40	20-40

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

In severe or refractory infections, these dosages may be increased to 160 mg/kg/day for a 1:1 ratio. The daily dose is divided into 2-4 equal parts.

The use of babies. 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.

A method for preparing solutions for parenteral use.

Intravenous administration. For the preparation of a solution for in/in infusion can be used lactic ringer solution, but it can not be used for initial dissolution, given the incompatibility of this mixture. Compatibility can be achieved by two — stage preparation of the solution-initially, the powder is dissolved in water for injection, and then diluted with a lacquered ringer solution.

For repeated infusions, the content of each vial of sulbactam/cefoperazone is dissolved in an adequate volume of 5% dextrose solution in water, 0, 9% sodium chloride solution for injection or sterile water for injection, and then diluted to 20 ml with the same solvent. Infusion is carried out for 15-60 minutes.

For b / b injection, the contents of each vial should be dissolved as above and administered for at least 3 minutes.

Intramuscular injection. To prepare a solution for the / m introduction can be used 2% lidocaine hydrochloride solution, but it can not be used for the initial dissolution, given their incompatibility. Compatibility can be achieved by two — stage preparation of the solution-initially, the powder is dissolved in water for injection, and then diluted with a 2% solution of lidocaine hydrochloride.

Solution preparation.

Table 3

Total dose (g)	Equivalent doses of sulbactam + cefoperazone (g)	The volume of solvent (ml)	Maximum final concentration (mg / ml)
2	1, 0 + 1, 0	6, 7	125 + 125

Sulbactam / cefoperazone is compatible with water for injection, 5% dextrose solution, isotonic sodium chloride solution, 5% dextrose solution in physiological solution at concentrations ranging from 10 mg/ml cefoperazone and 10 mg/ml sulbactam to 250 mg/ml and 250 mg/ml respectively.

Ringer lacquered solution.

To dissolve the powder should use sterile water for injection.

The solution is prepared in 2 stages: first, use sterile water for injection (see table. above), and then the resulting solution is diluted with a lactic ringer solution to a concentration of sulbactam 5 mg/ml (2 ml of the initial solution is diluted in 50 ml of the lactic ringer solution or 4 ml in 100 ml of the lactic ringer solution).

Lidocaine.

To dissolve the powder should use sterile water for injection. A solution containing cefoperazone at a concentration of 250 mg / ml or more, prepared in 2 steps: first, use sterile water for injection (see table. above), and then diluted with 2% lidocaine solution to obtain a solution containing up to 250 mg/ml cefoperazone and 250 mg/ml sulbactam in about 0.5% lidocaine hydrochloride solution.

Pregnancy and breast-feeding. During pregnancy and lactation, the drug is used only if the expected benefit to the mother exceeds the potential risk to the fetus.

Side effect. Anaphylactoid reactions: shock.

Gastrointestinal tract: nausea, vomiting, pseudomembranous colitis.

Skin reactions: maculopapular rash, urticaria, itching, Stevens - Johnson syndrome. Their risk is higher in patients with allergic reactions (especially penicillin) in the history.

Hematopoietic system: decrease in the number of neutrophils. In long-term treatment (as well as other beta-lactam antibiotics) can develop reversible neutropenia. Some patients had a positive Coombs test during treatment. There is also a decrease in hemoglobin and hematocrit levels. There is transient eosinophilia, leukopenia and thrombocytopenia, as well as hypoprothrombinemia.

Others: headache, fever, injection pain, chills, hematuria, vasculitis.

Laboratory indicators: transient increase in liver function parameters-AST, ALT, alkaline phosphatase and bilirubin in blood serum.

Local reactions: sulbactam/cefoperazone is well tolerated in / m introduction. Sometimes after I/m injection there is a transient pain. At/in the introduction of sulbactam/cefoperazone (as well as other cephalosporins and penicillins) by means of a catheter phlebitis may develop at the site of infusion (0, 1%).

Contraindications. Sulbactam / cefoperazone is contraindicated in patients with allergies to penicillins, sulbactam, cefoperazone or any other cephalosporins.

Special instruction. In patients receiving beta-lactam, including cephalosporins, described cases of serious hypersensitivity reactions (anaphylactic), which sometimes led to death. The risk of such reactions is higher in patients who have a history of hypersensitivity reactions. In the event of an allergic reaction, it is necessary to cancel the drug and prescribe adequate therapy.

In case of serious anaphylactic reactions need immediate administration of epinephrine. According to the indications, oxygen is prescribed, I / V is administered glucocorticosteroids and provide airway patency, including intubation.

Dose changes may be required in cases of severe biliary obstruction, severe liver disease, as well as kidney dysfunction, combined with any of these conditions.

In patients with impaired liver function and concomitant renal dysfunction, it is necessary to monitor the serum concentration of cefoperazone and correct its dose if necessary. If regular monitoring of serum concentration of cefoperazone in such cases is not carried out, its daily dose should not exceed 2 g.

The treatment with cefoperazone, like other antibiotics, in rare cases develop a deficiency of vitamin K. the Reason for it is probably the suppression of the normal intestinal flora which synthesizes this vitamin. The risk group includes patients who receive malnutrition, malabsorption suffering (for example, cystic fibrosis) and long-term in/in artificial nutrition. In such cases, as well as in patients receiving anticoagulants, it is necessary to monitor prothrombin time and in the presence of indications to prescribe vitamin K.

In long - term treatment with sulbactam/cefoperazone, as with other antibiotics, excessive growth of insensitive microorganisms can be observed. Patients should be carefully monitored during treatment. With long-term therapy, it is recommended to periodically monitor the performance of the internal organs, including the kidneys, liver and hematopoietic system. This is especially important for newborns, especially premature babies, and young children.

Cefoperazone does not displace bilirubin due to plasma proteins.

Overdose. Information about the acute toxicity of cefoperazone sodium and sulbactam sodium in humans is limited. In case of overdose, it is possible to expect the appearance of undesirable effects registered when using the drug. It is necessary to take into account the fact that the high concentration of beta - lactam antibiotics in the cerebrospinal fluid can lead to neurological disorders, including seizures. Both cefoperazone and sulbactam are removed from the blood by hemodialysis, so this method of treatment can help to eliminate the drug from the body in case of overdose in patients with impaired renal function.

Interaction with other drugs and other forms of interaction. Alcohol. When taking alcohol during the treatment with cefoperazone and within 5 days after its introduction, reactions characterized by tides, sweating, headache and tachycardia were recorded. Similar reactions were observed with the use of some other cephalosporins, so patients should be warned about the possibility of their appearance in the consumption of alcoholic beverages during treatment with sulbactam/cefoperazone. In patients who need artificial nutrition (inside or parenterally), the use of solutions containing ethanol should be avoided.

Influence on the results of laboratory tests. When using Benedict's solution or Fehling's may be a false-positive reaction for glucose in the urine.

Aminoglycosides. Solutions of sulbactam / cefoperazone and aminoglycosides should not be mixed directly, given the pharmaceutical incompatibility between them. If combined therapy with sulbactam/cefoperazone and aminoglycoside is carried out, then 2 drugs are administered by successive infusions using separate secondary catheters, and the primary catheter is washed with an adequate solution between doses of drugs. The intervals between the introduction of sulbactam/cefoperazone and aminoglycoside during the day should be as large as possible.

Form release. Sulbactam / cefoperazone is available in bottles of 2, 0 g (1 g of active substance). The clear, colourless glass vials type 1 with halobutyl rubber caps and Teflon coated aluminum foil.

Shelf life. 2 years.

Storage conditions. Store below 25 ° C, out of reach of children.