Composition, form of production and packaging
Powder for solution preparation for intravenous and intravenous administration 1 fl.
sulbactam 1 g
cefoperazone 1 g
bottles (1) - packs of cardboard.
bottles (50) - packs of cardboard.
Powder for solution preparation for intravenous and intravenous administration 1 fl.
sulbactam 500 mg
cefoperazone 500 mg
bottles (1) - packs of cardboard.
bottles (50) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
The antibacterial component of cefoperazone + sulbactam is cefoperazone, a third generation cephalosporin antibiotic that acts on sensitive microorganisms during their active propagation by inhibiting the biosynthesis of the cell wall mucopeptide. Sulbactam does not have clinically significant antibacterial activity (except for Neisseriaceae and Acinetobacter), but is an irreversible inhibitor of most of the major beta-lactamases that are produced by resistant to beta-lactam antibiotics by microorganisms. Sulbactam binds to some penicillin-binding proteins, resulting in a combination of cefoperazone and sulbactam which has a more pronounced effect on sensitive strains than just cefoperazone.
The combination of cefoperazone with sulbactam is active against all microorganisms sensitive to cefoperazone. In addition, it has a synergistic effect on various microorganisms, in particular: Haemophilus influenzae, Bacteroides species, Staphylococcus species, Acinelobacter calcoaceticus, Enterobacter aerobes, 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 relevant microorganisms:
Gram-positive microorganisms
Staphylococcus aureus, 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, Acinelobacler calcoacelicus. Neisseria gonorrhoeae, Neisseria meningitidis, Bordelella pertussis, Yersinia enlerocolitica.
Anaerobic microorganisms
Gram-negative rods (including Bacleroides fragilis, other Bacteroides species and Fusobacterium species).
Gram-positive and Gram-negative cocci (including Peptococcus species, Peplostreplococcus species and Veillonella species).
Gram-positive rods (including Clostridium species, Eubacterium species and Lactobacillus species).
PHARMACOKINETICS
Both sulbactam and cefoperazone are well distributed into various tissues and fluids, including bile, gall bladder, 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 of sulbactam, 1 g of cefoperazone) for 5 minutes averages 130.2 Ојg / ml and 236.8 Ојg / ml, respectively. This reflects a higher volume of distribution of sulbactam (Vd 18,0-27,6 l) in comparison with that of cefoperazone (V d = 10.2-11.3 l).
Approximately 84% of sulbactam and 25% of cefoperazone are excreted by the kidneys. The rest of cefoperazone is excreted mainly with bile. With parenteral administration of the drug, the half-life of sulbactam averages about 1 hour, cefoperazone - 1.7 hours. Serum concentration is proportional to the administered dose.
With repeated application of significant changes in the pharmacokinetics of both components of cefoperazone + sulbactam is not noted.
When the drug is administered every 8-12 hours, cumulation is not observed.
Pharmacokinetics for violations of liver function
Cefoperazone is actively excreted with bile. The half-life of cefoperazone usually lengthens, and the excretion of the drug by the kidneys increases in patients suffering from liver diseases and / or biliary tract obstruction. Even with severe violations of the liver in bile, the therapeutic concentration of cefoperazone is reached, and the elimination half-life is only 2-4 times.
Pharmacokinetics in renal dysfunction
In patients with varying degrees of renal dysfunction, receiving cefoperazone + sulbactam, a high correlation was found between the total clearance of sulbactam from the body and the estimated clearance of creatinine. In patients with terminal renal failure, a significant lengthening of the half-life of sulbactam (an average of 6.9 hours and 9.7 hours in various studies) was detected. Hemodialysis causes significant changes in the half-life, total clearance from the body and the volume of distribution of sulbactam.
Pharmacokinetics in the elderly
In elderly people with renal insufficiency and impaired liver function, an increase in the half-life period, a decrease in clearance and an increase in the volume of distribution of both sulbactam and cefoperazone are observed. The pharmacokinetics of sulbactam correlates with the degree of impaired renal function, and the pharmacokinetics of cefoperazone - with a degree of impaired hepatic function.
Pharmacokinetics in children
Children have no significant differences in the pharmacokinetics of the components of cefoperazone + sulbactam compared with adults. The half-life of sulbactam in children varies from 0.91 to 1.42 h, and cefoperazone from 1.44 to 1.88 h.
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;
- infections of bones and joints;
- inflammatory diseases of the pelvic organs, endometritis, gonorrhea and other infections of the genito-urinary tract.
DOSING MODE
Intravenous and intramuscular.
Application in adults
In adults, cefoperazone + sulbactam is recommended for use in the following daily doses:
Ratio of Cefoperazone + Sulbactam (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 cefoperazone + sulbactam can be increased to 8 g (with a 1: 1 ratio of the major components, ie 4 g of cefoperazone and 4 g of sulbactam). If you need more than 8 g (with a 1: 1 ratio of the main components), an increase in the dose is achieved by the 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 for renal dysfunction
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 creatinine clearance less than 15 ml / min - maximum 500 mg of sulbactam every 12 hours (maximum daily dose sulbactam - 1 g). In severe infections, additional administration of cefoperazone may be required.
The pharmacokinetics of sulbactam significantly changes during hemodialysis. The half-life of cefoperazone from the blood serum decreases slightly during hemodialysis. In this regard, the administration of the drug should be carried out after dialysis. In patients with impaired hepatic function and concomitant renal dysfunction, if regular monitoring of serum concentration of cefoperazone is not performed, the maximum daily dose should not exceed 2 g (see section "Special instructions").
Use in children
In children, cefoperazone + sulbactam is recommended for use in the following daily doses:
Ratio of Cefoperazone + Sulbactam (mg / kg / day) Sulbactam dose (mg / kg / day) Cefeperazone dose (mg / kg / day)
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, the daily dose of cefoperazone + sulbactam can be increased to 160 mg / kg / day (with a 1: 1 ratio of the major components, ie 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), an increase in dose is achieved through the additional administration of cefoperazone. The dose should be divided into equal parts and administered every 6-12 hours.
Neonatal application
In newborns during the first week of life, the drug should be injected every 12 hours.
The maximum daily dose of sulbactam in children should not exceed 80 mg / kg / day.
Method of preparing solutions for parenteral use
Preparation of the solution
Total dose (g) Equivalent doses of efoperazone + sulbactam (g) Volume of the solvent Max, final conc. (mg / ml)
1.0 0.5 + 0.5 3.4 125 + 125
Intramuscular injection
To prepare the solution for intramuscular injection, water for injection can be used (see table above).
For the convenience of administration, it is also possible to prepare a solution of the preparation with a concentration of cefoperazone 250 mg / ml or more. In this case, the solution is prepared in two steps, using as water first water for injection, and then 2% solution of lidocaine hydrochloride (see below), since for initial dissolution the lidocaine hydrochloride solution can not be directly applied.
Preparation of a solution using lidocaine. Initially, the powder is dissolved in 1.3 ml of sterile water for injection, and then 0.4 ml of a 2% solution of lidocaine hydrochloride is added. The total volume of the solvent is 1.7 ml. The final solution will contain in 1 ml of a 0.5% solution of lidocaine hydrochloride about 250 mg of cefoperazone and about 250 mg of sulbactam.
Intravenous administration
To prepare a solution for infusion of 1 g (0.5 g + 0.5 g) of cefoperazone + sulbactam dissolved in the initial volume (approximately 3.4 ml) of one of the following infusion solutions: 5% glucose solution (dextrose), 5% glucose solution in physiological saline, 5% glucose solution in 0.225% sodium chloride solution, 0.9% sodium chloride solution or sterile water for injection, and then dilute to 20 ml with the same solution.
Preparation of solution using Ringer's shackle. Since Ringer's lactate is not suitable for initial dilution, the solution is prepared in two steps: first, use sterile water for injection (see table above), and then dilute the resulting solution with Ringer's lactate solution to a 5 mg / ml sulbactam concentration (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 for 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 for a minimum of 3 minutes.
SIDE EFFECT
The drug is usually well tolerated. The following reactions were noted:
Cardiovascular system: lowering blood pressure.
Gastrointestinal tract: diarrhea, nausea, vomiting, pseudomembranous colitis.
Allergic reactions: maculopapular rash, hives, as well as itching, Stevens-Johnson syndrome, anaphylactic shock. The risk of reactions is higher in patients with allergic reactions in the anamnesis.
Hematopoiesis system: a decrease in the number of neutrophils; with long-term treatment-reversible neutropenia, decreased hemoglobin and hematocrit, transient eosinophilia, thrombocytopenia, leukopenia, hypoprothrombinemia, bleeding (due to vitamin K deficiency).
Local reactions: the drug is well tolerated by intramuscular injection. Sometimes, after intramuscular injection, there is transient pain and burning at the injection site.With intravenous administration through the catheter, phlebitis can develop at the site of administration.
Laboratory indicators: transient increase in "hepatic" transaminases-aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin in blood serum, hematuria, hypercreatininaemia. In some patients, a false positive Coombs test was observed during treatment. When using a solution of Benedict or Felling, a false positive reaction to glucose in the urine can be observed.
Others: headache, fever, chills, vasculitis.
CONTRAINDICATIONS
- allergy to penicillins, sulbactam, cefoperazone or any other beta-lactam antibiotics.
With caution: for severe violations of the liver and kidneys; with colitis (including history); in premature newborns.
PREGNANCY AND LACTATION
In pregnancy, the drug is used only if the expected benefit to the mother exceeds the potential risk to the fetus.
In the case of taking the drug during lactation, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution in severe violations of kidney function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution in severe violations of the liver.
APPLICATION FOR CHILDREN
The maximum daily dose of sulbactam in children should not exceed 80 mg / kg / day.
SPECIAL INSTRUCTIONS
Patients who received beta-lactam antibiotics, including cephalosporins, described cases of hypersensitivity reactions, the risk of which is higher in patients who have a history of hypersensitivity reactions. In case of an allergic reaction, it is necessary to cancel the drug and prescribe the appropriate therapy.
Anaphylactic reactions require the immediate administration of epinephrine. According to the indications, oxygen is prescribed, glucocorticosteroids are intravenously administered and airway patency, including intubation, is provided.
A dose change may be required in cases of severe obstruction of the biliary tract, severe impairment of liver function, and impaired renal function associated with any of these conditions.
In patients with impaired liver function and concomitant renal dysfunction, monitoring the serum concentration of cefoperazone and correcting its dose should be necessary.
In the treatment of cefoperazone, as well as other antibiotics, vitamin K deficiency was rare in rare cases. Its cause is probably suppression of normal intestinal microflora, which synthesizes this vitamin. The risk group can include patients receiving malnutrition, suffering from malabsorption (for example, in cystic fibrosis) and for a long time on intravenous artificial feeding. In such cases, as well as in patients receiving anticoagulants, it is necessary to monitor prothrombin time and, in the presence of indications, prescribe vitamin K.
With prolonged treatment with cefoperazonom + sulbactam, as with other antibiotics, excessive growth of insensitive microorganisms can be observed. With prolonged therapy, it is recommended to periodically monitor the performance of internal organs, including the kidneys, liver and hematopoiesis system. This is especially important for newborns, especially premature babies, and small children.
When used simultaneously with aminoglycosides, it is necessary to monitor kidney function.
OVERDOSE
Symptoms: neurological disorders, including convulsions.
Treatment: symptomatic.
In the case of an overdose in patients with impaired renal function, the removal of the drug from the body can be facilitated by hemodialysis.
DRUG INTERACTION
Aminoglycosides
Solutions cefoperazona + sulbactam and aminoglycosides should not be mixed, given the pharmaceutical incompatibility between them. If combined therapy with cefoperazone + sulbactam and aminoglycoside is given, the two drugs are administered by successive infusions using separate secondary catheters, and the primary catheter is washed between doses of the drugs. The intervals between the administration of cefoperazone + sulbactam and aminoglycoside during the day should be as much as possible.
Alcohol
When taking alcohol during treatment with cefoperazone and for 5 days after its administration, reactions characterized by hot flashes, sweating, headache and tachycardia were recorded, so patients should be warned about the possibility of their occurrence when consuming alcoholic beverages against the background of treatment with cefoperazone + sulbactam. In patients who need artificial feeding (inside or parenteral), the use of solutions containing ethanol should be avoided.
Ringer's solution, 2% lidocaine hydrochloride solution
The solution of cefoperazone + sulbactam is incompatible with Ringer's solution and 2% lidocaine hydrochloride solution with direct mixing. Compatibility is achieved as a result of two-stage preparation: initially, cefoperazone + sulbactam is dissolved in water for injections, and then Ringer's solution or 2% solution of lidocaine hydrochloride is added.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store in a dry, dark place at a temperature of no higher than 25 В° C. Keep out of the reach of children. List B. Shelf life - 2 years
