Sulperazone - instructions for use, dose, side effects, contraindications

Pharmacodynamics:The antibacterial component of sulbactam / cefoperazop is cefoperazone Third-generation cephalosporin, which acts on sensitive microorganisms during their active propagation by inhibiting the biosynthesis of the mucopeptide of the cell wall. Sulbactam does not have clinically significant antibacterial activity (except Ncisseriaceae and Acinetobacter). However, it was noted that it is an irreversible inhibitor of most of the major beta-lactamases that are produced by microorganisms resistant to beta-lactam antibiotics. The ability of sulbactam to prevent the destruction of penicillins and cephalosporins by resistant microorganisms was confirmed in studies using resistant strains for which sulbactam possessed a pronounced synergy with penicillins and cephalosporins.In addition, sulbactam interacts with some penicillin-binding proteins, so sulbactam / cefoperazone often has a more pronounced effect on sensitive strains than one sulbactam / cefopsrazone in a 1: 1 ratio in broth or agar media.

To determine the MPC by the disk-diffusion method, it is recommended to use a disc containing 30 μg of sulbactam and 75 μg of cefoperazone.

The following quality control standards are recommended when using discs containing 30 μg of sulbactam and 75 μg of cefoperazone. For the control strain Acinelobacler spp. (ATCC 43498), the diameter of the zone is 26-32; for Pseudomonas aeruginosa (ATCC 27853) - 22-28; for Escherichia coli (ATCC 25922) 27-33; for Staphylococcus aureus (ATCC 25923) - 23-30.

Pharmacokinetics:

The maximum concentrations of sulbactam and cefoperazone after intravenous administration of 2 g of sulbactam / cefopsrazone (1 g of sulbactam, 1 g of cefoperazone) for 5 minutes 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 with that of cefoperazone (Vd = 10.2-11.3 L).

After intramuscular injection, 1.5 g of sulbactam / cefopsrazone (0.5 g of sulbactam, 1 g of cefoperazone), the maximum concentrations of sulbactam and cefoperazone in the serum were observed from 15 minutes to 2 hours after administration. Maximum whey concentrations were 19.0 and 64.2 μg / ml of sulbactam and cefoperazone, respectively. Both sulbactam and cefoperazone well distributed into various tissues and fluids, including bile, gall bladder, skin, appendix, fallopian tubes, ovaries, uterus, etc.

Approximately 84% of the dose of sulbactam and 25% of the dose of cefoperazone administered as a combination - sulbactam / cefoperazone is excreted by the kidneys. Most of the remaining dose of cefoperazone is excreted with bile. Cefoperazone Do not displace bilirubin from the connection with plasma proteins. The half-life of sulbactam averages about 1 h, cefoperazone - 1.7 h. Serum concentration is proportional to the administered dose. There is no data on the presence of any pharmacokinetic interaction between sulbactam and cefoperazone upon the administration of sulbactam / cefopsrazone.

With repeated application of significant changes in the pharmacokinetics of both components of sulbactam / cefopsrazone was not noted. With the introduction of the drug every 8-12 hours cumulation was not observed.

Application for violations of liver function

Because cefoperazone actively output from bile. then the half-life of cefoperazone usually lengthens, and the excretion of the drug by the kidneys increases in patients with liver disease and / or biliary tract obstruction.Even with a serious violation of liver function in bile, the therapeutic concentration of cefoperazone is reached, and the elimination half-life increases only 2-4 times.

Application for renal dysfunction

In patients with varying degrees of renal dysfunction, receiving sulbactam / cefoperazone, 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 and 9.7 hours in various studies) was detected. Hemodialysis caused significant changes in the half-life, total clearance and volume of distribution of sulbactam.

Application in the elderly

Pharmacokinetics of sulbactam / cefoperazone has been studied in elderly people with renal insufficiency and impaired liver function. Compared with healthy volunteers, an increase in the half-life, a decrease in clearance, and an increase in the distribution of both sulbactam and cefoperazone have been found. The pharmacokinetics of sulbactam correlated with the degree of impaired renal function, and the pharmacokinetics of cefoperazone - with a degree of impaired hepatic function.

Use in children

In studies in children, no significant changes in the pharmacokinetics of the sulbactam / cefoperazone components were found in comparison with those in adults. The mean half-life of sulbactam in children was 0.91 to 1.42 h, of cefoperazone from 1.44 to 1.88 h.

Indications:

Sulperazone is indicated for the treatment of the following infections caused by microorganisms that are sensitive to the drug:

Infections of the upper and lower respiratory tract.

Urinary tract infections.

Peritonitis, cholecystitis, cholangitis and other intra-abdominal infections.

Sepsis.

Meningitis.

Infections of the skin and soft tissues.

Infections of bones and joints.

Gonorrhea.

Inflammatory diseases of the pelvic organs, endometritis and other infections of the genital tract.

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

Carefully:Impaired renal and hepatic function. Newborns, including premature infants.

Pregnancy and lactation:

Appropriate clinical studies of the use of sulbactam / cefoperazone in pregnant women have not been conducted.

Sulbactam and cefoperazone penetrate the placental barrier and into breast milk. In pregnancy and lactation, the drug is used only if the expected benefit to the mother exceeds the potential risk to the fetus and newborn.

Dosing and Administration:

Intravenous and intramuscular. Adult application

In adults, sulbactam / cefoperazone is recommended for use in the following daily doses:

Ratio	Sulbactam/Cefoperazone	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 with a ratio of major components 1:1 (i.e., 4 g of cefoperazone).

Patients receiving sulbactam / cefoperazone in a 1: 1 ratio 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 for renal dysfunction

In patients with a creatinine clearance of 15-30 ml / min, the maximum dose of sulbactam is 1 g every 12 hours (maximum daily dose of sulbactam 2 g),and in patients with creatinine clearance less than 15 ml / min, the maximum dose of sulbactam is 500 mg every 12 hours (maximum daily dose of 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. Therefore, the administration of the drug should be planned after dialysis.

Application for violations of liver function

Dose changes may be required in cases of severe obstruction of bile duct, severe liver disease, and renal dysfunction 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.

If the daily dose of cefoperazone does not exceed 2 g, there is no need to monitor its serum concentration (see section "Special instructions").

Use in children

In children, sulbactam / cefoperazone is recommended for use in the following daily doses:

Ratio	Sulbactam / Cefoperazone (mg / kg / day)	Sulbactam dose (mg / kg / day)	Cefoperazone 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, these doses may be increased to 160 mg / kg / day

for the ratio of the main components 1: 1. The daily dose is divided into 2-4 equal

parts.

Neonatal application

In newborns be administered every 12 hours. The maximum daily dose of sulbactam in children should not exceed 80 mg / kg / day during the first week of life of the drug.

Cooking method solutions for parenteral use

Preparation of the solution

Total dose (g)	Equivalent doses	Scope	Maximum
	sulbactam + cefoperazone	solvent	ultimate
	sulbactam + cefoperazone		concentration (mg / ml)
2,0	1,0+1,0	6,7	125+ 125

- Intramuscular injection

Preparation of a solution using lidocaine. To prepare a solution for intramuscular injection, a 2% solution of lidocaine hydrochloride can be used, but it can not be used for initial dissolution, given their incompatibility. Compatibility can be achieved by two-stage solution preparation - initially the powder is dissolved in sterile water for injection, and then diluted with a 2% solution of lidocaine hydrochloride. The total volume of the solvent is 6.7 ml.The final solution will contain cefoperazone / sulbactam in a ratio of 125 mg / 125 mg in 1 ml of a 0.5% lidocaine solution.

- Intravenous administration

For preparation solution for infusions bred 2 g (1g+lg) of the preparation Sulperazone in the initial volume of 6.7 ml of one of the following infusion solutions: 5% dextrose solution, 5% dextrose solution in 0.225% sodium chloride solution, 5% dextrose solution in 0.9% sodium chloride solution, 0.9% sodium chloride solution or sterile water for injections, and then diluted to 20 ml with the initial solution.

Preparation of the solution using Ringer's lactate. 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 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 6.7 ml of one of the solvents described in preparation of a solution for infusions (see above) and enter for a minimum of 3 minutes.

Side effects:In general, sulbactam / cefoperazone is well tolerated. The severity of most of the adverse events was mild and moderate, and they persist until the end of the treatment. The undesirable reactions listed below were observed both during clinical trials (comparative and noncomparative), and after registration of the drug.

All adverse reactions listed in the medication instructions are presented in accordance with the MedDRA classification. In each frequency category, adverse reactions are presented according to the degree of clinical importance.

Table of unwanted reactions

Class of organ systems	Often >1/10	Often > 1/100 and <1/10		Infrequently > 1/1000 and <1/100		Frequency unknown (impossible estimate based available data)
Violations of the blood and lymphatic system	Leukopenia^§, neutropenia^§, a positive direct Coombs reaction^§, decreased hemoglobin^§, a decrease in hematocrit^§, thrombocytopenia^§	Eosnophilia^§				Hypoprothrombinemia
Immune system disorders						Anaphylactoid reaction (including shock)⁺. hypersensitivity reactions⁺(including anaphylactic shock)
Disturbances from the nervous system				Headache
Vascular disorders						Vasculitis, arterial hypotension
Infringements from gastro- intestinal tract			Diarrhea, nausea, vomiting		PseudomembranoAcute colitis


Violations from	Increase activity		Increase		Jaundice
sides of the liver	alanine aminotransferase^§, aspartate aminotransferase^§,		concentrations
and			bilirubin in
bile excretory	alkaline phosphatase		blood^§
ways	blood^§
Violations from				Itching,	Toxic
the skin and				hives	epidermal
subcutaneous				tsa	necrolysis⁺,
fabrics					syndrome
					stevensa-
					Johnson,
					maculopapular
					rash
breaches of					hematuria
party nights and
urinary tract
ways
are common				phlebitis in
disorders and				place
violations in				infusion,
place of introduction				pain and
				burning in
				place
				injections,
				fever.
				chills

frequency according to categories cioms iii (Council of International Medical Scientific Organizations): very often > 1/10 (> 10%); often: > 1/100 and <1/10 (> 1% and <10%); infrequently: > 1/1000 and <1/100 (> 0.1% and <1%); It is not known: the frequency can not be determined from the available data.

§ When calculating the frequencies of undesired reactions in the form of deviations from the norm of the results of laboratory analyzes, all available data from the results of the analyzes are taken into account, including those of patients whose abnormalities were observed at baseline.this conservative approach was applied, since the baseline data did not allow to divide a subset of patients with the deviations of the results of analyzes at baseline, in which significant changes in the results of laboratory tests occurred after the start of treatment, and a subset of patients with deviations in the baseline analysis results, there were no significant changes in the results of laboratory tests.

as for the number of leukocytes, neutrophils, platelets, hemoglobin and hematocrit. in reports on studies only abnormalities are reported. does not indicate whether there has been an increase or decrease in indicators.

⁺ there are reports of fatal cases.

Overdose:

Information on the acute toxicity of cefoperazone and sulbactam in humans is limited. In case of overdose, it is possible to expect the appearance of undesirable effects registered with the use of the drug. It should be borne in mind that a high concentration of beta-lactam antibiotics in cerebrospinal fluid can lead to neurologic disorders, including convulsions.

Treatment: symptomatic, hemodialysis is effective, especially in patients with impaired renal function.

Interaction:

Solutions of the drug sulperazone and aminoglycosides should not be mixed, given the pharmaceutical incompatibility between them. If combined therapy with Sulperazone and aminoglycoside is carried out, the two drugs are administered by successive infusions using separate secondary catheters, and the primary catheter is washed fairly well with the solution between dosing of the drugs. The intervals between the administration of preparations of sulperazop and aminoglycoside during the day should be as large as possible.

Ethanol

When ethanol was taken during treatment with cefoperazone and for up to 5 days after its administration, disulfiramoid-like effects characterized by "hot flashes", sweating, headache and tachycardia were recorded. Patients who need artificial feeding (inside or parenteral) should avoid using solutions containing ethanol.

When using a solution of Benedict or Feling, a false-positive reaction to glucose in the urine can be observed.

Special instructions:

The development of hypersensitivity reactions, including those leading to a lethal outcome, against a background of beta-lactam antibiotic therapy or cephalosporins, including cefopsrazone / sulbactam, has been reported. The risk of reactions of hypersensitivity, including those leading to death, is higher in patients who have a history of hypersensitivity reactions to many allergens. In case of an allergic reaction, it is necessary to cancel the drug and prescribe adequate therapy.

Serious anaphylactic reactions require the urgent introduction of epinephrine, glucocorticosteroids, provide airway patency, including intubation.

Patients should be warned about the possibility of disulfiramoid-like effects when consuming alcoholic beverages against the background of treatment with Sulperazop.

Dose changes may be required in cases of severe biliary obstruction, severe liver disease, and renal dysfunction 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.If the daily dose of cefoperazone does not exceed 2 g, there is no need to monitor its serum concentration.

In the treatment of cefoperazonom in rare cases, a vitamin K deficiency developed. Its cause is probably suppression of normal intestinal microflora, which synthesizes this vitamin. The risk group can include patients receiving malnutrition, with malabsorption syndrome (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 long-term treatment with Sulperazone, as with other antibiotics, excessive growth of insensitive microorganisms can be observed. Patients must be carefully observed during treatment. 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.

ABOUT cases of diarrhea associated with Clostridium difficile, reported in connection with the use of almost all antibacterial drugs, including sulbactam / cefoperazone. The severity of diarrhea can range from mild to severe forms. Treatment with antibacterial drugs disrupts the normal intestinal microflora, which leads to excessive growth of Clostridium difficile.

Clostridium difficile produces toxins A and B, which lead to the development of diarrhea associated with Clostridium difficile. Excessive amount of toxins produced by strains Clostridium difficile, can cause increased legality among patients, since such infections can be resistant to antimicrobial therapy, and may require a columnectomy. The use of drugs that inhibit intestinal peristalsis is contraindicated.

The possibility of developing diarrhea associated with Clostridium difficile, should be considered in all patients with diarrhea that followed the use of antibiotics. Careful medical supervision for 2 months is necessary for patients who have had diarrhea associated with Clostridium difficile after the introduction of antibacterial drugs.

Neonatal application

Sulbactam / cefoprasone is effective in young children.The use of this drug has not been studied widely enough in newborns, including premature infants. Thus, before starting therapy with Sulperazone in preterm infants and newborns, the degree of benefit to the patient and the risk of serious adverse reactions should be assessed.

Cefoperazone does not displace bilirubin from protein compounds in the blood plasma.

Effect on the ability to drive transp. cf. and fur:Based on the clinical experience of using the drug Sulperazone its effect on the ability to drive vehicles and control mechanisms is unlikely.

Form release / dosage:Powder for the preparation of solution for intravenous and intramuscular injection 2 g (1r + 1r).

Packaging:Powder for the preparation of a solution for intravenous and intramuscular injection 2 g (1g + 1g) in a vial of clear, colorless glass, sealed with a plug of chlorobutyl rubber with an ETFE coating, coated with an aluminum cap with a plastic protective cover. 1 bottle with the instruction for use is placed in a cardboard box.

Storage conditions:Powder: at a temperature of no higher than 25 ° C. Reconstituted solution: room temperature. Keep out of the reach of children.

Shelf life:

Powder: 2 years

Reconstituted solution: 24 h.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N012160 / 01

Date of registration:08.07.2008

The owner of the registration certificate:Pfizer Ilachlari Co., Ltd.Pfizer Ilachlari Co., Ltd. Turkey

Manufacturer: & nbsp

PFIZER ILACLARI, Ltd. Sti. Turkey

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp31.10.2015

Illustrated instructions

Instructions

Sulperazone (Sulperason)