Universal reference book for medicines
Product name: CEPHOPERAZONE AND SULBACTAM SPENSER (CEFOPERAZONE & SULBACTAM SPENSER)

Active substance: cefoperazone, sulbactam

Type: Cephalosporin III generation with a beta-lactamase inhibitor

Manufacturer: SPENSER PHARMA UK (United Kingdom) manufactured by KILITCH DRUGS (India)
Composition, form of production and packaging
Powder for solution preparation for
intravenous and intravenous administration 1 fl.

sulbactam (in the form of the sodium salt) 1 g

cefoperazone (in the form of sodium salt) 1 g

Vials (1) - 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 that acts on sensitive microorganisms during their active propagation by inhibiting the cell wall mucopeptide biosynthesis.
Sulbactam does not have clinically significant antibacterial activity (except for Neisseriaceae and Acinetobacter). However, it was noted that it is an irreversible inhibitor of most of the major β-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 certain penicillin-binding proteins, so cefoperazone / sulbactam often exerts 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 synergistic effect on various microorganisms, in particular: Haemophilus influenzae, Bacteroides species, Staphylococcus species, Acinetobacter 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 clinically relevant microorganisms.

Gram-positive microorganisms: Staphylococcus aureus (producing and not producing penicillinase), 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, many strains of Streptococcus faecalis (enterococci).

Gram-negative microorganisms: Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia spp., Serratia spp.
(including Serratia marcescens), Salmonella and Shigella spp., Pseudomonas aeruginosa and some other Pseudomonas spp., Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.
Anaerobic microorganisms: gram-negative rods (including Bacteroides fragilis, other Bacteroides species and Fusobacterium spp.).

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

Gram-positive rods (including Clostridium spp., Eubacterium spp., And Lactobacillus spp.)

The following sensitivity levels were established for cefoperazone / sulbactam.
The minimum inhibitory concentration (MPC) in μg / ml expressed in the concentration of cefoperazone for sensitive microorganisms is less than or equal to 16, for organisms with intermediate sensitivity is in the range of 17-63, and for resistant ones - more than 64. Sensitivity zones when determined by the disk diffusion method are : for sensitive microorganisms more than 21 mm; with an intermediate sensitivity of 16 to 20 mm, and for resistant - more than 15 mm.
PHARMACOKINETICS

C max of sulbactam and cefoperazone after iv administration of 2 g of cefoperazone / sulbactam (1 g of sulbactam, 1 g of cefoperazone) for 5 minutes averaged 130.2 and 236.8 μg / ml, respectively.
This reflects a higher V d of sulbactam (V d = 18.0-27.6 l) compared with that of cefoperazone (V d = 10.2-11.3 L).
Both sulbactam and cefoperazone are well distributed into various tissues and fluids, including bile, gall bladder, skin, appendix, fallopian tubes, ovaries, uterus, etc. Sulbactam and cefoperazone penetrate the placental barrier.

There is no data on the presence of any pharmacokinetic interaction between sulbactam and cefoperazone with the introduction of cefoperazone / sulbactam.
With repeated use of significant changes in the pharmacokinetics of both components of sulbactam / cefoperazone was not noted. With the introduction of the drug every 8-12 hours cumulation was not observed.
Approximately 84% of the dose of sulbactam and 25% of the dose of cefoperazone, administered as a combination of -cefoperazone / sulbactam, is excreted by the kidneys.
Most of the remaining dose of cefoperazone is excreted with bile. Cefoperazone does not displace bilirubin from its association with plasma proteins. T 1/2 ofsulbactam averages about 1 hour, cefoperazone - 1.7 hours. Serum concentration is proportional to the administered dose.
When a violation of liver function

Cefoperazone is actively excreted with bile.
T 1/2 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 T 1/2increases only 2-4 times.
In case of impaired renal function

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 elongation of T 1/2 of sulbactam was found (an average of 6.9 and 9.7 hours in various studies). Hemodialysis caused significant changes in T 1/2 , total clearance and V d of sulbactam.
Application in the elderly

The pharmacokinetics of cefoperazone / sulbactam has been studied in elderly people with renal insufficiency and impaired liver function.
Compared with healthy volunteers, an increase in the duration of T 1/2 , a decrease in clearance to an increase in V d of both sulbactam and cefoperazone, was revealed. 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 components of cefoperazone / sulbactam were found in comparison with those in adults.Mean T 1/2 of sulbactam in children ranged from 0.91 to 1.42 h, of cefoperazone from 1.44 to 1.88 h.

INDICATIONS

Infectious-inflammatory diseases caused by sensitive microorganisms:

- infections of the upper and lower respiratory tract;

- urinary tract infection;

- peritonitis, cholecystitis, cholangitis;

- sepsis, meningitis,

- skin and soft tissue infections;

- infections of bones and joints;

- inflammatory diseases of the pelvic organs, including endometritis, gonorrhea.

Prevention of postoperative complications.

DOSING MODE

In / in and / m.

Application in adults

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

Ratio of cefoperazone and sulbactam to sulbactam dose (g) of 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).

Patients receiving cefoperazone / sulbactam 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 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 inpatients with creatinine clearance less than 15 ml / min the maximum dose of sulbactam is 500 mg every 12 hours the 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 .
T 1/2 of cefoperazone from blood serum decreases slightly during hemodialysis.Therefore, the administration of the drug should be planned after dialysis.
Application for violations of liver function

If regular monitoring of serum concentration of cefoperazone is not performed, the maximum daily dose should not exceed 2 g.

Use in children

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

Cefeperazone / Sulbactam ratio (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. For serious or refractory infections, these dosages can 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 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

Total dose (g) Equivalent doses of cefoperazone + sulbactam Solvent volume Max.
final 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 the / m introduction, 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 67 ml. The final solution will contain cefoperazone / sulbactam in a ratio of 125 mg / 125 mg in 1 ml of 0.5% lidocaine solution.
IV introduction

To prepare the solution for intravenous infusion, 2 g (1 g + 1 g) of cefoperazone and sulbactam are diluted in the initial volume of 6.7 ml of one of the following infusion solutions: 5% dextrose in water, 5% dextrose in 0.225% sodium chloride solution, 5% dextrose solution in physiological saline, 0.9% sodium chloride solution or sterile water for injection, and then diluted to 20 ml with the same solvent.

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, water for injection is used, and then the diluted solution is diluted with Ringer's lactate solution to a concentration of 5 mg / ml of sulbactam (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 6.7 ml of one of the solvents described above and administered for a minimum of 3 minutes.

SIDE EFFECT

From the cardiovascular system: a decrease in blood pressure.

From the digestive system: diarrhea, nausea, vomiting, pseudomembranous colitis.

Allergic reactions: hypersensitivity, manifested in the form of maculopapular rash and urticaria, as well as itching, Stevens-Johnson syndrome, anaphylactic shock.

On the part of the hematopoiesis system: a decrease in the number of neutrophils.
With long-term treatment, reversible neutropenia, a decrease in the level of hemoglobin and hematocrit can develop. There is transient eosinophilia, thrombocytopenia, leukopenia, hypoprothrombinemia.
Laboratory parameters: transient increase in hepatic transaminases, alkaline phosphatase and bilirubin in blood serum, hypercreatininaemia, hematuria.
In some patients, a 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.
Local reactions: after IM injection, transient pain and burning at the injection site are observed.
With intravenous administration with the help of a catheter, phlebitis can develop at the site of administration.
Others: headache, fever, pain with injection, chills, vasculitis.

CONTRAINDICATIONS

- hypersensitivity to sulbactam, cefoperazone or other cephalosporins, penicillin and beta-lactam antibiotics.

With caution: severe violations of the kidneys and liver, children under 3 months.

PREGNANCY AND LACTATION

In pregnancy, the drug is used only if the expected benefit to the mother exceeds the potential risk to the fetus.
If it is necessary to prescribe the drug during lactation, breastfeeding should be stopped.
APPLICATION FOR FUNCTIONS OF THE LIVER

With caution: severe renal dysfunction.

In patients with 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 inpatients with creatinine clearance less than 15 ml / min the maximum dose of sulbactam is 500 mg every 12 hours the 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.
T 1/2 of cefoperazone from blood serum decreases slightly during hemodialysis.Therefore, the administration of the drug should be planned after dialysis.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution: severe liver dysfunction.

If regular monitoring of serum concentration of cefoperazone is not performed, the maximum daily dose should not exceed 2 g.

APPLICATION FOR CHILDREN

With caution: children under 3 months.

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

Cefeperazone / Sulbactam ratio (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. For serious or refractory infections, these dosages can 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 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.

SPECIAL INSTRUCTIONS

Risk of hypersensitivity reactions, incl.
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 administration of epinephrine.
Assign oxygen, IV injection of GCS and provide airway patency, including intubation.
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 regular monitoring of serum concentration of cefoperazone in such cases is not carried out, then its daily dose should not exceed 2 g. When using a solution of Benedict or Felling, a false positive reaction to glucose in the urine can be observed.
With the simultaneous use of aminoglycosides, it is necessary to congulate the function of the kidneys.

In the treatment of cefoperazonom in rare cases, vitamin K deficiency was developing. Patients receiving malnutrition, suffering from malabsorption (for example, in cystic fibrosis) and long-term in / in artificial feeding can be classified as a risk group.
In such cases, as well as in patients receiving anti-coagulants, it is necessary to monitor prothrombin time and, in the presence of indications, prescribe vitamin K.
With prolonged treatment, excessive growth of insensitive microorganisms can be observed.
Patients should 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.
OVERDOSE

Symptoms: Information on the acute toxicity of sodium cefoperazone and sodium sulbactam is limited.
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.

DRUG INTERACTION

Solutions of cefoperazone / sulbactam and aminoglycosides should not be directly mixed, given the pharmaceutical incompatibility between them.
If combined therapy is provided, 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. Intervals between administration during the day should be as large as possible.
When ethanol is used during treatment with cefoperazone and for up to 5 days after its administration, development of disulfiram-like effects, characterized by "hot flashes", sweating, headache and tachycardia, is possible.
In patients who need artificial feeding (inside or parenteral), the use of solutions containing ethanol should be avoided.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

Store the drug in a dry, dark place at a temperature of no higher than 25 ° C.
Keep out of the reach of children.
Shelf life - 3 years.

Do not use after expiry date.

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