Bactsefort^® (Powder) Instructions for Use

Marketing Authorization Holder

Kraspharma, PJSC (Russia)

ATC Code

J01DD62 (Cefoperazone and beta-lactamase inhibitor)

Active Substances

Cefoperazone (Rec.INN registered by WHO)

Sulbactam (Rec.INN registered by WHO)

Dosage Forms

	Bactsefort®	Powder for preparation of solution for intravenous and intramuscular administration 0.5 g+0.5 g: vial 1 or 10 pcs.; vial 1 or 5 pcs. in a set with solvent
		Powder for preparation of solution for intravenous and intramuscular administration 1 g+1 g: vial 1 or 10 pcs.; vial 1 or 5 pcs. in a set with solvent
		Powder for preparation of solution for intravenous and intramuscular administration 1.5 g+1.5 g: vial 1 or 10 pcs.; vial 1 or 5 pcs. in a set with solvent
		Powder for preparation of solution for intravenous and intramuscular administration 2 g+2 g: vial 1 or 10 pcs.; vial 1 or 5 pcs. in a set with solvent

Dosage Form, Packaging, and Composition

Powder for preparation of solution for intravenous and intramuscular administration white or white with a yellowish tint; hygroscopic.

Solvent : water for injections – 5 ml.

Vials of colorless glass with a capacity of 10 ml or 20 ml (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (10) – cardboard boxes.
Vials of colorless glass with a capacity of 10 ml or 20 ml (1) in a set with solvent (amp. 5 ml 1 pc.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (5) – contour cell packaging (1) in a set with solvent (amp. 5 ml 5 pcs.) – contour cell packaging (1) – cardboard packs.

Powder for preparation of solution for intravenous and intramuscular administration white or white with a yellowish tint; hygroscopic.

Solvent : water for injections.

Vials of colorless glass with a capacity of 10 ml or 20 ml (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (10) – cardboard boxes.
Vials of colorless glass with a capacity of 10 ml or 20 ml (1) in a set with solvent (amp. 5 ml 2 pcs.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (1) in a set with solvent (amp. 10 ml 1 pc.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (5) – contour cell packaging (1) in a set with solvent (amp. 5 ml 10 pcs.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (5) – contour cell packaging (1) in a set with solvent (amp. 10 ml 5 pcs.) – contour cell packaging (1) – cardboard packs.

Powder for preparation of solution for intravenous and intramuscular administration white or white with a yellowish tint; hygroscopic.

Solvent : water for injections.

Vials of colorless glass with a capacity of 10 ml or 20 ml (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (10) – cardboard boxes.
Vials of colorless glass with a capacity of 10 ml or 20 ml (1) in a set with solvent (amp. 5 ml 2 pcs.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (1) in a set with solvent (amp. 10 ml 1 pc.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (5) – contour cell packaging (1) in a set with solvent (amp. 5 ml 10 pcs.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (5) – contour cell packaging (1) in a set with solvent (amp. 10 ml 5 pcs.) – contour cell packaging (1) – cardboard packs.

Powder for preparation of solution for intravenous and intramuscular administration white or white with a yellowish tint; hygroscopic.

Solvent : water for injections.

Vials of colorless glass with a capacity of 10 ml or 20 ml (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (10) – cardboard boxes.
Vials of colorless glass with a capacity of 10 ml or 20 ml (1) in a set with solvent (amp. 5 ml 2 pcs.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (1) in a set with solvent (amp. 10 ml 1 pc.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (5) – contour cell packaging (1) in a set with solvent (amp. 5 ml 10 pcs.) – contour cell packaging (1) – cardboard packs.
Vials of colorless glass with a capacity of 10 ml or 20 ml (5) – contour cell packaging (1) in a set with solvent (amp. 10 ml 5 pcs.) – contour cell packaging (1) – cardboard packs.

Clinical-Pharmacological Group

Third generation cephalosporin with beta-lactamase inhibitor

Pharmacotherapeutic Group

Systemic antibacterial agents; other beta-lactam antibacterial agents; third-generation cephalosporins

Pharmacological Action

A combined drug, a broad-spectrum antibiotic.

Cefoperazone is a third-generation cephalosporin antibiotic, acts bactericidally, has a broad spectrum of action; it is highly active against aerobic and anaerobic gram-positive and gram-negative microorganisms (including Pseudomonas aeruginosa), resistant to beta-lactamases of gram-positive and gram-negative microorganisms.

Sulbactam is an irreversible inhibitor of beta-lactamases, which are secreted by microorganisms resistant to beta-lactam antibiotics; prevents the destruction of penicillins and cephalosporins under the action of beta-lactamases of resistant microorganisms; by binding to penicillin-binding proteins, it exhibits synergy when used simultaneously with penicillins and cephalosporins.

The combination of Cefoperazone+Sulbactam is active against all microorganisms sensitive to cefoperazone, and exhibits synergy (reduces the MIC of the combination by up to 4 times compared to the values for each component separately) against microorganisms: Haemophilus influenzae, Bacteroides spp., Staphylococcus spp., Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Active in vitro against gram-positive bacteria – Staphylococcus aureus (including strains producing and not producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (beta-hemolytic strain group A), Streptococcus agalactiae (beta-hemolytic strain group B), most strains of beta-hemolytic Streptococcus spp., Enterococcus faecalis; gram-negative bacteria – Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Morganella morganii, Providencia rettgeri, Providencia spp., Serratia spp. (including Serratia marcescens), Salmonella spp., Shigella spp., Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis; Bordetella pertussis, Yersinia enterocolitica; anaerobic bacteria – Bacteroides fragilis, Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., Veillonella spp., Clostridium spp., Eubacterium spp., Lactobacillus spp.

Pharmacokinetics

C_max of sulbactam and cefoperazone after intravenous administration of the combination in a dose of 2 g (1 g sulbactam and 1 g cefoperazone) for 5 min averaged 130.2 µg/ml and 236.8 µg/ml, respectively. This reflects a higher V_d of sulbactam (from 18.0 to 27.6 L) compared to that of cefoperazone (from 10.2 to 11.3 L).

After intramuscular administration of 1.5 g sulbactam/cefoperazone (500 mg sulbactam, 1 g cefoperazone), C_max of sulbactam and cefoperazone in serum were observed in the period from 15 min to 2 h after administration. C_max in serum were 19.0 and 64.2 µg/ml for sulbactam and cefoperazone, respectively.

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

There are no data on any pharmacokinetic interaction between sulbactam and cefoperazone when administered as part of combined drugs.

No significant changes in the pharmacokinetic parameters of both components were noted with repeated use. When the drug was administered every 8-12 hours, no accumulation was observed.

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose when the combination is administered are excreted by the kidneys. The remaining portion of cefoperazone is excreted mainly with bile. When the combination is administered, the T_1/2 of sulbactam averages about 1 hour, the T_1/2 of cefoperazone is 1.7 hours. The plasma concentration is proportional to the administered dose.

Cefoperazone is actively excreted in bile. The T_1/2 of cefoperazone is usually prolonged, and urinary excretion increases in patients with liver diseases and/or biliary tract obstruction. Even with severe liver dysfunction, a therapeutic concentration of cefoperazone is achieved in bile, and the T_1/2 increases only 2-4 times.

In patients with varying degrees of renal impairment receiving this combination, a high correlation was found between the total clearance of sulbactam from the body and the estimated creatinine clearance. In patients with end-stage renal failure, a significant prolongation of the T_1/2 of sulbactam was found (on average 6.9 hours and 9.7 hours in various studies). Hemodialysis caused significant changes in the T_1/2, total clearance from the body and V_d of sulbactam.

In elderly people with renal failure and liver dysfunction compared to healthy volunteers, an increase in the duration of T_1/2, a decrease in clearance and an increase in V_d of both sulbactam and cefoperazone were found. The pharmacokinetics of sulbactam correlated with the degree of renal impairment, and the pharmacokinetics of cefoperazone correlated with the degree of liver dysfunction.

In studies in children, no significant changes in the pharmacokinetic parameters of the combination components were found compared to adults. The average T_1/2 of sulbactam in children ranged from 0.91 to 1.42 hours, that of cefoperazone from 1.44 to 1.88 hours.

Indications

Treatment of infectious and inflammatory diseases caused by microorganisms sensitive to the combination Cefoperazone+Sulbactam: pharyngitis, tonsillitis, sinusitis, bronchitis, pneumonia, bronchopneumonia, empyema, lung abscess, pyelonephritis, cystitis, prostatitis, endometritis, gonorrhea, vulvovaginitis; peritonitis, cholecystitis, cholangitis; acute otitis media, sinusitis, tonsillitis; furunculosis, abscess, pyoderma, lymphadenitis, lymphangitis; osteomyelitis, joint infections, sepsis, meningitis.

Prevention of infectious complications after abdominal, gynecological and orthopedic operations, in cardiovascular surgery.

ICD codes

Dosage Regimen

Administered intramuscularly or intravenously.

The component ratio of the combination is 1:1.

For adults, the daily dose of the combination is 2-4 g (Cefoperazone 1-2 g + Sulbactam 1-2 g). The daily dose should be divided into equal parts and administered every 12 hours.

For severe or refractory infections, the daily dose of the combination may be increased to 8 g (Cefoperazone 4 g + Sulbactam 4 g).

For children, the daily dose of the combination is 40-80 mg/kg/day (Cefoperazone 20-40 mg/kg + Sulbactam 20-40 mg/kg). The daily dose should be divided into equal parts and administered every 6-12 hours.

For serious or treatment-refractory infections, the daily dose of the combination may be increased to 160 mg/kg.

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

In patients with severe renal impairment ( CrCl 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 CrCl 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. Since the pharmacokinetics of sulbactam are significantly altered during hemodialysis and the T_1/2 of cefoperazone from serum is somewhat reduced, administration of this combination should be scheduled after dialysis.

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

If administration of more than 80 mg/kg/day, calculated based on cefoperazone activity, is necessary, the dose increase is achieved by additional administration of cefoperazone.

For intravenous bolus administration, the vial contents are dissolved in an adequate volume of 5% dextrose solution, 0.9% sodium chloride solution, 5% dextrose in 0.225% sodium chloride solution, 5% dextrose in 0.9% sodium chloride solution, or sterile water for injection, and administered over 3 minutes; for intravenous infusion administration, dissolve as indicated above, dilute to 20-100 ml and administer over 15-60 minutes; for intramuscular administration, use sterile water for injection for dissolution.

Preparation of a solution using lidocaine: dilution is carried out in 2 stages – with sterile water, then with a 2% lidocaine solution to obtain a 0.5% lidocaine solution. The total volume of solvent is 6.7 ml.

Adverse Reactions

Allergic reactions anaphylactic shock.

Digestive system diarrhea, nausea, vomiting, pseudomembranous colitis; transient increase in liver function tests – AST, ALT, ALP, serum bilirubin.

Allergic reactions maculopapular rash, itching, urticaria, Stevens-Johnson syndrome (the risk of developing these reactions is higher in patients with a history of allergic reactions).

Hematopoietic system decreased neutrophil count, reversible neutropenia (with prolonged treatment), decreased hemoglobin and hematocrit levels, transient eosinophilia, leukopenia, thrombocytopenia, hypoprothrombinemia; in some cases – positive Coombs test. False-positive urine glucose reaction may be observed when using Benedict’s or Fehling’s solution.

Urinary system hematuria.

Local reactions sometimes after intramuscular injection, transient pain and burning at the injection site are observed. With intravenous administration via a catheter, phlebitis may develop at the infusion site.

Other headache, fever, chills, vasculitis.

Contraindications

Hypersensitivity to cefoperazone, sulbactam, penicillins, other cephalosporins.

With caution renal and/or hepatic insufficiency, colitis (including history), premature newborns, pregnancy.

Use in Pregnancy and Lactation

Cefoperazone and Sulbactam cross the placental barrier.

Use of this combination during pregnancy and lactation is only possible if the intended benefit to the mother outweighs the potential risk to the fetus or child.

Use in Hepatic Impairment

With caution hepatic insufficiency.

Dosage adjustment and monitoring of serum cefoperazone concentration is required in cases of marked biliary obstruction, severe hepatic insufficiency (maximum daily dose – 2 g).

If it is necessary to use the drug in patients with impaired liver function, the instructions should be carefully studied.

Use in Renal Impairment

With caution renal insufficiency.

If it is necessary to use the drug in patients with impaired renal function, the instructions should be carefully studied.

Pediatric Use

With caution premature newborns.

If it is necessary to use the drug in children, the instructions should be carefully studied.

Special Precautions

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

In patients with liver disease and/or biliary obstruction, the T_1/2 of cefoperazone is increased, and renal excretion is elevated. In severe hepatic impairment, the concentration of cefoperazone in bile is therapeutic, and the T_1/2 is increased 2-4 times. Dosage adjustment and monitoring of serum cefoperazone concentration is required in cases of marked biliary obstruction, severe hepatic insufficiency (maximum daily dose – 2 g).

Patients with inadequate diet or malabsorption (patients with cystic fibrosis; patients on long-term parenteral nutrition) are at risk of developing vitamin K deficiency. In such patients, prothrombin time should be monitored; if necessary, vitamin K should be prescribed. The mechanism of vitamin K deficiency development is the suppression of intestinal flora, which normally synthesizes this vitamin.

During long-term treatment, renal, hepatic, and hematopoietic system function parameters should be monitored.

During treatment, false-positive results for urine glucose determination may be observed when using Benedict’s or Fehling’s solutions, and a false-positive Coombs reaction may occur.

Treatment of premature newborns, pregnant women, and during lactation is carried out only if the potential benefit outweighs the potential risk.

Drug Interactions

Compatible with water for injection, 5% dextrose solution, 0.9% sodium chloride solution, 5% dextrose in 0.225% sodium chloride solution, 5% dextrose in 0.9% sodium chloride solution.

Incompatible with Ringer’s solution, 2% lidocaine hydrochloride solution (initial use of water for injection results in a compatible mixture); aminoglycosides (if combination therapy is necessary, it should be carried out by sequential fractional intravenous infusion of the two drugs, using 2 separate systems for intravenous transfusion; between dose administrations, the system should be flushed with a compatible solvent).

Consumption of ethanol (concomitantly or within the following 5 days after treatment completion) increases the risk of developing a disulfiram-like reaction (“flushing,” increased sweating, headache, tachycardia).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.