Sulperacef^® (Powder) Instructions for Use

Marketing Authorization Holder

PFC Prebend, LLC (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

	Sulperacef®	Powder for preparation of solution for intravenous and intramuscular administration 1 g+1 g: vial 1 or 5 pcs. in a set with solvent or without it
		Powder for preparation of solution for intravenous and intramuscular administration 250 mg+250 mg: vial 1 or 5 pcs. in a set with solvent or without it
		Powder for preparation of solution for intravenous and intramuscular administration 500 mg+500 mg: vial 1 or 5 pcs. in a set with solvent or without it

Dosage Form, Packaging, and Composition

Powder for preparation of solution for IV and IM administration white or white with a yellowish tint.

Solvent water for injections (5 ml).

Vials (1) – cardboard packs.
Vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.
Vials (1) in a set with solvent (amp. 1 pc.) – contour cell packs (1) – cardboard packs.
Vials (5) – contour cell packs (1) – cardboard packs.
Vials (5) in a set with solvent (amp. 5 pcs.) – contour cell packs (2) – cardboard packs.

Powder for preparation of solution for IV and IM administration white or white with a yellowish tint.

Solvent water for injections (5 ml).

Vials (1) – cardboard packs.
Vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.
Vials (1) in a set with solvent (amp. 1 pc.) – contour cell packs (1) – cardboard packs.
Vials (5) – contour cell packs (1) – cardboard packs.
Vials (5) in a set with solvent (amp. 5 pcs.) – contour cell packs (2) – cardboard packs.

Powder for preparation of solution for IV and IM administration white or white with a yellowish tint.

Solvent water for injections (5 ml).

Vials (1) – cardboard packs.
Vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.
Vials (1) in a set with solvent (amp. 1 pc.) – contour cell packs (1) – cardboard packs.
Vials (5) – contour cell packs (1) – cardboard packs.
Vials (5) in a set with solvent (amp. 5 pcs.) – contour cell packs (2) – cardboard packs.

Clinical-Pharmacological Group

Third generation cephalosporin with beta-lactamase inhibitor

Pharmacotherapeutic Group

Antibiotic, cephalosporin + beta-lactamase inhibitor

Pharmacological Action

The antibacterial component of Cefoperazone-Sulbactam is Cefoperazone, a third-generation cephalosporin that acts on susceptible microorganisms during their active reproduction by inhibiting the biosynthesis of the cell wall mucopeptide.

Sulbactam does not possess clinically significant antibacterial activity (except for Neisseriaceae and Acinetobacter) and is an irreversible inhibitor of most major beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics.

Sulbactam also binds to some penicillin-binding proteins, so Sulbactam/Cefoperazone often has a more pronounced effect on susceptible strains than Cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all microorganisms susceptible to cefoperazone.

Furthermore, it exhibits synergy against various microorganisms, primarily: Haemophilus influenzae, Bacteroides species, Staphylococcus species, Acinetobacter colcoaceticus, 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 significant microorganisms:

Gram-positive microorganisms: Staphylococcus aureus (penicillinase-producing and non-producing), 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 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 aeruginosa, 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 bacilli (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, and others.

The C_max of sulbactam and cefoperazone after intravenous administration of 2 g sulbactam/cefoperazone (1 g sulbactam, 1 g cefoperazone) over 5 min averages 130.2 and 236.8 µg/ml, respectively. This reflects a higher V_d of sulbactam (V_d=18.0-27.6 L) compared to that of cefoperazone (V_d=10.2-11.3 L).

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose when administering cefoperazone-sulbactam are excreted by the kidneys. The remaining portion of cefoperazone is excreted mainly in the bile. With parenteral administration of Cefoperazone/sulbactam, the T_1/2 of sulbactam averages about 1 hour, and that of cefoperazone is 1.7 hours. Serum concentration is proportional to the administered dose.

No significant changes in the pharmacokinetics of either component of sulbactam/cefoperazone are noted upon repeated administration. No accumulation is observed when the drug is administered every 8-12 hours.

Pharmacokinetics in hepatic impairment

Cefoperazone is actively excreted in the bile. The T_1/2 of cefoperazone is usually prolonged, and the excretion of the drug in the urine increases in patients suffering from liver diseases and/or biliary obstruction. Even with severe hepatic impairment, a therapeutic concentration of cefoperazone is achieved in the bile, and the T_1/2 increases 2-4 times.

Pharmacokinetics in renal impairment

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

Pharmacokinetics in the elderly

In elderly patients with renal failure and impaired liver function, an increase in the duration of T_1/2, a decrease in clearance, and an increase in V_d of both sulbactam and cefoperazone are observed. The pharmacokinetics of sulbactam correlates with the degree of renal impairment, and the pharmacokinetics of cefoperazone correlates with the degree of hepatic impairment.

Pharmacokinetics in children

In children, there are no significant differences in the pharmacokinetics of the sulbactam/cefoperazone components compared to adults. The average T_1/2 of sulbactam in children ranges from 0.91 to 1.42 hours, and that of cefoperazone ranges from 1.44 to 1.88 hours.

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;
• Septicemia;
• Meningitis;
• Skin and soft tissue infections;
• Bone and joint infections;
• Inflammatory diseases of the pelvic organs, endometritis, gonorrhea and other genital tract infections.

ICD codes

Dosage Regimen

IV or IM.

Adults – 2-4 g/day at 12-hour intervals; for severe, persistent infections – 8 g/day. Maximum daily dose – 8 g.

Patients with chronic renal failure (CrCl less than 30 ml/min – dose adjustment; CrCl 15-30 ml/min – 1 g 2 times/day,. CrCl less than 14 ml/min – 500 mg 2 times/day).

Children– 40-80 mg/kg/day in 2-4 divided doses; for severe, long-term infections – 160 mg/kg/day. Maximum daily dose – 160 mg/kg/day. 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 IV administration, dissolve the vial contents in an adequate volume of 5% dextrose solution, 0.9% sodium chloride injection solution, or sterile water for injection, dilute to 20 ml with the same solution and administer over 15-60 minutes, IV injections – 3 minutes.

For IM administration, use sterile water for injection for dissolution. To obtain a cefoperazone concentration of 250 mg/ml or more, dilution is carried out in 2 stages: with sterile water, then with 2% lidocaine solution to obtain a 0.5% lidocaine solution.

Adverse Reactions

Allergic reactions anaphylactic shock, transient eosinophilia, fever.

Gastrointestinal tract diarrhea, nausea, vomiting, pseudomembranous colitis.

Skin reactions maculopapular rash, urticaria, pruritus, Stevens-Johnson syndrome. The risk is higher in patients with a history of allergic reactions (especially to penicillin).

Hematopoietic system bleeding (vitamin K deficiency), decreased neutrophil count. With prolonged treatment (as with other beta-lactam antibiotics), reversible neutropenia may develop. Some patients had a positive Coombs’ test during treatment. A decrease in hemoglobin and hematocrit levels is also noted. Transient leukopenia and thrombocytopenia, as well as hypoprothrombinemia, are observed.

Others Headache, fever, injection site pain, chills, hematuria, vasculitis.

Laboratory parameters increased activity of hepatic transaminases and ALP, hypercreatininemia, hyperbilirubinemia, hypoprothrombinemia.

Local reactions Sulbactam/Cefoperazone is well tolerated with IM administration. Sometimes transient pain is observed after IM injection. With IV administration of the drug (as with other cephalosporins and penicillins) via a catheter, phlebitis may develop at the infusion site (0.1%).

Contraindications

• Allergy to penicillins, Sulbactam, Cefoperazone and any other cephalosporins.

Use in Pregnancy and Lactation

During pregnancy and lactation, the drug is used only if the expected benefit to the mother outweighs the potential risk to the fetus.

Use in Hepatic Impairment

Dosage adjustments may be required in cases of severe biliary obstruction, severe liver diseases.

Use in Renal Impairment

Patients with chronic renal failure (CRF) (creatinine clearance (CrCl) less than 30 ml/min) – dose adjustment: CrCl 15-30 ml/min – 1 g 2 times a day. CrCl less than 14 ml/min – 500 mg 2 times a day.

Pediatric Use

Children – 40-80 mg/kg/day in 2-4 divided doses; for severe, long-term infections – 160 mg/kg/day. Maximum daily dose – 160 mg/kg/day.

Special Precautions

Cases of serious hypersensitivity reactions (anaphylactic) have been described in patients receiving beta-lactam antibiotics, including cephalosporins. The risk of such reactions is higher in patients with a history of hypersensitivity reactions. If an allergic reaction occurs, it is necessary to discontinue the drug and prescribe adequate therapy. For serious anaphylactic reactions, emergency administration of epinephrine is necessary. Oxygen, intravenous corticosteroids, and airway patency, including intubation, should be provided as indicated.

Dosage adjustments may be required in cases of severe biliary obstruction, severe liver disease, and renal impairment combined with any of the listed conditions.

In patients with hepatic impairment and concomitant renal impairment, monitoring of serum cefoperazone concentration and dose adjustment if necessary is required. If regular monitoring of serum cefoperazone concentration is not performed in such cases, its daily dose should not exceed 2 g.

During treatment with cefoperazone, as with other antibiotics, vitamin K deficiency may rarely develop. The cause is likely the suppression of normal intestinal flora, which synthesizes this vitamin. The risk group includes patients receiving inadequate nutrition, suffering from malabsorption (e.g., in cystic fibrosis), and those on long-term intravenous artificial nutrition. In such cases, as well as in patients receiving anticoagulants, it is necessary to monitor prothrombin time and, if indicated, administer vitamin K.

During prolonged treatment with sulbactam/cefoperazone, as with other antibiotics, overgrowth of non-susceptible microorganisms may be observed. Patients should be carefully monitored during treatment. During long-term therapy, periodic monitoring of indicators of the function of internal organs, including the kidneys, liver, and hematopoietic system, is recommended. This is especially important for newborns, primarily premature ones, and young children.

Given the broad spectrum of activity, adequate monotherapy can be conducted. When aminoglycosides are used concomitantly, renal function should be monitored. Dose adjustment and monitoring of serum cefoperazone concentration is required in cases of severe biliary obstruction, severe hepatic insufficiency (maximum daily dose – 2 g). During prolonged treatment, indicators of renal, hepatic, and hematopoietic system function should be monitored. During therapy, 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 is carried out only if the potential benefit outweighs the potential risk.

Overdose

Symptoms epileptic seizure.

Treatment sedative therapy. If anaphylactic shock develops – intravenous administration of epinephrine, oxygen inhalation, glucocorticosteroids.

Drug Interactions

When alcohol was consumed during treatment with cefoperazone and within 5 days after its administration, reactions characterized by flushing, sweating, headache, and tachycardia were recorded; therefore, patients should be warned about the possibility of their occurrence when consuming alcoholic beverages during treatment with sulbactam/cefoperazone. In patients requiring artificial nutrition (enteral or parenteral), the use of solutions containing ethanol should be avoided.

When using Benedict’s or Fehling’s solution, a false-positive reaction for glucose in urine may be observed.

Sulbactam/cefoperazone and aminoglycoside solutions should not be mixed directly, given the physical incompatibility between them. If combined therapy with Cefoperazone/sulbactam and an aminoglycoside is conducted, the two drugs are administered by sequential infusion using separate secondary catheters, and the primary catheter is flushed with an adequate solution between drug administrations. The intervals between the administration of Cefoperazone/sulbactam and the aminoglycoside during the day should be as long as possible.

Storage Conditions

List B. In a dry place, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use the drug after the expiration date printed on the packaging.

A freshly prepared solution for injection is suitable for use for 18 hours at a temperature not exceeding 25°C (77°F).

Dispensing Status

The drug is dispensed by prescription.

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.