Cephpar SV (Powder) Instructions for Use

Marketing Authorization Holder

Rusyurapharm, LLC (Russia)

Manufactured By

Karnataka Antibiotics & Pharmaceuticals Limited (India)

ATC Code

J01DD62 (Cefoperazone and beta-lactamase inhibitor)

Active Substances

Cefoperazone (Rec.INN)

Sulbactam (Rec.INN)

Dosage Forms

	Cephpar SV	Powder for preparation of solution for intravenous and intramuscular administration 1 g+1 g: vial 1 pc.
		Powder for preparation of solution for intravenous and intramuscular injections 500 mg+500 mg: vial 1 or 50 pcs.

Dosage Form, Packaging, and Composition

Vials (1) – cardboard packs.
Vials (50) – cardboard packs.

Vials (1) – cardboard packs.
Vials (50) – 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 mucopeptide in the cell wall. Sulbactam does not possess clinically significant antibacterial activity (with the exception of Neisseriaceae and Acinetobacter). However, it has been noted to be an irreversible inhibitor of most major beta-lactamases 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, against which sulbactam exhibited pronounced synergism with penicillins and cephalosporins. Furthermore, sulbactam interacts with some penicillin-binding proteins, therefore Cefoperazone + Sulbactam 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. In addition, it exhibits synergism against various microorganisms, primarily: Haemophilus influenzae, Bacteroides spp., Staphylococcus spp., Acinetobacter calcoaceticus, Enterobacter aerogenes, 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 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 Enterococcus faecalis.

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 spp. and Shigella spp., Pseudomonas aeruginosa and some other Pseudomonas spp., Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.

Anaerobic microorganisms

Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides spp. and Fusobacterium spp.). Gram-positive and gram-negative cocci (including Peptococcus spp., Peptostreptococcus spp. and Veillonella spp.). Gram-positive bacilli (including Clostridium spp., Eubacterium spp. and Lactobacillus spp.).

Pharmacokinetics

The maximum concentrations of sulbactam and cefoperazone after intravenous administration (IV) of 2 g of cefoperazone + sulbactam (1 g sulbactam, 1 g cefoperazone) over 5 minutes averaged 130 and 237 µg/ml, respectively. This reflects a higher volume of distribution of sulbactam compared to that of cefoperazone.

Both Sulbactam and Cefoperazone are well distributed in various tissues and fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, and others. Sulbactam and Cefoperazone cross the placental barrier. With repeated use, no significant changes in the pharmacokinetics of either component of the drug were noted. 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, administered as the combination – Cefoperazone + Sulbactam, are excreted by the kidneys. The remaining portion of cefoperazone is excreted in the bile. Cefoperazone does not displace bilirubin from its binding to plasma proteins. The T_1/2 of sulbactam averages about 1 hour, that of cefoperazone – 1.7 hours. The serum concentration is proportional to the administered dose.

In case of impaired liver function

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

In case of impaired renal function

In patients with varying degrees of renal impairment receiving Cefoperazone + Sulbactam, 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 (up to 9.7 hours) was detected. Hemodialysis caused significant changes in the half-life, total clearance, and volume of distribution of sulbactam.

Use in the elderly

The pharmacokinetics of cefoperazone + sulbactam were studied in elderly patients with renal failure and impaired liver function. Compared to healthy volunteers, an increase in T_1/2 duration, a decrease in clearance, and an increase in Vd for 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 impairment.

Use in children

Studies in children did not reveal significant changes in the pharmacokinetics of the components of cefoperazone + sulbactam compared to adults. The T_1/2 of sulbactam in children ranged from 0.9 to 1.4 hours, that of cefoperazone – from 1.4 to 1.9 hours.

Indications

Infectious and inflammatory diseases caused by susceptible microorganisms

• Infections of the upper and lower respiratory tract;
• Urinary tract infections;
• Peritonitis, cholecystitis, cholangitis;
• Sepsis, meningitis;
• Skin and soft tissue infections;
• Bone and joint infections;
• Inflammatory diseases of the pelvic organs, including endometritis, gonorrhea.

ICD codes

Dosage Regimen

Intravenously (bolus and drip) and intramuscularly.

Use in adults

In adults, Cefoperazone + Sulbactam is recommended to be used in the following daily doses

The daily dose should be divided into equal parts and administered every 12 hours. For severe and standard dose-resistant infections, the daily dose of cefoperazone + sulbactam can be increased to 8 g with a ratio of the main components of 1:1 (i.e., 4 g of cefoperazone). If administration of more than 8 g (with a ratio of the main components of 1:1) is necessary, the dose increase is achieved by 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.

Use in renal impairment

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 a creatinine clearance of less than 15 ml/min, the maximum dose of sulbactam is 500 mg every 12 hours (maximum daily dose of sulbactam 1 g). For severe infections, additional administration of cefoperazone may be required.

The pharmacokinetics of sulbactam are significantly altered by hemodialysis. The half-life of cefoperazone from plasma decreases somewhat during hemodialysis. Therefore, administration of the drug should be planned after dialysis.

Use in hepatic impairment

If regular monitoring of the serum concentration of cefoperazone is not performed, then the maximum daily dose should not exceed 2 g (see section “Special Instructions”).

Use in children

In children, Cefoperazone + Sulbactam is recommended to be used in the following daily doses

The dose should be divided into equal parts and administered every 6-12 hours.

For severe and standard dose-resistant infections, the daily dose can be increased to 160 mg/kg/day with a ratio of the main components of 1:1. The daily dose is divided into 2-4 equal parts. 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.

Use in newborns

In newborns during the first week of life, the drug should be administered every 12 hours. The maximum daily dose of sulbactam in children should not exceed 80 mg/kg/day. Method for preparation of solutions for parenteral administration Dilution

Intramuscular injection

Use sterile water for injections for dissolution (see table). If the drug is to be administered at a concentration exceeding 250 mg/ml, preparation of the solution using lidocaine is recommended. Dilution is carried out in 2 stages – add 1.3 ml of sterile water for injections to the vial containing 1 g of the drug, add 2.6 ml to the vial containing 2 g, shake until completely dissolved, and then add 0.4 ml to the vial containing 1 g of the drug, add 0.8 ml of 2% lidocaine hydrochloride solution to the vial containing 2 g. The final solution will contain about 250 mg of cefoperazone and about 250 mg of sulbactam per 1 ml of 0.5% lidocaine hydrochloride solution.

Intravenous injection

For IV administration, dissolve the contents of the vial in an adequate volume (see table) 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 injections and administer over 3 minutes.

For IV infusion administration, dissolve as indicated above, then dilute to 20-100 ml with the same solvent and administer over 15-60 minutes.

Preparation of solution using Ringer’s lactate. Since Ringer’s lactate is not suitable for initial dilution, the solution is prepared in two stages: first, use sterile water for injections (see table), and then dilute the resulting solution with Ringer’s lactate solution to a sulbactam concentration of 5 mg/ml. Infusion is carried out over 15-60 minutes.

Adverse Reactions

From the cardiovascular system decreased blood pressure.

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

Allergic reactions maculopapular rash, urticaria, itching, Stevens-Johnson syndrome, anaphylactic shock.

From the hematopoietic system bleeding (vitamin K deficiency), decreased neutrophil count. With prolonged treatment, reversible neutropenia, decreased hemoglobin and hematocrit levels, transient eosinophilia, thrombocytopenia, leukopenia, hypoprothrombinemia develop.

Local reactions sometimes after IM injection, transient pain and burning at the injection site are observed. With IV administration of the drug, phlebitis may develop at the injection site.

Laboratory parameters hypercreatininemia, transient increase in hepatic transaminases, alkaline phosphatase and bilirubin in blood serum, hematuria, false-positive Coombs test. When using Benedict’s or Fehling’s solution, a false-positive reaction for glucose in urine may be observed.

Other headache, fever, chills, vasculitis.

Contraindications

• Hypersensitivity to sulbactam, cefoperazone, penicillins and other beta-lactam antibiotics.

With caution severe impairment of renal and hepatic function, colitis (including in the anamnesis), children under 3 months of age.

Use in Pregnancy and Lactation

During pregnancy, the drug should be used only if the expected benefit to the mother outweighs the potential risk to the fetus. If it is necessary to prescribe the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

With caution severe hepatic impairment.

Use in Renal Impairment

With caution severe renal impairment.

Pediatric Use

With caution children under 3 months of age.

Special Precautions

The risk of hypersensitivity reactions, including fatal ones, is higher in patients with a history of hypersensitivity reactions to multiple allergens. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy instituted.

In case of serious anaphylactic reactions, emergency administration of epinephrine is necessary. Glucocorticosteroids are administered intravenously and airway patency is ensured, including intubation.

Dosage adjustment may be required in cases of severe biliary obstruction, severe liver disease, and impaired renal function combined with any of the above conditions.

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

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

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

During treatment with cefoperazone, vitamin K deficiency has developed in rare cases. Patients at risk include those with inadequate nutrition, malabsorption (e.g., in cystic fibrosis), and those on long-term intravenous artificial nutrition. In such cases, as well as in patients receiving anticoagulants, prothrombin time should be monitored and vitamin K should be prescribed if indicated.

With prolonged treatment, overgrowth of non-susceptible microorganisms may be observed. During long-term therapy, it is recommended to periodically monitor the parameters of the function of internal organs, including kidneys, liver, and the hematopoietic system.

Overdose

Symptoms neurological disorders, including seizures.

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

Drug Interactions

Cefoperazone+Sulbactam and aminoglycoside solutions should not be directly mixed, given the pharmaceutical incompatibility between them. If combination therapy is carried out, the two drugs are administered by sequential infusions using separate secondary catheters, and the primary catheter is flushed between drug administrations. The intervals between administrations during the day should be as long as possible.

When consuming ethanol during treatment with cefoperazone and for up to 5 days after its administration, disulfiram-like effects may develop, characterized by “flushing”, sweating, headache, and tachycardia.

In patients requiring artificial nutrition (enteral or parenteral), the use of solutions containing ethanol should be avoided.

Storage Conditions

List B. Store in a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

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.