Sulcef (Powder) Instructions for Use

Marketing Authorization Holder

Medochemie, Ltd. (Cyprus)

Contact Information

MEDOCHEMIE Ltd. (Cyprus)

ATC Code

J01DD62 (Cefoperazone and beta-lactamase inhibitor)

Active Substances

Cefoperazone (Rec.INN registered by WHO)

Sulbactam (Rec.INN registered by WHO)

Dosage Form

Sulcef

Powder for solution for intravenous and intramuscular administration 1 g+1 g: vial 1 or 100 pcs.

Dosage Form, Packaging, and Composition

Powder for preparation of solution for intravenous and intramuscular administration from white to almost white with a yellowish tint.

2.18 g – glass vials (1) – cardboard packs.
2.18 g – glass vials (100) – 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

Combined antimicrobial drug.

Cefoperazone is 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 have clinically significant antibacterial activity (except for Neisseriaceae and Acinetobacter), is an irreversible inhibitor of most major beta-lactamases, the presence of which causes resistance of microorganisms to beta-lactam antibiotics. Sulbactam also binds to some penicillin-binding proteins, so the Sulbactam/Cefoperazone combination often has a more pronounced effect on susceptible strains than Cefoperazone alone.

Sulcef is active against all microorganisms susceptible to cefoperazone. In addition, the drug has synergism against various microorganisms, primarily: Haemophilus influenzae, Bacteroides spp., Staphylococcus spp., Acinetobacter colcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

The drug in vitro is active against a wide range of clinically significant microorganisms, including gram-positive microorganisms: Staphylococcus aureus (penicillinase-producing and non-penicillinase-producing), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (beta-hemolytic group A streptococcus), Streptococcus agalactiae (beta-hemolytic group B 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 S. marcescens), Salmonella spp., Shigella spp., Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis; Bordetella pertussis, Yersinia enterocolitica; anaerobic gram-negative bacilli, including Bacteroides spp. (including Bacteroides fragilis), 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

Absorption and Distribution

C_max of cefoperazone and sulbactam in blood plasma after intravenous administration of the cefoperazone/sulbactam combination (1 g cefoperazone, 1 g sulbactam) at a dose of 2 g over 5 min averages 130.2 and 236.8 µg/ml, respectively. This reflects a higher volume of distribution of sulbactam (V_d – 18-27.6 L) compared to cefoperazone (V_d – 10.2-11.3 L).

Both Cefoperazone and Sulbactam are well distributed in various tissues and fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus. Plasma concentrations are proportional to the administered dose.

With repeated use, no significant changes in the pharmacokinetics of both components of sulbactam/cefoperazone are noted. When the drug is administered every 8-12 hours, no accumulation is observed.

Elimination

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 actively 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 – 1.7 hours.

Pharmacokinetics in Special Clinical Cases

The T_1/2 of cefoperazone usually increases, and the excretion of the drug in the urine 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 T_1/2 increases by 2-4 times.

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 end-stage renal failure, patients showed a significant increase in T_1/2 to 6.9-9.7 hours. Hemodialysis causes significant changes in T_1/2, total body clearance and V_d of sulbactam.

In elderly patients with renal failure and liver dysfunction, an increase in T_1/2 duration, 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 liver impairment.

In children, there are no significant differences in the pharmacokinetics of the cefoperazone/sulbactam 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 from 1.44 to 1.88 hours.

Indications

Treatment of infectious and inflammatory diseases caused by microorganisms susceptible to the drug

• Infections of the upper and lower respiratory tract;
• Urinary tract infections;
• Intra-abdominal infections (including cholecystitis, cholangitis);
• Peritonitis;
• Septicemia;
• Meningitis;
• Skin and soft tissue infections;
• Bone and joint infections;
• Inflammatory diseases of the pelvic organs (including endometritis);
• Genital tract infections;
• Gonorrhea.

ICD codes

Dosage Regimen

The drug is administered intravenously or intramuscularly.

Adults are prescribed 2-4 g/day at 12-hour intervals; for severe, long-term infections – 8 g/day. The maximum daily dose is 8 g.

Patients with chronic renal failure (creatinine clearance less than 30 ml/min) require dose adjustment: with creatinine clearance 15-30 ml/min the drug is prescribed 1 g 2 times/day, with creatinine clearance less than 15 ml/min – 500 mg 2 times/day.

In severe biliary obstruction, severe liver diseases, dose adjustment of the drug may be required, the maximum daily dose in such cases is 2 g. In patients with impaired liver function and concomitant renal impairment, monitoring of the plasma concentration of cefoperazone and dose adjustment of the drug is necessary if required. If regular monitoring of the cefoperazone concentration in such cases is not performed, then the daily dose of the drug should not exceed 2 g.

Children are prescribed the drug at a dose of 40-80 mg/kg/day in 2-4 administrations; for severe, long-term infections – 160 mg/kg/day. The maximum daily dose is 160 mg/kg/day. If it is necessary to administer more than 80 mg/kg/day (calculated based on cefoperazone content), the dose increase is achieved by additional administration of cefoperazone.

Rules for preparation and administration of solutions

For intravenous administration, the contents of the vial are dissolved in an adequate volume of 5% dextrose solution, 0.9% sodium chloride injection solution or sterile water for injection, diluted to 20 ml with the same solution and administered intravenously by drip over 15-60 minutes; intravenously as a bolus over 3 minutes. For intramuscular administration, sterile water for injection is used 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 a 2% lidocaine solution to obtain a 0.5% lidocaine solution.

Adverse Reactions

Allergic reactions anaphylactic shock, transient eosinophilia, fever, maculopapular rash, urticaria, itching, Stevens-Johnson syndrome. The risk of these reactions is higher in patients with a history of allergic reactions (especially to penicillin).

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

From laboratory parameters increased activity of liver transaminases and alkaline phosphatase, hyperbilirubinemia, hypercreatininemia, hypoprothrombinemia.

From the hematopoietic system: decrease in the number of neutrophils, leukopenia and thrombocytopenia, decrease in hemoglobin and hematocrit levels; with long-term treatment (as with the use of other beta-lactam antibiotics), reversible neutropenia is possible.

From the blood coagulation system: hypoprothrombinemia, bleeding (vitamin K deficiency).

Local reactions after intramuscular injection, transient pain is possible; with intravenous administration of the drug (as with other cephalosporins and penicillins) using a catheter, phlebitis may develop at the infusion site (0.1%); injection pain is possible.

Others: headache, fever, chills, hematuria, vasculitis.

The drug is well tolerated when administered intramuscularly.

Contraindications

• Hypersensitivity to the components of the drug;
• Hypersensitivity to penicillins and other cephalosporins.

Use in Pregnancy and Lactation

During pregnancy and lactation, the drug is used only if the expected benefit of therapy for the mother outweighs the potential risk to the fetus or breastfed infant.

Use in Hepatic Impairment

In severe biliary obstruction, severe liver diseases, dose adjustment of the drug may be required, the maximum daily dose in such cases is 2 g. In patients with impaired liver function and concomitant renal impairment, monitoring of the plasma concentration of cefoperazone and dose adjustment of the drug is necessary if required. If regular monitoring of the cefoperazone concentration in such cases is not performed, then the daily dose of the drug should not exceed 2 g.

Use in Renal Impairment

Patients with chronic renal failure (creatinine clearance less than 30 ml/min) require dose adjustment: with creatinine clearance 15-30 ml/min the drug is prescribed 1 g 2 times/day, with creatinine clearance less than 15 ml/min – 500 mg 2 times/day. In patients with impaired liver function and concomitant renal impairment, monitoring of the plasma concentration of cefoperazone and dose adjustment of the drug is necessary if required. If regular monitoring of the cefoperazone concentration in such cases is not performed, then the daily dose of the drug should not exceed 2 g

Special Precautions

Cases of anaphylactic reactions have been described in patients who received beta-lactam antibiotics (including cephalosporins). The risk of such reactions is higher with a history of hypersensitivity reactions. If an allergic reaction occurs, it is necessary to discontinue the drug and prescribe adequate therapy.

In case of serious anaphylactic reactions, emergency administration of epinephrine is necessary. Oxygen, intravenous corticosteroids are prescribed as indicated, and airway patency is ensured, including intubation.

During treatment with cefoperazone (as with the use of other antibiotics), vitamin K deficiency rarely develops, apparently due to the suppression of normal intestinal flora, which synthesizes this vitamin. The risk group includes patients receiving inadequate nutrition, suffering from malabsorption (for example, in cystic fibrosis) and 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, prescribe vitamin K.

With long-term treatment with Sulcef (as with other antibiotics), excessive growth of non-susceptible microorganisms is possible.

During therapy, patients require careful medical supervision.

During long-term therapy, it is recommended to periodically monitor the indicators of the function of internal organs (including kidneys, liver) and the hematopoietic system.

Given the broad spectrum of antimicrobial activity, adequate monotherapy can be conducted.

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

In cases of biliary obstruction or severe hepatic insufficiency (maximum daily dose is 2 g), dose adjustment of Sulcefa and monitoring of plasma cefoperazone concentration are required.

During treatment, false-positive results for urinary glucose may occur when using Benedict’s or Fehling’s solutions, as well as a false-positive Coombs’ test.

Use in Pediatrics

Treatment of premature newborns is carried out only if the expected benefit of therapy outweighs the potential risk. When using the drug in young children, careful monitoring of the functions of internal organs (including kidneys, liver) and the hematopoietic system is required.

Overdose

Symptoms: epileptic seizure.

Treatment: sedative therapy. In case of anaphylactic shock development – intravenous administration of epinephrine, oxygen inhalation, application of corticosteroids.

Drug Interactions

Reactions characterized by flushing, sweating, headache, and tachycardia have been reported with ethanol intake during drug use and for 5 days after its administration (patients should be warned about the possibility of such reactions when consuming alcohol during treatment). In patients requiring artificial nutrition (enteral or parenteral), the use of solutions containing ethanol should be avoided.

Pharmaceutical Incompatibility

Sulcefa and aminoglycoside solutions should not be mixed, considering the physical incompatibility between them. If combined therapy with Sulcef and an aminoglycoside is conducted, the two drugs are administered via sequential infusions using separate secondary catheters, and the primary catheter is flushed with an adequate solution between drug administrations. The interval between the administration of Sulcefa and the aminoglycoside during the day should be as long as possible.

Storage Conditions

The drug should be stored out of the reach of children, in a light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 2 years.

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.