Cefopektam

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFOPECTAM (CEFOPECTAM)

Composition:

Active substances: cefoperazone, sulbactam;

1 vial contains cefoperazone (as sterile sodium salt) – 500 mg or 1 g and sulbactam (as sterile sodium salt) – 500 mg or 1 g, respectively.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white to almost white powder, free from visible particles.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Beta-lactam antibiotics. Third-generation cephalosporins. ATC code J01D D62.

Pharmacological properties.

Pharmacodynamics.

Cefopectam is a combination of sodium sulbactam and sodium cefoperazone. Sodium sulbactam is a derivative of the basic penicillin nucleus. It is an irreversible inhibitor of beta-lactamase and is administered only parenterally. Chemically, it is the sodium sulphonate of penicillinate.

The antibacterial component of sulbactam/cefoperazone is sodium cefoperazone—a semi-synthetic, broad-spectrum, third-generation cephalosporin antibiotic administered only parenterally. It acts against susceptible microorganisms during active multiplication by inhibiting the biosynthesis of the murein of the cell membrane.

Sulbactam has no significant intrinsic antibacterial activity, except for activity against Neisseriaceae and Acinetobacter. However, biochemical studies on cell-free bacterial systems have shown that sulbactam is an irreversible inhibitor of the most important beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics.

The potential of sulbactam to prevent the degradation of penicillins and cephalosporins by resistant microorganisms has been confirmed in studies on resistant strains in intact microorganisms, where sulbactam demonstrated pronounced synergy with penicillins and cephalosporins. Since sulbactam also binds to certain penicillin-binding proteins, susceptible strains become more vulnerable to sulbactam/cefoperazone than to cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all microorganisms susceptible to cefoperazone. In addition, synergistic action has been observed (approximately a 4-fold reduction in minimum inhibitory concentrations in combination compared to each component alone) against the following microorganisms: Haemophilus influenzae, species of Bacteroides, species of Staphylococcus, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Sulbactam/cefoperazone demonstrates in vitro activity against a broad spectrum of clinically significant microorganisms:

Gram-positive microorganisms: Staphylococcus aureus (strains producing or not producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae (former name Diplococcus pneumoniae), Streptococcus pyogenes (beta-hemolytic streptococcus group A), Streptococcus agalactiae (beta-hemolytic streptococcus group B), most other strains of beta-hemolytic streptococci, many strains of Streptococcus faecalis (enterococci).

Gram-negative microorganisms: Escherichia coli, species of Klebsiella, species of Enterobacter, species of Citrobacter, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (former name Proteus morganii), Providencia rettgeri (former name Proteus rettgeri), species of Providencia, species of Serratia (including S. marcescens), species of Salmonella and Shigella, Pseudomonas aeruginosa and some species of Pseudomonas, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.

Anaerobic microorganisms: Gram-negative bacilli (including Bacteroides fragilis, other species of Bacteroides, and species of Fusobacterium), Gram-positive and Gram-negative cocci (including species of Peptococcus, Peptostreptococcus, and Veillonella), Gram-positive bacilli (including species of Clostridium, Eubacterium, and Lactobacillus).

Pharmacokinetics.

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose administered as the sulbactam/cefoperazone combination are excreted by the kidneys. Cefoperazone is largely excreted via bile. After administration of sulbactam/cefoperazone, the mean elimination half-life of sulbactam is 1 hour and that of cefoperazone is 1.7 hours. Plasma concentrations are proportional to the administered dose. These data are consistent with previously published pharmacokinetic studies of these components when administered separately.

Mean peak plasma concentrations of sulbactam and cefoperazone after intravenous administration of 2 g sulbactam/cefoperazone (1 g sulbactam, 1 g cefoperazone) over 5 minutes are 130 and 236.8 µg/mL, respectively. This indicates a larger volume of distribution for sulbactam (Vα = 18.0–27.6 L) compared to cefoperazone (Vα = 10.2–11 L).

Sulbactam and cefoperazone are well distributed into tissues and body fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus.

There is no evidence of any pharmacokinetic interaction between sulbactam and cefoperazone when co-administered as a combined product.

After repeated administration, no significant changes in the pharmacokinetics of the components or any accumulation were observed when administered every 8–12 hours.

Studies conducted in children showed no significant differences in the pharmacokinetics of the components (sulbactam/cefoperazone) compared to data in adult patients. In children, the mean elimination half-life of sulbactam ranges from 0.91 to 1.42 hours and that of cefoperazone from 1.44 to 1.88 hours.

The pharmacokinetics of the sulbactam/cefoperazone combination have been studied in elderly patients with impaired renal and hepatic function. Prolongation of elimination half-life, reduced clearance, and increased volume of distribution of both components were observed compared to healthy volunteers. Pharmacokinetic parameters for sulbactam correlate with the degree of renal impairment, whereas those for cefoperazone correlate with the degree of hepatic impairment.

Hepatic impairment. See section "Special precautions".

Renal impairment. In patients with various degrees of renal impairment receiving sulbactam/cefoperazone, total clearance of sulbactam closely correlates with creatinine clearance. In patients with severe renal impairment, a significant prolongation of sulbactam elimination half-life is observed (on average 6.9 and 9.7 hours according to different studies). Hemodialysis significantly affects the elimination half-life, total clearance, and volume of distribution of sulbactam. No significant changes in the pharmacokinetics of cefoperazone have been observed in patients with renal insufficiency.

Cefoperazone does not displace bilirubin from its binding to serum albumin.

Clinical characteristics.

Indications.

Infectious-inflammatory diseases caused by microorganisms sensitive to the drug:

• respiratory tract infections (upper and lower respiratory tract);
• urinary tract infections (upper and lower urinary tract);
• peritonitis, cholecystitis, cholangitis, and other intra-abdominal infections;
• skin and soft tissue infections;
• bone and joint infections;
• meningitis;
• septicemia;
• inflammatory diseases of the pelvic organs, endometritis, gonorrhea, and other genital infections.

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

Due to the broad spectrum of antibacterial activity of sulbactam/cefoperazone, monotherapy with this drug is possible in most infections. However, under certain indications, sulbactam/cefoperazone may be used in combination with other antibiotics. If *aminoglycosides* are used concomitantly, renal function should be monitored throughout the course of therapy due to possible nephrotoxic reactions (see also section "Incompatibility").

*Alcohol (ethanol)*: disulfiram-like reactions (flushing, sweating, headache, and tachycardia) have been reported when alcohol is consumed during treatment with cefoperazone and for 5 days after the end of treatment. Patients should avoid alcohol consumption and the use of alcohol-containing products during treatment and for 5 days after its completion. Ethanol-containing solutions should not be used during enteral or parenteral nutrition.

*Nonsteroidal anti-inflammatory drugs, antiplatelet agents, vitamin K antagonists* *(warfarin)*: increased risk of bleeding.

*Loop diuretics* and *nephrotoxic drugs*: possible increased risk of nephrotoxicity.

*Laboratory tests*: false-positive results may occur when testing for glucose in urine using Benedict's or Fehling's solution.

The combination of sulbactam/cefoperazone is physically incompatible with *aminoglycosides*, *amifostine*, *filgrastim*, *labetalol*, *meperidine*, *nicardipine*, *ondansetron*, *perphenazine*, *promethazine*, *sargramostim*, *vinorelbine*.

Special precautions.

Hypersensitivity. Severe, and sometimes fatal, hypersensitivity reactions (anaphylactic reactions) have been reported in patients receiving beta-lactam or cephalosporin antibiotics, including the cefoperazone/sulbactam combination. The likelihood of hypersensitivity reactions is higher in patients with known sensitivity to multiple allergens.

In case of allergic reactions, the drug must be discontinued immediately and appropriate therapy initiated. Severe anaphylactic reactions require immediate administration of epinephrine and intravenous glucocorticoids. Oxygen therapy, airway maintenance including intubation, may be indicated as needed.

Cases of severe skin reactions, sometimes fatal, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis, have been reported in patients receiving cefoperazone. If a serious skin reaction occurs, treatment with the drug should be discontinued and appropriate therapy initiated.

Use in hepatic impairment. Cefoperazone is predominantly excreted via bile. In patients with hepatic disease and/or biliary obstruction, the elimination half-life of cefoperazone is usually prolonged, and urinary excretion increases. Even in severe hepatic impairment, therapeutic concentrations of cefoperazone are detectable in bile, while the elimination half-life increases only 2- to 4-fold. Dose adjustment may be necessary in cases of severe biliary obstruction, severe liver disease, or renal impairment associated with any of these conditions. Patients with hepatic impairment and concomitant renal dysfunction should have serum cefoperazone concentrations closely monitored, and dosage adjusted as needed. In the absence of serum concentration monitoring, the cefoperazone dose should not exceed 2 g/day.

Use in renal impairment. See sections "Pharmacokinetics" and "Dosage and administration".

General warnings. Serious bleeding events, including fatal cases, have been reported with cefoperazone/sulbactam use. As with other antibiotics, treatment with cefoperazone/sulbactam may lead to vitamin K deficiency, potentially resulting in coagulopathy. This mechanism is likely related to suppression of intestinal flora normally synthesizing this vitamin. High-risk patients include those with poor nutrition, malabsorption (e.g., in cystic fibrosis), and those on prolonged parenteral (intravenous) nutrition. Such patients, as well as those who have received prolonged anticoagulant therapy prior to Cefopectam administration, should have prothrombin time (or International Normalized Ratio) monitored regularly at the beginning and throughout treatment with Cefopectam. These patients should be closely observed for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. If prolonged bleeding occurs without other identifiable cause, the drug should be discontinued. Exogenous vitamin K should be administered if indicated.

Prolonged treatment with Cefopectam, as with other antibiotics, may lead to overgrowth of resistant microorganisms. Therefore, patients should be closely monitored during therapy.

As with any potent systemic agent, renal, hepatic, and hematopoietic functions should be periodically monitored during prolonged treatment with cefoperazone/sulbactam. This is particularly important for neonates, especially preterm infants, and other infants.

C. difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including cefoperazone sodium/sulbactam sodium combination. The severity of manifestations may range from mild diarrhea to fatal colitis. Antibacterial therapy suppresses normal colonic flora, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of C. difficile-associated diarrhea. Hyperproducing toxin strains of C. difficile are associated with increased morbidity and mortality, as such infections may be resistant to antibacterial therapy and often require colectomy. CDAD must be considered in all patients who develop diarrhea during or after antibiotic use. Careful medical history is essential, as CDAD has been reported up to two months after antibacterial treatment. In case of severe and persistent diarrhea, the drug should be discontinued immediately and appropriate therapy initiated (e.g., oral vancomycin). Antiperistaltic agents are contraindicated. Without appropriate treatment, toxic megacolon, peritonitis, and shock may develop.

Alcohol. See section "Interaction with other medicinal products and other forms of interaction".

False-positive results may occur when measuring urinary glucose concentration by non-enzymatic methods and in the Coombs test.

Children. Cefoperazone/sulbactam has been successfully used in children. However, extensive studies of this combination in preterm or full-term neonates have not been conducted. Therefore, the potential benefits and possible risks of using the drug should be adequately assessed before initiating treatment in these patient groups.

In neonates with pathological neonatal jaundice, cefoperazone does not displace bilirubin from serum albumin binding.

The drug contains sodium (63 mg of sodium per 1 g of drug); this should be taken into account when prescribing to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Sulbactam and cefoperazone cross the placental barrier. Data on the use of the drug for treatment during pregnancy are lacking. Therefore, use during pregnancy is possible only in exceptional cases and only for life-threatening indications.

Cefopectam should be administered with caution to breastfeeding women, despite the fact that the components of the drug pass into breast milk in insignificant amounts.

Ability to affect reaction speed when driving or operating machinery.

Clinical experience with cefoperazone/sulbactam suggests that the drug is unlikely to impair reaction speed when driving or operating machinery.

Administration and Dosage

Adults. The usual dose of Cefopectam for adults is 2–4 g per day (i.e., 1–2 g per day of cefoperazone), administered intravenously or intramuscularly in equally divided doses every 12 hours.

Table 1

In severe or refractory infections, the daily dose of Cefopektam may be increased up to 8 g (i.e., cefoperazone dose – 4 g) administered intravenously in evenly divided doses every 12 hours. The recommended maximum daily dose of sulbactam is 4 g (8 g of Cefopektam).

Hepatic impairment. See section "Special precautions".

Renal impairment. The dosage regimen of Cefopektam should be adjusted in patients with significantly reduced renal function (creatinine clearance < 30 mL/min) to compensate for reduced sulbactam clearance. In patients with creatinine clearance of 15–30 mL/min, sulbactam should be administered at a maximum dose of 1 g given every 12 hours (maximum daily sulbactam dose – 2 g). In patients with creatinine clearance less than 15 mL/min, sulbactam should be administered at a maximum dose of 500 mg given every 12 hours (maximum daily sulbactam dose – 1 g). In severe infections, additional separate administration of cefoperazone may be required.

The pharmacokinetic profile of sulbactam is significantly altered during hemodialysis.

The elimination half-life of cefoperazone is slightly reduced during hemodialysis. Therefore, the dosing regimen of Cefopektam should be adjusted when dialysis is performed.

Elderly patients. See section "Pharmacokinetics".

Children. The usual dose of Cefopektam in children is 40–80 mg/kg/day (20–40 mg/kg/day of cefoperazone), divided into 2–4 equal doses.

Table 2

For severe or refractory infections, the daily dose may be increased up to 160 mg/kg body weight (80 mg/kg/day of cefoperazone), divided evenly into 2–4 doses.

Neonates. Neonates during the first week of life should receive the drug every 12 hours. The maximum daily dose of sulbactam in pediatric patients should not exceed 80 mg/kg body weight (160 mg/kg/day of Cefopektam preparation). If a dose of cefoperazone exceeding 80 mg/kg/day is required, the additional cefoperazone dose should be administered separately.

Intravenous administration.

Reconstitution method.

Step 1. Preparation of the primary solution.

The contents of the vial should be dissolved in an appropriate volume of 5% glucose injection solution, 0.9% sodium chloride injection solution, or sterile water for injection, according to the volumes specified in Table 3.

Table 3

2nd stage. Preparation of the secondary solution.

For intravenous infusion, the obtained primary solution is added to a suitable diluent to achieve a final concentration of Cefopectam 10–20 mg/mL in the total volume of the solution. The prepared secondary solution is administered by intravenous infusion over 15–60 minutes.

For intravenous bolus injection, the obtained primary solution of Cefopectam is diluted with diluent to a volume of 20 mL and administered slowly over at least 3 minutes.

Cefopectam is compatible with the following solutions:

• sterile water for injection;
• 5% glucose solution;
• 0.9% sodium chloride solution;
• 5% glucose in 0.225% sodium chloride solution;
• 5% glucose in 0.9% sodium chloride solution.

Ringer’s lactate solution is acceptable as a diluent for intravenous infusion, but not for primary dilution (see section "Incompatibility"). A two-step dilution is required. For reconstitution, sterile water for injection should be used (see Table 3); the resulting solution is then further diluted with Ringer’s lactate solution to achieve a sulbactam concentration of 5 mg/mL (2 mL or 4 mL of the initially reconstituted solution is added to 50 mL or 100 mL of Ringer’s lactate solution, respectively).

Intramuscular administration. A 2% lidocaine solution is acceptable as a diluent for preparing a solution for intramuscular injection, but not for primary dilution (see section "Incompatibility").

Lidocaine. For intramuscular injection, the drug solution should be prepared in two steps. First, prepare the primary solution using sterile water for injection (see Table 3), followed by dilution with 2% lidocaine solution. The approximate concentration of lidocaine in the secondary solution is 0.5%.

Any unused product or waste material should be disposed of in accordance with local requirements.

Children.

Can be used in children from the first days of life.

Use with caution in newborns and premature infants. When administered to newborns, especially premature infants and infants, transient disturbances in kidney, liver, and hematopoietic system function may occur. Therefore, the potential benefits and possible risks of therapy should be carefully evaluated before initiating treatment.

In newborns with bilirubin encephalopathy, cefoperazone does not displace bilirubin from its binding to plasma proteins.

Overdose.

Information on acute toxicity of sodium cefoperazone and sodium sulbactam in humans is limited.

Symptoms: the expected manifestations of overdose are primarily an intensification of adverse effects. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may cause neurological reactions, including seizures. Renal impairment and prolonged prothrombin time are also possible.

Treatment: symptomatic. Maintain vital functions and fluid-electrolyte balance, monitor prothrombin time, and administer vitamin K if necessary. In case of seizures, sedative therapy should be administered. Hemodialysis may be performed to enhance drug elimination, especially in patients with impaired renal function.

Adverse reactions.

The sulbactam/cefoperazone combination is generally well tolerated. Most adverse reactions are mild to moderate in severity.

Blood and lymphatic system: eosinophilia, hypoprothrombinemia, neutropenia (associated with prolonged use, reversible), thrombocytopenia, leukopenia, decreased hemoglobin and/or hematocrit levels, anemia, bleeding, vitamin K deficiency, prolonged prothrombin time.

Immune system (these reactions occur more frequently in patients with allergies, especially to penicillins): hypersensitivity reactions, anaphylactic reactions (including laryngospasm, bronchospasm, dyspnea, anaphylactic shock), anaphylactoid reactions (including shock).

Skin and subcutaneous tissues: maculopapular rash, pruritus, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis.

Nervous system: oral mucosal hyperesthesia, restlessness, headache, dizziness.

Cardiovascular system: vasculitis, hemorrhage (including fatal outcome), arterial hypotension, flushing, bradycardia/tachycardia, cardiogenic shock, cardiac arrest.

Gastrointestinal tract: diarrhea, nausea, vomiting, pseudomembranous enterocolitis.

Hepatobiliary system: transient increases in plasma levels of AST, ALT, alkaline phosphatase, and bilirubin; jaundice.

Urinary system: hematuria.

General disorders and administration site conditions: fever, chills, fasciculations, increased sweating, phlebitis at catheter insertion site, injection site pain.

Laboratory findings: increased blood urea nitrogen and serum creatinine levels (transient), cylindruria, positive direct Coombs test.

Effects due to the biological action of the drug: possible development of superinfection (e.g. candidiasis, genital mycosis) caused by resistant microorganisms.

Shelf life.

2 years.

Storage conditions.

In the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities.

Aminoglycosides

Solutions of Cefopektam and aminoglycosides should not be mixed in the same syringe or infusion system due to physical incompatibility. If combination therapy with Cefopektam and aminoglycosides is necessary, sequential separate intravenous infusions should be administered using separate secondary intravenous tubing. The primary intravenous line should be thoroughly flushed with an appropriate solution between infusions of the two drugs. It is also advisable to maximize the time intervals between administration of Cefopektam and aminoglycosides within a 24-hour period.

Lactated Ringer’s solution

Primary dilution with Lactated Ringer’s solution is not recommended due to incompatibility. However, a two-step dilution process, using water for injections as the primary solvent, allows avoidance of incompatibility when further diluted with Lactated Ringer’s solution (see section “Dosage and administration”).

Lidocaine

Primary dilution with 2% lidocaine solution is not recommended due to incompatibility. However, a two-step dilution process, using water for injections as the primary solvent, allows avoidance of incompatibility when further diluted with 2% lidocaine solution (see section “Dosage and administration”).

Packaging.

1 vial; 1 vial per pack; 5 vials per cassette, 1 cassette per case.

Prescription category. Prescription only.

Manufacturer.

Public Joint-Stock Company “Scientific and Production Center “Borshchahivskiy Chemical and Pharmaceutical Plant”.

Manufacturer’s address and place of business.

17 Miru Street, Kyiv, 03134, Ukraine.