Hepacef combo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GEPACEF COMBY (GEPACEF COMBY)

Composition:

Active substances: cefoperazone, sulbactam;

One vial contains a sterile mixture of sodium cefoperazone and sodium sulbactam (1:1), calculated as cefoperazone – 1.0 g and sulbactam – 1.0 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white powder.

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

Pharmacological Properties

Pharmacodynamics

Hepacef Combi is a combination of sodium sulbactam and cefoperazone sodium.

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 sodium sulphonate of penicillinate. It contains 92 mg of sodium (4 mEq) per 1 gram. Sulbactam is a highly water-soluble, almost white crystalline powder. Molecular weight is 255.22.

Cefoperazone sodium is a broad-spectrum, semi-synthetic, third-generation cephalosporin antibiotic administered only parenterally. It contains 34 mg of sodium (1.5 mEq) per 1 gram. Cefoperazone is a white, water-soluble crystalline powder. Molecular weight is 667.65.

Mechanism of Action

The antibacterial component of Hepacef Combi is cefoperazone, a third-generation cephalosporin that acts against susceptible microorganisms during the active multiplication phase by inhibiting the biosynthesis of the murein of the bacterial cell wall. 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 key beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics.

The potential of sulbactam to prevent the destruction of penicillins and cephalosporins by resistant microorganisms has been confirmed in studies using intact microorganisms and resistant strains, during which sulbactam demonstrated marked synergy with penicillins and cephalosporins. Since sulbactam also binds to certain penicillin-binding proteins, susceptible strains often become more vulnerable to Hepacef Combi 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 (reduction of minimum inhibitory concentrations of the combination approximately fourfold compared to each component alone) against various microorganisms, with particularly pronounced effects against the following: 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.

Hepacef Combi 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 group A streptococci);
• Streptococcus agalactiae (beta-hemolytic group B streptococci);
• 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 other Pseudomonas species;
• 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).

The following range of sensitivity to Hepacef Combi has been established.

Minimum Inhibitory Concentrations (MICs) (μg/mL, as cefoperazone concentrations):

Size of the sensitivity zone disk (mm, Kirby-Bauer test):

Serial dilutions of Hepacef Combi can be used for determination of MIC by means of agar or broth dilution methods. It is recommended to use a disk susceptibility test containing 30 mcg of sulbactam and 75 mcg of cefoperazone. A laboratory report of "susceptible" indicates that therapy with Hepacef Combi is likely to be effective against the infecting microorganism, while a report of "resistant" indicates that such effective action is unlikely. A report of "intermediate" means that the microorganism may be susceptible to Hepacef Combi when the drug is administered at higher doses or if the infection has developed in those tissues or body fluids where high antibiotic concentrations are achieved.

Recommended quality control limits for the 30 mcg/75 mcg sulbactam/cefoperazone susceptibility disks:

Pharmacokinetics.

Distribution.

Mean maximum concentrations of sulbactam and cefoperazone after 5-minute intravenous administration of a single 2 g dose (in a 1:1 ratio) of Hepacef Combi (1 g sulbactam + 1 g cefoperazone) in healthy volunteers were 130 and 236.8 mcg/mL, respectively. This indicates a larger volume of distribution of sulbactam (Vd = 18.0–27.6 L) compared to that of cefoperazone (Vd = 10.2–11.3 L).

Mean maximum concentrations of sulbactam and cefoperazone after 15-minute intravenous administration of a single 4.5 g dose (in a 1:2 ratio) of Hepacef Combi (1.5 g sulbactam + 3 g cefoperazone) in healthy volunteers were 88.3 mcg/mL and 416.1 mcg/mL, respectively.

Maximum serum concentrations of sulbactam and cefoperazone after the first intramuscular administration of 1.5 g of Hepacef Combi (0.5 g sulbactam + 1 g cefoperazone) in healthy volunteers were 11 mcg/mL and 45.3 mcg/mL, and 29.9 mcg/mL and 58.4 mcg/mL, respectively, after the seventh dose when the drug was administered every 12 hours.

Elimination.

Following administration of Hepacef Combi, approximately 84% of the sulbactam dose and 25% of the cefoperazone dose are excreted by the kidneys. Most of the remaining cefoperazone dose is excreted via bile. After administration of Hepacef Combi, the mean elimination half-life of sulbactam is approximately 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.

After intramuscular administration of 1.5 g of Hepacef Combi (0.5 g sulbactam and 1 g cefoperazone), maximum plasma concentrations of sulbactam and cefoperazone were achieved within 15 minutes to 2 hours after injection. Mean maximum plasma concentrations were 19 and 64.2 mcg/mL for sulbactam and cefoperazone, respectively.

With repeated administration, no significant changes in the pharmacokinetics of the components of Hepacef Combi have been reported, and no accumulation was observed when the drug was administered every 8–12 hours.

Patients with hepatic impairment.

See section "Special precautions for use".

Patients with renal impairment.

In patients with varying degrees of renal impairment receiving Hepacef Combi, total systemic clearance of sulbactam strongly correlated with creatinine clearance. In patients with non-functioning kidneys, the elimination half-life of sulbactam was considerably prolonged (on average 6.9 and 9.7 hours, according to different studies). Hemodialysis significantly alters the elimination half-life, total systemic clearance, and volume of distribution of sulbactam. No significant differences in the pharmacokinetics of cefoperazone were observed in patients with renal insufficiency.

Elderly patients.

The pharmacokinetics of Hepacef Combi have been studied in elderly patients with impaired renal and hepatic function. Both components of the drug, sulbactam and cefoperazone, exhibited a longer elimination half-life, lower clearance, and larger volume of distribution compared to healthy volunteers. Pharmacokinetic data for sulbactam correlate well with the degree of renal impairment, whereas data for cefoperazone correlate well with the degree of hepatic impairment.

Children.

Studies conducted in children have demonstrated no significant differences in the pharmacokinetics of the components of Hepacef Combi compared to data in adult patients. In children, the mean elimination half-life of sulbactam ranged from 0.91 to 1.42 hours, and that of cefoperazone from 1.44 to 1.88 hours.

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

There is no evidence of any pharmacokinetic interaction between sulbactam and cefoperazone when they are co-administered in the form of Hepacef Combi.

Cefoperazone does not displace bilirubin from plasma protein binding sites.

Clinical characteristics.

Indications.

The drug is indicated for the treatment of infections caused by susceptible strains of microorganisms:

• respiratory tract infections (upper and lower);
• urinary tract infections (upper and lower);
• 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 infections.

Contraindications.

Hepacef Combi is contraindicated in patients with known hypersensitivity to the active substances (sulbactam, cefoperazone), to beta-lactams, or to any of the excipients.

Interaction with other medicinal products and other forms of interactions.

Combination therapy. Due to the broad spectrum of activity of sulbactam/cefoperazone, Hepacef Combi can be used as monotherapy for adequate treatment of most infections. However, under certain indications, Hepacef Combi may be used concomitantly with other antibiotics. When aminoglycosides are used simultaneously, renal function should be monitored throughout the course of therapy (see sections "Method of administration and dosage" and "Incompatibility").

Alcohol. Reactions such as facial flushing, sweating, headache, and tachycardia have been reported when alcohol is consumed during treatment with cefoperazone and within 5 days after its administration. Similar reactions have also been observed with some other cephalosporins. Patients should be warned about possible adverse reactions that may occur when consuming alcoholic beverages during treatment with this drug. Solutions containing ethanol should not be administered to patients requiring artificial nutrition (oral or parenteral).

Interaction with substances used in laboratory tests. A false-positive glucose urine test may occur when using Benedict's or Fehling's solution.

Special precautions.

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

Before initiating therapy with sulbactam/cefoperazone, the patient’s history of hypersensitivity reactions to cephalosporins, penicillins, or other drugs should be carefully evaluated (see section "Contraindications"). Antibiotics should be administered cautiously to patients with any type of allergic predisposition, especially to drugs.

If allergic reactions occur, the drug should be discontinued immediately and appropriate therapy initiated. Severe anaphylactic reactions require immediate administration of epinephrine. If necessary, oxygen therapy, intravenous corticosteroids, and measures to ensure airway patency, including intubation, should be implemented (see section "Adverse reactions").

Cases of severe skin reactions, sometimes with fatal outcomes, such as toxic epidermal necrolysis, Stevens–Johnson syndrome, and exfoliative dermatitis, have been reported in patients treated with sulbactam/cefoperazone. If a severe skin reaction occurs, therapy with sulbactam/cefoperazone should be discontinued and appropriate treatment initiated (see section "Adverse reactions").

Use in hepatic impairment. Cefoperazone is predominantly excreted via bile. In patients with liver disease and/or biliary obstruction, the serum half-life of cefoperazone is usually prolonged, and renal excretion increases. Even in severe hepatic impairment, therapeutic concentrations of cefoperazone are observed in bile, with only a 2- to 4-fold prolongation of the elimination half-life.

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 impaired liver function and concomitant renal impairment require monitoring of cefoperazone serum concentrations, and dosage should be adjusted if necessary. In such cases, without careful monitoring of serum concentrations, the cefoperazone dose should not exceed 2 g/day.

General warnings. Serious bleeding events, including fatal cases, have been reported with cefoperazone/sulbactam use. As with other antibiotics, vitamin K deficiency leading to coagulopathy has been observed in patients receiving sulbactam/cefoperazone. The mechanism is likely related to suppression of normal gut bacterial flora responsible for vitamin K synthesis. Patients at risk include those with poor nutrition, malabsorption, and those receiving long-term parenteral (intravenous) nutrition. In these patients and in patients taking oral anticoagulants, prothrombin time (or international normalized ratio) should be monitored to detect signs of bleeding, thrombocytopenia, and hypoprothrombinemia, and vitamin K supplementation should be administered if indicated. If prolonged bleeding occurs without other identifiable cause, cefoperazone/sulbactam should be discontinued.

As with other antibiotics, prolonged use of Hepacef Combi may lead to overgrowth of resistant microorganisms. Patients should be closely monitored during therapy. As with other potent systemic agents, periodic monitoring of organ system functions—including renal, hepatic, and hematopoietic systems—is recommended during prolonged treatment, especially in premature infants and other neonates.

Clostridium difficile-associated diarrhea has been reported with the use of nearly all antibacterial agents, including sodium sulbactam/sodium cefoperazone. The severity may range from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of C. difficile-associated diarrhea. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as such infections may be resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in all patients presenting with diarrhea following antibacterial therapy. Careful medical history is essential, as cases of C. difficile-associated diarrhea have been reported up to two months after completion of antibacterial treatment.

Children.

Hepacef Combi has been effectively used in infants; however, comprehensive studies on its use in premature or full-term neonates have not been conducted. Therefore, the potential benefits and risks should be carefully evaluated before initiating treatment in premature or full-term neonates.

In neonates with bilirubin encephalopathy, cefoperazone does not displace bilirubin from plasma protein-binding sites.

One vial of Hepacef Combi contains 0.063 g of sodium. This should be taken into account when administering the drug to patients with impaired renal function or those on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Studies on reproductive function in rats at doses 10 times higher than the human dose showed no evidence of impaired fertility or teratogenic effects. Sulbactam and cefoperazone cross the placental barrier, but comprehensive and well-controlled studies in pregnant women have not been conducted. Since animal study results may not always predict human response, Hepacef Combi should be used during pregnancy only if clearly needed.

Lactation. Only a small portion of the administered doses of sulbactam and cefoperazone is excreted into breast milk. Hepacef Combi should be administered with caution to breastfeeding women, despite the fact that both components are excreted in breast milk in small amounts.

Ability to affect reaction speed when driving or operating machinery.

Clinical experience with sulbactam/cefoperazone suggests that its effect on a patient’s ability to drive or operate machinery is unlikely.

Administration and Dosage

Hepacef Combi (sulbactam sodium/cefoperazone sodium) is supplied in vials and is intended for parenteral use only.

The sulbactam sodium/cefoperazone sodium combination is provided as a dry powder for reconstitution in a 1:1 ratio, calculated as free sulbactam and cefoperazone. Vials with powder in a 1:1 ratio contain the equivalent of 1000 mg + 1000 mg of sulbactam and cefoperazone, respectively.

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

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

Hepatic impairment. See section "Special precautions".

Renal impairment. The dosing regimen of Hepacef Combi should be adjusted in patients with significantly reduced renal function (creatinine clearance less than 30 mL/min) to compensate for the reduced clearance of sulbactam. For patients with creatinine clearance of 15–30 mL/min, sulbactam should be administered at a dose not exceeding 1 g given every 12 hours (maximum daily dose of sulbactam – 2 g). For patients with creatinine clearance less than 15 mL/min, sulbactam should be administered at a dose not exceeding 500 mg every 12 hours (maximum daily dose of sulbactam – 1 g). In severe infections, additional administration of cefoperazone alone may be required.

The pharmacokinetic profile of sulbactam is significantly altered during hemodialysis.

The serum half-life of cefoperazone is slightly reduced during hemodialysis. Therefore, the dosing regimen should be adjusted according to the dialysis schedule.

Elderly patients. See section "Pharmacokinetics".

Children. The usual dose of Hepacef Combi in children is 40 to 80 mg/kg body weight/day (i.e., 20–40 mg cefoperazone/kg body weight/day), divided evenly into 2–4 doses.

In severe or refractory infections, this dose may be increased up to 160 mg/kg body weight/day (80 mg of cefoperazone/kg body weight/day), divided evenly into 2–4 doses (see section "Dosage and Administration").

Neonates. In neonates during the first week of life, the drug should be administered every 12 hours. The maximum daily dose of sulbactam in pediatric patients should not exceed 80 mg/kg body weight/day (160 mg/kg body weight/day of Hepacef Combi). When doses of cefoperazone exceeding 80 mg/kg body weight/day are required, additional cefoperazone should be administered separately (see section "Dosage and Administration").

Route of administration.

Intravenous administration.

For intravenous infusion, the contents of each Hepacef Combi vial should be reconstituted with an appropriate volume of 5% dextrose solution, 0.9% sodium chloride injection solution, or water for injections, then further diluted to 20 ml with the same diluent and administered over 15–60 minutes.

Reconstitution.

Lactated Ringer's solution is an acceptable solvent for intravenous infusion, but not for primary reconstitution (see section "Incompatibility").

For intravenous injection, the contents of each vial should be diluted as described above and administered over at least 3 minutes.

Intramuscular administration.

2% lidocaine hydrochloride solution is an acceptable solvent for preparing a solution for intramuscular injection, but not for primary dilution (see section "Incompatibility").

Hepacef Combi has been found to be compatible with Water for Injections, 5% dextrose solution, 0.9% sodium chloride solution, 5% dextrose in 0.225% sodium chloride solution, and 5% dextrose in 0.9% sodium chloride solution at concentrations ranging from 10 mg cefoperazone and 5 mg sulbactam per 1 mL to 250 mg cefoperazone and 125 mg sulbactam per 1 mL.

Lactated Ringer's solution. Sterile Water for Injections should be used for reconstitution (see section "Incompatibility"). A two-step dilution process using Sterile Water for Injections is required (see table above); the resulting solution should then be further diluted with Lactated Ringer's solution to achieve a sulbactam concentration of 5 mg/mL (add 2 mL or 4 mL of initially diluted solution to 50 mL or 100 mL of Lactated Ringer's solution, respectively).

Lidocaine. Sterile Water for Injections should be used for reconstitution (see section "Incompatibility").

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

Children. The drug is administered to children (see above).

Overdose.

There is insufficient information regarding acute toxicity of sodium cefoperazone and sodium sulbactam in humans. Overdose is expected to produce manifestations that are primarily an extension of the adverse effects reported during drug administration. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may cause neurological reactions, including seizures. Since cefoperazone and sulbactam are removed from circulation by hemodialysis, this procedure may enhance drug elimination in cases of overdose in patients with impaired renal function.

Adverse Reactions

Sulbactam/cefoperazone is generally well tolerated. Most adverse reactions are of mild to moderate severity and have a favorable course during prolonged treatment.

The adverse reactions listed below were observed during administration of sulbactam/cefoperazone. The frequency of adverse reactions is categorized according to the classification of the Council for International Organizations of Medical Sciences (CIOMS III): very common ≥ 1/10 (≥ 10%), common ≥ 1/100 – < 1/10 (≥ 1% – < 10%), uncommon ≥ 1/1000 – < 1/100 (≥ 0.1% – < 1%), frequency not known (cannot be estimated based on available information). All adverse reactions listed below are presented by MedRA system organ class in order of clinical importance.

Blood and lymphatic system disorders:

Very common: neutropenia†, leukopenia†, direct positive Coombs test†, decreased hemoglobin level†, decreased hematocrit level†, thrombocytopenia†.

Common: coagulopathy*, eosinophilia†.

Frequency not known: hypoprothrombinemia.

Immune system disorders:

Frequency not known: anaphylactic shock*§, anaphylactic reaction*§, anaphylactoid reaction§, including shock*, hypersensitivity*§.

Nervous system disorders:

Uncommon: headache.

Vascular disorders:

Frequency not known: hemorrhage (including fatal outcome), vasculitis*, arterial hypotension*.

Gastrointestinal disorders:

Common: diarrhea, nausea, vomiting.

Frequency not known: pseudomembranous colitis*.

Hepatobiliary disorders:

Very common: increased alanine aminotransferase level†, increased aspartate aminotransferase level†, increased alkaline phosphatase level in blood†.

Common: increased blood bilirubin level†.

Frequency not known: jaundice*.

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, urticaria.

Frequency not known: toxic epidermal necrolysis*§, exfoliative dermatitis*§, Stevens-Johnson syndrome, maculopapular rash.

Renal and urinary system disorders:

Frequency not known: hematuria*.

General disorders and administration site conditions:

Uncommon: phlebitis at injection site, pain at injection site, pyrexia, chills.

* Adverse reactions reported during the post-marketing period.

† The frequency calculations for laboratory parameter abnormalities included all available laboratory values, including those from patients with baseline abnormalities. This conservative approach was adopted because baseline data did not allow differentiation between patient subgroups with baseline abnormalities who experienced treatment-related significant changes in laboratory parameters and those who did not.

Changes in parameters such as leukocyte, neutrophil, platelet, hemoglobin, and hematocrit levels were observed only during clinical trials. Increases and decreases in levels were not differentiated.

§ Fatal outcomes have been reported.

Reporting of suspected adverse reactions.

After marketing authorization of a medicinal product, it is very important to report suspected adverse reactions. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions in accordance with national legislative requirements.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, at a temperature not exceeding 25 °C, in a place inaccessible to children.

Incompatibilities.

Aminoglycosides. Solutions of Hepacef Combi and aminoglycosides should not be mixed directly due to physical incompatibility. If combination therapy with Hepacef Combi and aminoglycosides is required, sequential separate intravenous infusions should be administered, using a separate secondary intravenous infusion system. The primary intravenous infusion system must be thoroughly flushed with an approved diluent between infusions of the specified drugs. It is also advisable to maximize the time intervals between administration of Hepacef Combi and aminoglycosides within a 24-hour period.

Lactated Ringer’s solution. Primary dilution with lactated Ringer’s solution is not recommended, as these substances have been shown to be incompatible. However, a two-step dilution process, in which the initial diluent is water for injections, may avoid 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, in which the initial diluent is water for injections, may avoid incompatibility when further diluted with 2% lidocaine hydrochloride solution (see section "Dosage and Administration").

Packaging.

2.0 g of powder in vials, 1 or 10 vials per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.