Hepacef Combi powder for solution for injection 1 g + 1 g vial No. 1

Instructions for Gepacef Combi powder for solution for injection 1 g + 1 g vial No. 1

Composition

active ingredients: cefoperazone, sulbactam;

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

Dosage form

Powder for solution for injection.

Main physicochemical properties: white or almost white powder.

Pharmacotherapeutic group

Antibacterials for systemic use. Beta-lactam antibiotics. Third-generation cephalosporins. ATX code J01D D62.

Pharmacological properties

Pharmacodynamics

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

Sulbactam sodium is a derivative of the main penicillin nucleus. It is an irreversible beta-lactamase inhibitor and is used only parenterally. According to its chemical structure, it is sodium sulfone penicillinate. Contains 92 mg of sodium (4 mEq) per 1 gram. Sulbactam is a very easily soluble in water crystalline powder of almost white color. The molecular weight is 255.22.

Cefoperazone sodium is a semi-synthetic cephalosporin antibiotic of the third generation with a broad spectrum of action, used only parenterally. Contains 34 mg of sodium (1.5 mEq) per 1 gram. Cefoperazone is a white crystalline powder, easily soluble in water. The molecular weight is 667.65.

Mechanism of action

The antibacterial component of the drug Gepacef Combi is cefoperazone - a cephalosporin of the third generation, which acts against sensitive microorganisms in the stage of active multiplication by inhibiting the biosynthesis of cell wall mucopeptide. Sulbactam does not have pronounced antibacterial activity, with the exception of 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 organisms has been demonstrated in whole-organism studies using resistant strains, in which sulbactam demonstrated marked synergism with penicillins and cephalosporins. Since sulbactam also binds to some penicillin-binding proteins, susceptible strains are often more susceptible to Gepacef Combi than to cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all microorganisms sensitive to cefoperazone. In addition, synergism of action (a decrease in the minimum concentrations of the combination that inhibit microorganisms by approximately 4 times compared to such concentrations for each component separately) is observed against various microorganisms with the most pronounced effect against the following microorganisms: Haemophilus influenzae, Bacteroides species, Staphylococcus species, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Hepacef Combi exhibits in vitro activity against a wide range of clinically significant microorganisms.

Gram-positive microorganisms:

Staphylococcus aureus (penicillinase-producing and -non-penicillinase-producing strains); Staphylococcus epidermidis; Streptococcus pneumoniae (previously known as Diplococcus pneumoniae); Streptococcus pyogenes (group A beta-hemolytic streptococci); Streptococcus agalactiae (group B beta-hemolytic streptococci); most other strains of beta-hemolytic streptococci; many strains of Streptococcus faecalis (enterococcus).

Gram-negative microorganisms:

Escherichia coli; Klebsiella species; Enterobacter species; Citrobacter species; Haemophilus influenzae; Proteus vulgaris; Morganella morganii (previous name Proteus morganii) Providencia rettgeri (previous name Proteus rettgeri); Providencia species; Serratia species (including S. marcescens); Salmonella and Shigella species; 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 the drug Gepacef Combi has been established.

Minimum inhibitory concentrations (MICs) (µg/ml as cefoperazone concentrations):

Dimensions of the sensitive zone disk (mm, Kirby-Bauer test):

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

Pharmacokinetics

Distribution

The mean peak concentrations of sulbactam and cefoperazone after intravenous administration over 5 minutes of a single dose of 2 g (in a 1:1 ratio) of Gepacef Combi (1 g sulbactam + 1 g cefoperazone) in healthy volunteers were 130 and 236.8 μg/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).

The mean maximum concentrations of sulbactam and cefoperazone after intravenous administration over 15 minutes of a single dose of 4.5 g (in a ratio of 1:2) of the drug Gepacef Combi (1.5 g sulbactam + 3 g cefoperazone) in healthy volunteers were 88.3 μg/ml and 416.1 μg/ml, respectively.

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

Breeding

When using the drug Gepacef Combi, approximately 84% of the dose of sulbactam and 25% of the dose of cefoperazone are excreted by the kidneys. Most of the remaining dose of cefoperazone is excreted in the bile. After administration of the drug Gepacef Combi, the mean 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 results of pharmacokinetic studies of these components when they are used separately.

After intramuscular administration of 1.5 g of Gepacef Combi (0.5 g of sulbactam and 1 g of cefoperazone), maximum plasma concentrations of sulbactam and cefoperazone were reached within 15 minutes to 2 hours after administration. The mean maximum plasma concentrations were 19 and 64.2 μg/ml for sulbactam and cefoperazone, respectively.

After multiple administration of the drug, no significant changes in the pharmacokinetics of the components of the drug Gepacef Combi were reported, and their cumulation was not observed when administered every 8–12 hours.

Patients with liver dysfunction

See the section "Application features".

Patients with renal impairment

In patients with varying degrees of renal impairment administered Gepacef Combi, the total body clearance of sulbactam was significantly correlated with the determined creatinine clearance. In patients with renal insufficiency, the half-life of sulbactam was significantly longer (on average 6.9 and 9.7 hours according to different studies). The use of hemodialysis significantly changes the half-life, total body 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 Gepacef Combi have been studied in elderly patients with renal and hepatic impairment. Both components of the drug, sulbactam and cefoperazone, had a longer half-life, lower clearance and a larger volume of distribution compared with the corresponding values in healthy volunteers. The pharmacokinetic data for sulbactam correlate well with the degree of renal impairment, while the data for cefoperazone correlate well with the degree of hepatic impairment.

Children

Studies conducted in children have shown no significant changes in the pharmacokinetics of the components of Gepacef Combi compared to adult patients. In children, the mean 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 in various tissues and fluids of the body, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, etc.

There is no evidence of any pharmacokinetic interaction between sulbactam and cefoperazone when they are used together in the form of the drug Gepacef Combi.

Cefoperazone does not displace bilirubin from plasma protein binding sites.

Indication

The drug is used to treat infections caused by sensitive strains of microorganisms:

respiratory tract infections (upper and lower); urinary tract infections (upper and lower); peritonitis, cholecystitis, cholangitis and other abdominal infections; septicemia; meningitis; skin and soft tissue infections; pelvic inflammatory disease, endometritis, gonorrhea and other genital infections.

Contraindication

Hepacef Combi is contraindicated in patients with known hypersensitivity to penicillins, sulbactam, cefoperazone, or any cephalosporin.

Interaction with other medicinal products and other types of interactions

Combination therapy. Given the broad spectrum of activity of sulbactam/cefoperazone, Gepacef Combi can be used as monotherapy for adequate treatment of most infections. However, for certain indications, Gepacef Combi can be used together with other antibiotics. When using aminoglycosides simultaneously, renal function should be monitored throughout the course of therapy (see sections “Method of administration and dosage” and “Incompatibility”).

Alcohol. When drinking alcohol during the course of treatment and within 5 days after the use of cefoperazone, reactions such as facial flushing, sweating, headache, tachycardia were noted. Similar reactions were observed with the use of some other cephalosporins. Patients should be warned about possible adverse reactions that occur when drinking alcoholic beverages during the use of the drug. Patients requiring artificial nutrition (oral or parenteral) should not be administered solutions containing ethanol.

Interaction with substances used in laboratory tests. When using Benedict's or Fehling's solution, a false-positive reaction to glucose in the urine may occur. Aksaganskogo, 139.

Application features

Hypersensitivity: Severe and sometimes fatal hypersensitivity reactions (anaphylactic reactions) have been reported in patients receiving beta-lactam or cephalosporin antibiotics, including sulbactam/cefoperazone. These reactions are more likely to occur in individuals with a history of hypersensitivity reactions to multiple allergens.

If allergic reactions develop, the drug should be discontinued and appropriate treatment should be initiated. Severe anaphylactic reactions require immediate administration of epinephrine. If necessary, oxygen therapy, intravenous steroids, and airway management, including intubation, should be considered (see Adverse Reactions).

Severe skin reactions, sometimes fatal, such as toxic epidermal necrolysis, Stevens-Johnson syndrome and exfoliative dermatitis, have been reported in patients receiving sulbactam/cefoperazone. If a severe skin reaction occurs, sulbactam/cefoperazone should be discontinued and appropriate treatment initiated (see section 4.8).

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

Dose adjustment may be necessary in cases of severe biliary obstruction, severe liver disease, or renal dysfunction associated with any of these conditions.

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

General Warnings: Serious bleeding, including fatal cases, has been reported with cefoperazone/sulbactam. Patients at risk include those with restricted nutrition, malabsorption, and those receiving prolonged parenteral nutrition. Such patients should be monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. If persistent bleeding occurs without other causes being identified, cefoperazone/sulbactam should be discontinued.

As with other antibiotics, prolonged use of Gepacef Combi may lead to increased growth of insensitive microflora. During treatment, patients should be carefully monitored. As with other potent systemic agents, with prolonged use of the drug, it is recommended to periodically monitor for signs of organ system dysfunction, including renal, hepatic, and hematopoietic dysfunction, especially in premature infants and other infants.

C. difficile produces toxins A and B, which contribute to the development of C. difficile-associated diarrhea. Hypertoxin-producing strains of C. difficile increase morbidity and mortality because such infections may be resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in all patients with diarrhea associated with antibacterial therapy. A careful history is necessary, as C. difficile-associated diarrhea has been reported to develop 2 months after completion of antibacterial therapy.

Children

Gepacef Combi has been used effectively in infants, but comprehensive studies of the drug in premature or full-term newborns have not been conducted. Therefore, before starting treatment in premature or full-term newborns, the potential benefits and risks of using the drug should be carefully evaluated.

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

1 bottle of Gepacef Combi contains 0.063 g of sodium. This information should be taken into account when using the drug in patients with impaired renal function or patients on a controlled sodium diet.

Ability to influence reaction speed when driving vehicles or other mechanisms

Clinical experience with sulbactam/cefoperazone suggests that the drug is unlikely to affect the patient's ability to drive or use machines.

Use during pregnancy or breastfeeding

Pregnancy. Studies of the drug's effects on reproductive function, conducted in rats at doses 10 times the human dose, did not reveal evidence of impaired fertility or teratogenic effects. Sulbactam and cefoperazone cross the placental barrier, but there are no comprehensive and well-controlled studies in pregnant women. Since the results of studies of the drug's effects on reproductive function in animals will not always be the same when used in humans, Gepacef Comfy should be used during pregnancy only if there are clear indications.

Breastfeeding. Only a small portion of the administered dose of sulbactam and cefoperazone passes into breast milk. Gepacef Combi should be administered with caution to women who are breastfeeding, despite the fact that both components of the drug pass into breast milk in small amounts.

Method of administration and doses

Hepacef Combi (sulbactam sodium/cefoperazone sodium combination) is available in vials and is used parenterally only.

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

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

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

Hepatic impairment. See section "Special warnings and precautions for use".

Renal impairment. The dosage regimen for Gepacef Combi should be adjusted for patients with significantly reduced renal function (creatinine clearance less than 30 ml/min) to compensate for the reduced clearance of sulbactam. Patients with creatinine clearance 15–30 ml/min should be given sulbactam in a dose not exceeding 1 g, which should be administered every 12 hours (maximum daily dose of sulbactam is 2 g), and patients with creatinine clearance less than 15 ml/min should be given sulbactam in a dose not exceeding 500 mg, which should be administered every 12 hours (maximum daily dose of sulbactam is 1 g). In severe infections, additional use of cefoperazone alone may be necessary.

The pharmacokinetic profile of sulbactam is significantly altered during hemodialysis.

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

Elderly patients: See Pharmacokinetics section.

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

Neonates. Neonates of the 1st week of life should be given the drug every 12 hours. The maximum daily dose of sulbactam for children should not exceed 80 mg/kg body weight/day (160 mg/kg body weight/day of the drug Gepacef Combi). In cases where a dose of cefoperazone exceeding 80 mg/kg body weight/day is necessary, an additional dose of cefoperazone should be administered separately (see section "Special instructions").

Method of application

Intravenous administration

For drip infusion, the contents of each vial of Gepacef Combi should be reconstituted in an appropriate amount of 5% aqueous dextrose solution, 0.9% sodium chloride solution for injection, or water for injection, and then diluted to 20 ml with the same solution, followed by administration over 15–60 minutes.

Restoration

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

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

Intramuscular injection

2% lidocaine hydrochloride solution is an acceptable solvent for the preparation of a solution for intramuscular administration, but not for initial dilution (see section "Incompatibilities").

Gepacef Combi has been shown to be compatible with water for injection, 5% dextrose solution, 0.9% sodium chloride solution, 5% dextrose solution 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 mL to 250 mg cefoperazone and 125 mg sulbactam per mL.

Lactated Ringer's solution. Sterile water for injections should be used for reconstitution (see section "Incompatibilities"). A two-step dilution using sterile water for injections is required (see table above); the resulting solution should then be diluted with lactated Ringer's solution to obtain a sulbactam concentration of 5 mg/ml (50 ml or 100 ml of lactated Ringer's solution should be added to 2 ml or 4 ml of the initially diluted solution, respectively).

Lidocaine: Sterile water for injections should be used for reconstitution (see section "Incompatibilities").

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

Children

The drug is used in children (see above).

Overdose

Information on the acute toxicity of cefoperazone sodium and sulbactam sodium in humans is limited. Overdosage is expected to produce effects that are primarily an increase in the adverse effects reported with the drug. It should be noted that high concentrations of beta-lactam antibiotics in the cerebrospinal fluid may cause neurological reactions, including convulsions. Since cefoperazone and sulbactam are removed from the circulation by hemodialysis, this procedure may enhance the elimination of the drug in patients with renal impairment in case of overdose.

Adverse reactions

Sulbactam/cefoperazone is generally well tolerated. Most adverse reactions are mild to moderate in severity and have a favorable course with long-term treatment.

The following adverse reactions have been observed with sulbactam/cefoperazone. The frequency of adverse reactions is listed according to the classification of the Council of International Organizations for 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 unknown (cannot be estimated from the available information).

From the blood and lymphatic system:

Very common: neutropenia, leukopenia, direct positive Coombs test, decreased haemoglobin, decreased haematocrit, thrombocytopenia.

Common: coagulopathy, eosinophilia.

Frequency unknown: hypoprothrombinemia.

On the part of the immune system:

Frequency unknown: anaphylactic shock, anaphylactic reaction, anaphylactoid reaction (including shock), hypersensitivity.

From the nervous system:

Uncommon: headache.

From the vascular system:

Frequency unknown: hemorrhage (including fatal outcome), vasculitis, hypotension.

From the gastrointestinal tract:

Common: diarrhea, nausea, vomiting.

Frequency unknown: pseudomembranous colitis.

From the hepatobiliary system:

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

Common: increased bilirubin levels in the blood.

Frequency unknown: jaundice.

Skin and subcutaneous tissue disorders:

Uncommon: itching, urticaria.

Frequency unknown: toxic epidermal necrolysis, exfoliative dermatitis, Stevens-Johnson syndrome, maculopapular rash.

From the kidneys and urinary system:

Frequency unknown: hematuria.

General condition and disorders related to the method of administration of the drug:

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

Expiration date

2 years.

Storage conditions

Store in the original packaging, at a temperature not exceeding 25 °C, out of the reach of children.

Incompatibility

Aminoglycosides. Solutions of Gepacef Combi and aminoglycosides should not be directly mixed, as there is a physical incompatibility between them. If there is a need for combined therapy with Gepacef Combi and aminoglycosides, their sequential separate drip infusion should be used, using a separate secondary intravenous infusion system, while the primary intravenous infusion system should be thoroughly flushed with an approved solution between infusions of the specified drugs. It is also advisable that the intervals between the administration of the drug and aminoglycosides during the day should be as long as possible.

Lactated Ringer's Solution: Initial dilution with lactated Ringer's Solution is not recommended as these substances have been shown to be incompatible. However, the use of a two-step dilution process, in which the primary solvent is water for injections, allows the avoidance of incompatibility upon further dilution with lactated Ringer's Solution (see section 4.2).

Lidocaine: Initial dilution with 2% lidocaine solution is not recommended as these substances are incompatible. However, the use of a two-step dilution process, in which the primary solvent is water for injections, allows to avoid incompatibility upon further dilution with 2% lidocaine chloride solution (see section "Method of administration and dosage").

Packaging

2.0 g of powder in vials, 1 vial in a pack.

Vacation category

According to the recipe.

Producer

PJSC "Kyivmedpreparat".

Location of the manufacturer and its business address

Ukraine, 01032, Kyiv, Saksaganskoho St., 139.