Hepacef®

INSTRUCTION for medical use of the medicinal product GEPACEF® (GEPACEF)

Composition:

active substance: cefoperazone;

1 vial contains cefoperazone sodium salt equivalent to cefoperazone 1.0 g.

Dosage form. Powder for solution for injection.

Main physico-chemical properties: white powder or white with a yellowish tinge, hygroscopic.

Pharmacotherapeutic group. Third-generation cephalosporins. ATC code J01D D12.

Pharmacological Properties

Pharmacodynamics

The bactericidal action of Hepacef® is due to inhibition of bacterial cell wall synthesis.

Hepacef® is active in vitro against a wide range of clinically significant microorganisms. At the same time, it is resistant to the action of many beta-lactamases.

The following microorganisms are susceptible to Hepacef®:

Gram-positive microorganisms:

Staphylococcus aureus (strains producing and 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), Streptococcus faecalis (enterococcus), beta-hemolytic streptococci.

Gram-negative microorganisms:

Escherichia coli, genus Klebsiella, genus Enterobacter, genus Citrobacter, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri), genus Providencia, genus Serratia (including S. marcescens), genus Salmonella and Shigella, Pseudomonas aeruginosa and some other Pseudomonas, Acinetobacter calcoaceticus, Neisseria gonorrhoeae (strains producing and not producing beta-lactamase), Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.

Anaerobic microorganisms:

Gram-positive and gram-negative cocci (including genus Peptococcus, Peptostreptococcus, and Veillonella);

Gram-positive bacilli (including genus Clostridium, Eubacterium, and Lactobacillus);

Gram-negative bacilli (including genus Fusobacterium, many strains of Bacteroides fragilis, and other representatives of the genus Bacteroides).

Pharmacokinetics

High concentrations in blood, bile, and urine are achieved after single administration of the drug. Table 1 shows the concentrations of the drug in serum of healthy adult volunteers. These data were obtained after 15-minute intravenous administration of 1, 2, 3, or 4 g of the drug or after single intramuscular administration of 1 or 2 g of the drug. Probenecid does not affect the serum concentration levels of cefoperazone.

Average serum concentrations of cefoperazone (µg/mL) Table 1.

• Time elapsed after administration of the drug (counting starts immediately after completion of infusion).

** Results obtained 15 minutes after administration of the drug.

The elimination half-life of Hepacef® from blood serum is approximately 2 hours, regardless of the route of administration.

Hepacef® achieves therapeutic levels in all body fluids and tissues, including ascitic and cerebrospinal fluid (during meningitis), urine, bile and gallbladder wall, sputum and lungs, palatine tonsils and sinus mucosa, atria, kidneys, ureters, prostate, testes, uterus and fallopian tubes, bones, umbilical cord blood, and amniotic fluid.

Hepacef® is excreted via bile and urine. The concentration of the drug in bile reaches very high levels (usually within 1–3 hours after administration) and exceeds serum concentrations by 100-fold.

Biliary concentrations of the drug have been recorded as follows: from 66 mcg/mL at 30 minutes to 6000 mcg/mL at 3 hours after intravenous administration of 2 g of the drug to patients without biliary obstruction.

Twelve hours after administration at various doses and by different routes, the increase in cefoperazone concentration in urine of patients with normal renal function averages 20–30%. A drug concentration exceeding 2200 mcg/mL in urine was achieved 15 minutes after intravenous administration of 2 g of Hepacef®. After intramuscular administration of 2 g of the drug, maximum urinary concentration was approximately 1000 mcg/mL.

Repeated administration of Hepacef® does not lead to drug accumulation in healthy volunteers.

Patients with hepatic impairment

In patients with impaired liver function, the serum half-life of the drug increases, but urinary excretion also increases. In patients with both renal and hepatic insufficiency, Hepacef® may accumulate in blood serum.

Patients with renal impairment

In patients with renal insufficiency, maximum drug concentration in serum, area under the pharmacokinetic curve, and serum half-life are similar to those observed in healthy volunteers.

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to Hepacef®:

• infections of the upper and lower respiratory tract;
• infections of the upper and lower urinary tract;
• 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 tract infections.

Prophylaxis of postoperative complications during abdominal, gynecological, cardiovascular, and orthopedic surgeries.

Contraindications.

Hypersensitivity to cefoperazone or to any of the cephalosporin antibiotics.

Interaction with other medicinal products and other forms of interaction.

Alcohol

Disulfiram-like reactions, characterized by flushing, increased sweating, headache, and tachycardia, have been reported when alcohol is consumed during treatment with Hepacef® and even within 5 days after the last dose of cefoperazone. Similar reactions have also occurred with other cephalosporins; therefore, patients should be warned against consuming alcoholic beverages during cefoperazone therapy. Patients requiring oral or parenteral nutritional support should avoid solutions containing ethanol.

Interactions affecting laboratory test results

A false-positive urine glucose reaction may occur when testing with Benedict's or Fehling's solutions.

Special precautions for use.

Hypersensitivity

Serious hypersensitivity reactions (anaphylactic reactions), sometimes fatal, have been reported in patients receiving beta-lactam agents or cephalosporin drugs, including cefoperazone. These reactions occurred more frequently in patients with a history of hypersensitivity to multiple allergens.

A thorough medical history should be obtained prior to initiating cefoperazone to determine whether the patient has previously experienced hypersensitivity reactions to cephalosporins, penicillins, or other drugs. This drug should be administered with caution to patients with known penicillin sensitivity.

Antibiotics should be used cautiously in patients who have previously experienced any type of allergic reaction, especially drug allergies.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy initiated. Severe anaphylactic reactions require immediate emergency administration of epinephrine. Oxygen, intravenous corticosteroids, and maintenance of airway patency, including intubation if necessary, should be provided as indicated.

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 severe skin reaction occurs, cefoperazone therapy should be discontinued and appropriate treatment initiated (see section "Adverse reactions").

Use in patients with hepatic impairment

Cefoperazone is predominantly excreted in bile. In patients with hepatic disease and/or biliary obstruction, the serum half-life of cefoperazone is prolonged and renal excretion of the drug in urine is increased. Even in cases of severe hepatic dysfunction, therapeutic concentrations of cefoperazone are achieved in bile, and the half-life increases only 2–4 fold.

General warnings

Cases of severe bleeding, including fatal events, have been reported during cefoperazone therapy.

Patients at risk include those with poor nutrition, malabsorption, and those receiving long-term parenteral (intravenous) nutrition. Such patients should be monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. If prolonged bleeding occurs without other identifiable cause, cefoperazone should be discontinued.

As with other antibiotics, prolonged use of cefoperazone may result in overgrowth of resistant microorganisms; therefore, patients should be carefully monitored during therapy. As with any potent systemic agent, periodic laboratory evaluations to assess possible functional disturbances of organs, particularly kidneys, liver, and the hematopoietic system, are recommended during prolonged cefoperazone therapy. Such monitoring is especially important in neonates, including premature and other infants.

Diarrhea associated with Clostridium difficile [Clostridium difficile associated diarrhea] (CDAD), ranging in severity from mild diarrhea to fatal colitis, has been reported with nearly all antibacterial agents, including cefoperazone. 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 CDAD. Strains of C. difficile with hyperproduction of toxins are associated with increased morbidity and mortality, as the infections they cause may be refractory to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients who develop diarrhea following antibiotic use. A careful medical history is essential, as CDAD has been reported to occur more than two months after administration of antibacterial agents.

Patients on a low-sodium diet should be informed that the drug Hepacef® contains 34 mg of sodium.

Use during pregnancy or breastfeeding.

Pregnancy

Reproductive function studies in animals at doses 10 times higher than the human dose revealed no evidence of impaired fertility or teratogenic effects. However, adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproductive studies do not always predict human response, this drug should be used during pregnancy only if clearly needed.

Period of breastfeeding

Only small amounts of cefoperazone are excreted in breast milk. Although cefoperazone poorly penetrates into breast milk, the drug should be administered with caution during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage

The drug is administered intravenously or intramuscularly.

Adults.

The usual adult dose is 2–4 g per day, given every 12 hours in evenly divided doses. In particularly severe infections, the dose may be increased to 8 g per day, administered every 12 hours in evenly divided doses. Administration of Hepacef® at daily doses of 12–16 g, divided into 3 equal doses (with an 8-hour interval), has not been associated with any complications. Treatment with the drug may be initiated before the results of microbial susceptibility testing are available.

The recommended dose for uncomplicated gonococcal urethritis is a single 500 mg dose administered intramuscularly.

Intramuscular injection should be performed deeply into the gluteus maximus muscle or into the anterolateral aspect of the thigh.

Combination therapy.

The broad spectrum of activity of Hepacef® allows monotherapy for most infections. However, the drug may also be used in combination with other antibiotics when indicated. When administered concomitantly with aminoglycosides, renal function should be monitored. Official guidelines for antibiotic use should be taken into account.

Patients with hepatic impairment.

Dose adjustment may be necessary in cases of biliary obstruction, severe liver disease, or concomitant renal impairment. If serum drug concentrations are not monitored, the dose should not exceed 2 g per day.

Patients with renal impairment.

Since the kidneys are not the primary route of elimination for Hepacef®, the usual daily dose (2–4 g) may be administered without dose adjustment in patients with renal impairment. For patients with a glomerular filtration rate below 18 mL/min or serum creatinine levels exceeding 3.5 mg/100 mL, the maximum daily dose is 4 g.

The serum half-life of Hepacef® is slightly reduced during hemodialysis. The drug should be administered after completion of the dialysis procedure.

Patients with hepatic impairment and concomitant renal impairment.

In patients with hepatic impairment and concomitant renal impairment, serum drug concentrations should be monitored and the dose adjusted as necessary. If serum drug concentrations are not monitored, the dose should not exceed 2 g per day.

Children.

For treatment of children, Hepacef® should be administered at daily doses of 50 to 200 mg per kg of body weight, given in 2 doses (every 8–12 hours). The maximum dose should not exceed 12 g per day (see section "Special Warnings and Precautions for Use").

Daily doses up to 300 mg/kg have been used in children with severe infections, including several patients with bacterial meningitis, without causing complications.

Neonates.

In neonates (up to 8 days of age), the drug should be administered every 12 hours.

Intravenous administration in children and adults.

For intermittent intravenous infusion, 1 g of Hepacef® (contents of one vial) should be dissolved in 20–100 mL of a compatible sterile intravenous solution and administered over 15 minutes to 1 hour. If sterile water is used as the solvent, no more than 20 mL should be added to the vial.

For continuous intravenous infusion, 1 g of Hepacef® should be reconstituted either with 5 mL of sterile water for injection or 5 mL of bacteriostatic water for injection; this solution is then added to an appropriate intravenous infusion solution.

For direct intravenous injection, the maximum single dose of Hepacef® is 2 g for adult patients and 50 mg/kg body weight for children. The drug should be dissolved in an appropriate solvent to achieve a final concentration of 100 mg/mL and administered over not less than 3–5 minutes.

For antibacterial prophylaxis of postoperative complications, 1 g or 2 g of the drug is administered intravenously 30–90 minutes before the start of surgery. The dose may be repeated every 12 hours, but in most cases, not for more than 24 hours. In surgeries with a high risk of infection (e.g., colorectal surgery) or when infection may lead to severe complications (e.g., open-heart surgery or joint prosthesis implantation), prophylactic use of the drug may continue for up to 72 hours after surgery.

Intravenous administration.

Sterile Hepacef® powder may first be dissolved using any compatible solvent (at least 2.8 mL per g of cefoperazone) suitable for intravenous administration. To facilitate reconstitution, it is recommended to use 5 mL of solvent per 1 g of Hepacef®.

Solvents recommended for reconstitution of sodium cefoperazone powder: 5% dextrose for injection; 10% dextrose for injection; 5% dextrose and 0.9% sodium chloride for injection; 0.9% sodium chloride for injection; Normosol-M and 5% dextrose for injection; 5% dextrose and 0.2% sodium chloride for injection; Normosol-R; sterile water for injection.

After reconstitution, the resulting solution should be further diluted with one of the standard intravenous solutions: 5% dextrose for injection; 10% dextrose for injection; 5% dextrose and lactated Ringer's solution for injection; lactated Ringer's solution for injection; 0.9% sodium chloride for injection; 5% dextrose and 0.9% sodium chloride; Normosol-M and 5% dextrose for injection; Normosol-R; 5% dextrose and 0.2% sodium chloride for injection.

Intramuscular administration.

For preparing a solution intended for intramuscular injection, sterile or bacteriostatic water for injection may be used. If a solution with a concentration of 250 mg/mL or higher is intended for administration, a lidocaine solution is recommended for reconstitution. Such a solution may be prepared using a combination of sterile water for injection and 2% lidocaine hydrochloride solution, resulting in a final concentration approximately equivalent to 0.5% lidocaine hydrochloride.

A two-step reconstitution method is recommended: first, add the required amount of sterile water for injection and shake until the Hepacef® powder is completely dissolved; then, add the required amount of 2% lidocaine hydrochloride solution and mix.

Table 2

* The available excess allows for the withdrawal and administration of the specified volumes.

Intramuscular administration should be performed deeply into the gluteus maximus muscle or into the anterolateral aspect of the thigh.

Storage of solutions

Stability

Chemical and physical stability of cefoperazone solutions prepared using the parenteral diluents listed below with the indicated approximate cefoperazone concentrations ensures solution stability provided the specified storage temperatures and durations are maintained. After the specified period, any unused solution must be discarded.

Solutions of cefoperazone may be stored at stable room temperature (15–25°C) for 24 hours in the following diluents (approximate cefoperazone concentrations in parentheses): bacteriostatic water for injection (300 mg/mL); 5% dextrose for injection (2 mg to 50 mg/mL); 5% dextrose and lactated Ringer’s injection (2 mg to 50 mg/mL); 5% dextrose and 0.9% sodium chloride for injection (2 mg to 50 mg/mL); 5% dextrose and 0.2% sodium chloride for injection (2 mg to 50 mg/mL); 10% dextrose for injection (2 mg to 50 mg/mL); lactated Ringer’s injection (2 mg/mL); 0.5% lidocaine hydrochloride for injection (300 mg/mL); 0.9% sodium chloride for injection (2 mg to 300 mg/mL); Normosol-M and 5% dextrose for injection (2 mg to 50 mg/mL); Normosol-R (2 mg to 50 mg/mL); sterile water for injection (300 mg/mL). Reconstituted solutions of Hepacef® may be stored in glass or plastic syringes, glass or flexible plastic containers intended for parenteral solutions.

For 5 days in the refrigerator (2–8°C), reconstituted solutions of Hepacef® may be stored in the following diluents (approximate cefoperazone concentrations in parentheses): bacteriostatic water for injection (300 mg/mL); 5% dextrose for injection (2 mg to 50 mg/mL); 5% dextrose and 0.9% sodium chloride for injection (2 mg to 50 mg/mL); 5% dextrose and 0.2% sodium chloride for injection (2 mg to 50 mg/mL); lactated Ringer’s injection (2 mg/mL); 0.5% lidocaine hydrochloride for injection (300 mg/mL); 0.9% sodium chloride for injection (2 mg to 300 mg/mL); Normosol-M and 5% dextrose for injection (2 mg to 50 mg/mL); Normosol-R (2 mg to 50 mg/mL); sterile water for injection (300 mg/mL) in glass or plastic syringes, glass or flexible plastic containers intended for parenteral solutions.

Cefoperazone solutions in the following diluents (approximate cefoperazone concentrations in parentheses) may be stored in the freezer (from -20 to -10°C) for 3 weeks: 5% dextrose for injection (50 mg/mL); 5% dextrose and 0.9% sodium chloride for injection (2 mg/mL); 5% dextrose and 0.2% sodium chloride for injection (2 mg/mL), or for 5 weeks: 0.9% sodium chloride for injection (300 mg/mL); sterile water for injection (300 mg/mL). Reconstituted solutions may be stored in plastic syringes or flexible plastic containers intended for parenteral solutions.

The product must be thawed at room temperature prior to administration. After thawing, any unused solution must be discarded. The solution must not be refrozen.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage time and conditions prior to use are the responsibility of the user and generally should not exceed 24 hours at 2–8°C, unless reconstitution/dilution has been carried out under controlled and validated aseptic conditions.

Children.

See section "Dosage and administration".

Cefoperazone has been effectively used in children from birth. Extensive studies involving premature infants and neonates have not been conducted. Therefore, the potential benefits and possible risks of therapy with this drug should be carefully weighed before prescribing cefoperazone to premature infants and neonates.

In neonates with kernicterus, cefoperazone does not displace bilirubin from its plasma protein binding sites.

Overdose.

Data on acute toxicity of sodium cefoperazone are limited. The expected manifestations of overdose are primarily an intensification of adverse reactions typical of the drug. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may cause neurological effects and seizures. Since cefoperazone is removed by hemodialysis, this procedure may accelerate drug elimination if overdose occurs in patients with impaired renal function.

Adverse reactions.

The adverse reactions listed below have been identified and reported during cefoperazone therapy. The frequency of adverse reactions is defined according to the classification of the Council for International Organizations of Medical Sciences (CIOMS III): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: very common – decreased hemoglobin level, decreased hematocrit level; common – neutropenia, positive direct Coombs test, thrombocytopenia, eosinophilia; frequency not known – hypoprothrombinemia; coagulopathy.

Immune system disorders: frequency not known – anaphylactic shock, anaphylactic reaction, anaphylactoid reaction (including shock), hypersensitivity.

Vascular disorders: common – phlebitis at the catheter site; rare – hemorrhage.

Gastrointestinal disorders: common – diarrhea; uncommon – vomiting; frequency not known – pseudomembranous colitis.

Hepatobiliary disorders: common – increased levels of ALT, AST, increased blood alkaline phosphatase levels, jaundice.

Skin and subcutaneous tissue disorders: common – pruritus, urticaria, maculopapular rash; frequency not known – toxic epidermal necrolysis, Stevens–Johnson syndrome, exfoliative dermatitis.

Renal and urinary disorders:
frequency not known: hematuria.

General disorders and administration site conditions: uncommon – pain at injection site, fever.

Reporting of suspected adverse reactions.

It is important to report suspected adverse reactions after the medicinal product has been authorized. This enables continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature of 2 to 8 °C.

Keep out of the reach of children.

Incompatibilities.

Solutions of Hepacef® and aminoglycosides should not be mixed due to physical incompatibility. If combination therapy with Hepacef® and an aminoglycoside is intended, it can be administered by alternating intravenous infusions, provided that a separate secondary intravenous administration system is used and the primary intravenous administration system is flushed with an appropriate solution between infusions. It is recommended to administer Hepacef® before aminoglycosides.

Packaging.

1.0 g in vials, 10 vials per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.
139 Saksaganskogo St., Kyiv, 01032, Ukraine.