Foceraz - 1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOCERAZ – 1000 (FOCERAZ – 1000)

Composition:

Active substance: cefoperazone;

1 vial contains sodium cefoperazone equivalent to cefoperazone 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder ranging from white to light yellow.

Pharmacotherapeutic group.

Antibacterial agent for systemic use. Third-generation cephalosporins.

ATC code J01D D12.

Pharmacological properties.

Pharmacodynamics.

The bactericidal activity of the drug is due to inhibition of bacterial cell wall synthesis.

Cefoperazone is in vitro active against a wide range of clinically significant microorganisms. At the same time, it is resistant to degradation by many β-lactamases.

The following microorganisms are susceptible to the drug.

Gram-positive microorganisms:

Staphylococcus aureus (strains producing and non-producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae (former name: Diplococcus pneumoniae), Streptococcus pyogenes (β-hemolytic streptococci group A), Streptococcus agalactiae (β-hemolytic streptococci group B), Streptococcus faecalis (enterococcus), β-hemolytic streptococci.

Gram-negative microorganisms:

Escherichia coli, genus Klebsiella, genus Enterobacter, genus Citrobacter, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (previously Proteus morganii), Providencia rettgeri (previously Proteus rettgeri), genus Providencia, genus Serratia (including S. marcescens), genus Salmonella and Shigella, Pseudomonas aeruginosa and some other Pseudomonas species, Acinetobacter calcoaceticus, Neisseria gonorrhoeae (strains producing and non-producing β-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 members of the genus Bacteroides).

Pharmacokinetics.

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

Table 1

Mean serum concentrations of cefoperazone (μg/mL)

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

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

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

Foceraz–1000 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.

Foceraz–1000 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 up to 100-fold.

Bile concentrations 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 in 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 the drug. After intramuscular administration of 2 g of the drug, the maximum concentration in urine was approximately 1000 mcg/mL.

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

Patients with impaired liver function

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

Patients with impaired renal function

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

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to Foceraz–1000:

• infections of upper and lower respiratory tract;
• infections of 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 pelvic organs, endometritis, gonorrhea, and other genital tract infections.

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

Contraindications.

Hypersensitivity to cefoperazone or to any cephalosporin antibiotic.

Interaction with other medicinal products and other forms of interaction.

Aminoglycosides

Mixing the drug with aminoglycosides in the same syringe leads to mutual inactivation; if these groups of antibacterial agents need to be administered simultaneously, they should be injected at different sites with a 1-hour interval. The drug increases the risk of nephrotoxicity associated with aminoglycosides and furosemide.

Bacteriostatic agents (chloramphenicol, erythromycin, sulfonamides, tetracyclines) reduce the activity of the drug.

Alcohol

Disulfiram-like reactions, characterized by flushing, increased sweating, headache, and tachycardia, have been reported when alcohol is consumed during treatment with the drug 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 artificial nutrition should avoid solutions containing ethanol.

Combination therapy

Due to the broad spectrum of antibacterial activity of cefoperazone, most infections can be adequately treated with this antibiotic as monotherapy. However, under certain indications, cefoperazone may be used in combination with other antibiotics. If aminoglycosides are used concomitantly, renal function should be monitored throughout the course of therapy (see also section "Incompatibilities").

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

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

A careful medical history should be obtained prior to initiating cefoperazone therapy 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 a known penicillin sensitivity. Antibiotics should be used cautiously in any patient with a history of any type of allergy, 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 adrenaline (epinephrine). Oxygen, intravenous corticosteroids, and airway maintenance, including intubation if necessary, should be provided as indicated.

Cases of severe skin reactions, sometimes fatal, including 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 increases. Even in cases of severe hepatic dysfunction, therapeutic concentrations of cefoperazone are achieved in bile, and the half-life increases only 2–4 times.

General warnings

As with other antibiotics, treatment with cefoperazone may lead to vitamin K deficiency in some patients. The mechanism is likely related to suppression of normal gut flora that normally synthesizes this vitamin. Thus, at-risk patients include those with poor nutrition, malabsorption (e.g., due to biliary fibrosis), and those receiving long-term parenteral (intravenous) nutrition. Prothrombin time should be monitored in such patients. Similarly, monitoring is recommended in patients receiving anticoagulant therapy. In these cases, supplementation with exogenous vitamin K should be considered.

Cases of serious bleeding, including fatal events, have been reported during cefoperazone therapy. At-risk patients include those with poor nutrition, malabsorption, and those on long-term parenteral (intravenous) nutrition. Such patients should be closely monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. If prolonged bleeding occurs without other identifiable causes, cefoperazone should be discontinued.

As with other antibiotics, prolonged use of cefoperazone may result in overgrowth of resistant microorganisms; therefore, patients should be carefully observed during treatment. As with any potent systemic agent, periodic monitoring is recommended during prolonged cefoperazone therapy to detect possible organ system dysfunction, particularly of the kidneys, liver, and hematopoietic system. Such monitoring is especially important in newborns, particularly preterm infants, 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 the use of nearly all antibacterial agents, including cefoperazone. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hyperproducing toxin strains of C. difficile 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. Careful medical history is essential, as CDAD has been reported to occur more than 2 months after administration of antibacterial agents.

Appropriate therapy should be initiated if superinfection occurs.

Use in the elderly. Prolongation of half-life, reduced total clearance, and increased volume of distribution have been observed with cefoperazone use compared to data in younger volunteers. The pharmacokinetics of cefoperazone correlate well with hepatic dysfunction.

Use in pediatric patients. Studies in the pediatric population have not revealed any differences in pharmacokinetics of the drug components compared to adults, and no significant differences have been observed.

Patients on a low-sodium diet should be advised that Foceraz – 1000 contains 34 mg of sodium (1.5 mmol).

Use during pregnancy or breastfeeding.

Pregnancy

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

Breastfeeding

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

Ability to influence reaction rate 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.

Method of 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 the drug at a daily dose of 12–16 g, divided into 3 equal doses (with an 8-hour interval), has not revealed 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 intramuscular dose of 500 mg.

Intramuscular administration should be performed deeply into the gluteal muscle or the anterior thigh.

Combination Therapy.

The broad spectrum of activity of the drug allows monotherapy for most infections. However, Foceraz–1000 may also be used as part of combination therapy with other antibiotics when indicated. When treating concomitantly with aminoglycosides, renal function should be monitored. Official recommendations regarding antibiotic use should be taken into account.

Use in Patients with Hepatic Impairment.

Dosage 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.

Use in Patients with Renal Impairment.

Since the kidneys are not the primary route of elimination for Foceraz–1000, patients with renal impairment may receive the usual daily dose (2–4 g) without dosage adjustment. 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 elimination half-life of the drug from plasma is slightly reduced during hemodialysis. The drug should be administered after completion of the dialysis procedure.

Use in 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, the drug 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").

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

Use in Neonates.

Neonates (up to 8 days of age) should receive the drug every 12 hours.

Intravenous Administration in Children and Adults.

For intermittent intravenous infusion, 1 g of the drug (contents of 1 vial) should be dissolved in 20–100 mL of a compatible sterile intravenous solution and infused 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 the drug should be reconstituted with either 5 mL of sterile water for injection or 5 mL of bacteriostatic water for injection, and then added to an appropriate intravenous solution.

For direct intravenous injection, the maximum single dose 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 powder Foceraz–1000 may first be dissolved using any compatible solvent (at least 2.8 mL/g of cefoperazone), suitable for intravenous administration. To facilitate reconstitution, it is recommended to use 5 mL of solvent per 1 g of the drug.

Solutions 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 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 preparation of a solution intended for intramuscular administration, 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 concentration close 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 powder is completely dissolved; then add the required amount of 2% lidocaine hydrochloride solution and mix.

Table 2

* The available excess allows for selecting and administering the specified volumes.

Intramuscular administration must be performed deeply into the gluteus maximus muscle or into the anterior 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 storage period, any unused solution must be discarded.

At stable room temperature (15–25 °C) for up to 24 hours, cefoperazone solutions may be stored in the following diluents (approximate cefoperazone concentrations are indicated 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 with 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 may be stored in glass or plastic syringes, or in glass or flexible plastic containers intended for parenteral solutions.

For up to 5 days in the refrigerator (2–8 °C), the following diluents (approximate cefoperazone concentrations in parentheses) are suitable: 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 with 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 may be stored in glass or plastic syringes, or in 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 up to 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 up to 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 should 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 duration and conditions prior to use are the responsibility of the user and, under normal circumstances, 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. However, extensive studies in 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 lead to neurological effects and seizures. Since cefoperazone is removed by hemodialysis, this procedure may accelerate drug elimination in cases of overdose in patients with impaired renal function.

Adverse reactions.

Listed below are adverse reactions that have been identified and reported during cefoperazone therapy. The frequency of adverse reactions is specified according to the classification of the Council for International Organizations of Medical Sciences (CIOMS III): very common: ≥ 1/10 (≥ 10%); common: ≥ 1/100 to < 1/10 (≥ 1% – < 10%); uncommon: ≥ 1/1000 to < 1/100 (≥ 0.1% – < 1%); rare: ≥ 1/10000 to < 1/1000 (≥ 0.01% – < 0.1%); frequency not known (frequency cannot be estimated from the available data).

Frequency of adverse reactions according to the classification of the Council for International Organizations of Medical Sciences (CIOMS III): very common: ≥ 1/10 (≥ 10%), common: ≥ 1/100 to < 1/10 (≥ 1% to < 10%), uncommon: ≥ 1/1,000 to < 1/100 (≥ 0.1% to < 1%), frequency not known: cannot be estimated from available data.

* 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 abnormal baseline values. 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.

Abnormalities in leukocyte, neutrophil, platelet, hemoglobin, and hematocrit levels were observed only during clinical studies. Increases and decreases in levels were not differentiated.

§ Reports of fatal outcomes have been received.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Incompatibility.

Solutions of this medicinal product and aminoglycosides should not be mixed due to physical incompatibility. If combined therapy with this medicinal product 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 line is flushed with an appropriate solution between infusions. It is recommended to administer Foceraz–1000 before aminoglycosides.

Packaging.

1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and location of operations.

VI/51B, Post Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.