Cefoperazone combo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFOPERAZONE COMBI

Composition:

Active substances: cefoperazone, sulbactam;

1 vial contains sodium cefoperazone equivalent to cefoperazone 1000 mg, sodium sulbactam equivalent to sulbactam 1000 mg;

Excipients: none.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: white or almost white powder.

Pharmacotherapeutic group. Antibacterials for systemic use.

Beta-lactam antibiotics. Third-generation cephalosporins.

ATC code J01D D62.

Pharmacological properties.

Pharmacodynamics.

Cefoperazone sodium is a semi-synthetic, broad-spectrum, third-generation cephalosporin antibiotic administered exclusively by parenteral route. Sulbactam sodium is a derivative of the basic penicillin nucleus. Cefoperazone acts by inhibiting the biosynthesis of the bacterial cell wall mucopeptide. Sulbactam acts as a beta-lactamase inhibitor, thereby restoring cefoperazone's activity against strains that produce beta-lactamase.

Mechanism of action.

The antibacterial component of the medicinal product Cefoperazone Combi is cefoperazone—a third-generation cephalosporin that acts against susceptible microorganisms during active multiplication by inhibiting the biosynthesis of the cell wall mucopeptide. Sulbactam has no significant intrinsic antibacterial activity, except for activity against Neisseriaceae and Acinetobacter. However, biochemical studies on cell-free bacterial systems have shown that sulbactam is an irreversible inhibitor of the most important beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics.

The potential of sulbactam to prevent the degradation of penicillins and cephalosporins by resistant microorganisms has been confirmed in studies using whole microorganisms and resistant strains, in which sulbactam demonstrated marked synergy with penicillins and cephalosporins. Since sulbactam also binds to certain penicillin-binding proteins, susceptible strains often become more sensitive to the action of Cefoperazone Combi than to cefoperazone alone.

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

Cefoperazone 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 the medicinal product Cefoperazone Combi has been established:

Minimum inhibitory concentrations (MICs) (µg/mL, expressed as cefoperazone concentrations)

Disk diffusion zone diameter (mm, Kirby-Bauer test)

The MIC can be determined by serial dilution of the drug Cefoperazone Combi using agar or broth dilution methods. It is recommended to use a disk diffusion test containing 30 mcg of sulbactam and 75 mcg of cefoperazone. A laboratory report of "susceptible" indicates that therapy with the drug Cefoperazone Combi is likely to be effective against the infecting microorganism, whereas a report of "resistant" indicates that such effective action is unlikely. A report of "intermediate" indicates that the microorganism may be susceptible to Cefoperazone Combi when the drug is administered at higher doses or if the infection occurs in tissues or body fluids where high antibiotic concentrations are achieved.

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

Pharmacokinetics.

Distribution.

Mean maximum concentrations (Cmax) of sulbactam and cefoperazone after intravenous administration of the combination at a dose of 2 g (1 g sulbactam + 1 g cefoperazone) over 5 minutes averaged 130 and 236.8 mcg/mL, respectively. This indicates a larger volume of distribution of sulbactam (Vd = 18.0–27.6 L) compared to cefoperazone (Vd = 10.2–11.3 L).

Mean Cmax values of sulbactam and cefoperazone after intravenous administration of the combination at a dose of 4.5 g (1.5 g sulbactam + 3 g cefoperazone) over 15 minutes were 88.3 mcg/mL and 416.1 mcg/mL, respectively.

After intravenous administration of 1.5 g sulbactam/cefoperazone (500 mg sulbactam + 1 g cefoperazone), Cmax of the combination was 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 combination was administered every 12 hours.

Elimination.

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose are excreted by the kidneys following administration of the combination. Most of the remaining cefoperazone dose is excreted via bile. After administration of the combination, 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 sulbactam/cefoperazone (0.5 g sulbactam and 1 g cefoperazone), Cmax of sulbactam and cefoperazone in plasma were achieved between 15 minutes and 2 hours after administration. Mean plasma Cmax values were 19 and 64.2 mcg/mL for sulbactam and cefoperazone, respectively.

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

Patients with hepatic impairment. See section "Use in specific populations".

Patients with renal impairment.

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

Elderly patients.

The pharmacokinetics of the drug were studied in elderly patients with impaired renal and hepatic function. Both components of the drug, sulbactam and cefoperazone, had 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 demonstrated no significant changes in the pharmacokinetics of the drug components 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 pharmacokinetic interaction between sulbactam and cefoperazone when co-administered in the form of the medicinal product Cefoperazone Combi.

Cefoperazone does not displace bilirubin from binding sites on plasma proteins.

Clinical characteristics.

Indications.

Cefoperazone Combi is indicated for the treatment of infections caused by susceptible microorganisms:

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

Contraindications.

The medicinal product is contraindicated in patients with 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 interaction.

Aminoglycosides. Mixing the medicinal product with aminoglycosides in the same syringe leads to mutual inactivation; if these groups of antibacterial agents need to be administered simultaneously, they should be given at different sites with a 1-hour interval.

The medicinal product increases the risk of nephrotoxicity associated with aminoglycosides and furosemide.

Antibacterial agents with bacteriostatic activity (chloramphenicol, erythromycin, sulfonamides, tetracyclines) reduce the activity of the medicinal product.

Probenecid decreases tubular secretion of sulbactam; this results in increased plasma concentrations and prolonged elimination half-life of the drugs, as well as an increased risk of intoxication.

The medicinal product increases the risk of bleeding when used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs).

Combination therapy. Due to the broad spectrum of activity of the medicinal product, Cefoperazone Combi can be used as monotherapy for adequate treatment of most infections. However, under certain indications, the medicinal product may be prescribed together with other antibiotics. When aminoglycosides are used concomitantly (see section "Administration and dosage"), renal function should be monitored throughout the treatment course (see section "Incompatibility").

Alcohol. Reactions such as facial flushing, sweating, headache, and tachycardia have been reported during alcohol consumption while on cefoperazone therapy 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 when consuming alcoholic beverages during treatment with Cefoperazone Combi. When using artificial nutrition (oral or parenteral), solutions containing ethanol should not be used.

Interaction with substances used in laboratory tests. False-positive glucose reactions in urine may occur when using Benedict's or Fehling's solutions.

Special precautions for use.

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.

Prior to initiating therapy with sulbactam/cefoperazone, the patient’s history should be carefully reviewed for hypersensitivity reactions to cephalosporins, penicillins, or other drugs (see section "Contraindications"). Antibiotics should be administered cautiously to patients with any form of allergic manifestations, 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, airway maintenance including intubation, should be provided (see section "Adverse reactions").

Cases of severe skin reactions, sometimes fatal, including 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 urinary excretion is increased. Even in severe hepatic impairment, therapeutic concentrations of cefoperazone are achieved in bile, while the elimination half-life is prolonged by 2–4 times.

Dosage adjustment may be necessary in cases of severe biliary obstruction, severe liver disease, or concomitant renal impairment associated with these conditions.

In patients with hepatic impairment and concomitant renal dysfunction, serum cefoperazone concentrations should be monitored, and dosage adjusted as needed. If close monitoring of serum concentrations is not feasible, the cefoperazone dose should not exceed 2 g/day.

Use in elderly patients. Prolonged elimination half-life, reduced total clearance, and increased volume of distribution have been observed for both sulbactam and cefoperazone in elderly patients compared to younger individuals. Sulbactam pharmacokinetics are directly correlated with renal function, while cefoperazone pharmacokinetics are closely related to hepatic function.

General warnings. Serious, sometimes fatal, bleeding events have been reported with sulbactam/cefoperazone use. As with other antibiotics, vitamin K deficiency leading to coagulopathy has been observed in patients receiving sulbactam/cefoperazone. This effect is likely due to suppression of intestinal bacterial flora responsible for vitamin K synthesis. Patients at risk include those with poor nutritional intake, malabsorption, or those on prolonged parenteral (intravenous) nutrition. In such patients and in patients receiving oral anticoagulants, prothrombin time (or international normalized ratio) should be monitored to detect potential bleeding or thrombocytopenia, and vitamin K supplementation should be administered if indicated. If prolonged bleeding occurs without other identifiable cause, sulbactam/cefoperazone should be discontinued.

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

Clostridium difficile-associated diarrhea has been reported with 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-toxigenic strains of C. difficile are associated with increased morbidity and mortality, as these infections may be resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in all patients who develop diarrhea during or after 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.

Pediatric use. Cefoperazone 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.

This medicinal product contains sodium; therefore, caution is advised when administering to patients with impaired renal function or to those on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Studies in rats investigating the effect of the drug on reproductive function 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. Because animal reproductive study results are not always predictive of human response, the drug should be used during pregnancy only if clearly needed.

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

Effect on ability to drive and use machines. The effect of the medicinal product on the ability to drive vehicles or operate machinery is unlikely.

Method of administration and dosage.

Cefoperazone Combi (a combination of sulbactam sodium / cefoperazone sodium) is supplied in vials and is administered only by the parenteral route.

Adults. The usual dose of the medicinal product 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 the drug may be increased up to 8 g (i.e., the dose of cefoperazone is 4 g). Cefoperazone Combi is administered intravenously in evenly divided doses every 12 hours. The recommended maximum daily dose of sulbactam is 4 g (8 g of the drug).

Hepatic impairment. See section "Special precautions".

Use in renal impairment. Dosage regimen should be adjusted in patients with significantly impaired renal function (creatinine clearance less than 30 mL/min) to compensate for reduced sulbactam clearance. For patients with creatinine clearance of 15–30 mL/min, the maximum dose of sulbactam should be 1 g administered every 12 hours (maximum daily sulbactam dose—2 g). For patients with creatinine clearance less than 15 mL/min, the maximum dose of sulbactam should be 500 mg administered every 12 hours (maximum daily sulbactam dose—1 g). In severe infections, additional separate administration of cefoperazone may be required.

The pharmacokinetic profile of sulbactam is significantly altered during hemodialysis.

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

Use in elderly patients. See section "Pharmacokinetics".

Use in children. The usual dose of the drug in 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.

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

Use in newborns. In newborns 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 Cefoperazone Combi medicinal product). If it becomes necessary to administer a dose of cefoperazone exceeding 80 mg/kg body weight/day, the additional cefoperazone dose should be given separately (see section "Special instructions").

Route of administration.

Intravenous administration.

For intravenous infusion, the contents of each vial of Cefoperazone Combi should be reconstituted with an appropriate volume of 5% dextrose solution, 0.9% sodium chloride injection solution, or water for injections, then diluted to 20 ml with the same solution 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 "Incompatibilities").

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

Intramuscular administration.

The medicinal product is compatible with the following diluents: 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. Cefoperazone is compatible at concentrations ranging from 10 to 250 mg per 1 mL of diluent. Sulbactam is compatible at concentrations ranging from 5 to 125 mg per 1 mL of diluent.

Lactated Ringer's solution. Sterile water for injections should be used for reconstitution (see section "Incompatibilities"). 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 50 mL or 100 mL of lactated Ringer's solution to 2 mL or 4 mL of initially diluted solution, respectively).

Lidocaine. A 2% lidocaine hydrochloride solution is an acceptable solvent for preparing a solution for intramuscular injection, but not for primary reconstitution. Sterile water for injections should be used for reconstitution (see section "Incompatibilities").

Any unused medicinal product or waste material must be disposed of in accordance with current requirements.

Children. The medicinal product is used in children (see section "Dosage and administration"). However, comprehensive studies on the use of the medicinal product in premature infants or neonates have not been conducted. Therefore, the potential benefits and possible risks of therapy should be carefully evaluated before initiating treatment in premature infants or neonates.

Overdose.

Symptoms. There is insufficient information regarding the acute toxicity of sodium cefoperazone and sodium sulbactam in humans. Overdose of the medicinal product is expected to produce manifestations that are primarily an extension of its known adverse effects. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may cause neurological reactions, including seizures.

Treatment. Since cefoperazone and sulbactam are removed from systemic circulation by hemodialysis, this procedure may enhance drug elimination in cases of overdose in patients with impaired renal function.

Adverse reactions.

The medicinal product is generally well tolerated. Most adverse reactions are of mild to moderate severity and resolve favorably during prolonged treatment.

Listed below are adverse reactions observed during the use of the medicinal product Cefoperazone Combi. The frequency of adverse reactions is defined as: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1000 – < 1/100), rare (≥ 1/10000 – < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

Adverse reactions are listed by organ systems according to MedDRA [Medical Dictionary for Regulatory Activities] in order of clinical importance.

* Adverse reactions reported during the post-marketing period.

† The frequency calculations for adverse reactions such as laboratory test abnormalities included all available laboratory values, including those from patients with baseline abnormalities. This conservative approach was adopted because initial 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 parameters such as white blood cell count, neutrophil count, platelet count, hemoglobin, and hematocrit were observed only during clinical trials. Increases and decreases in levels were not differentiated.

§ Reports of fatal outcomes have been received.

Reporting suspected adverse reactions

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

Shelf life. 2 years (from the date of manufacture of the in bulk form).

Storage conditions.

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

Incompatibilities.

Aminoglycosides. Solutions of the medicinal product Cefoperazone Combi and aminoglycosides should not be mixed directly due to physical incompatibility. If combination therapy with Cefoperazone Combi and aminoglycosides is necessary, sequential separate intravenous infusions should be administered using separate secondary intravenous infusion sets. The primary intravenous infusion line must be thoroughly flushed with an approved solution between infusions of these agents. It is also advisable to maximize the time intervals between administration of Cefoperazone Combi and aminoglycosides within a 24-hour period.

Lactated Ringer’s solution. Primary dilution with lactated Ringer’s solution is not recommended, as incompatibility between these substances has been established. However, a two-step dilution process, in which the initial diluent is water for injections, can avoid incompatibility when further dilution with lactated Ringer’s solution is required (see section “Instructions for use and dosage”).

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, can avoid incompatibility when further dilution with 2% lidocaine hydrochloride solution is performed (see section “Instructions for use and dosage”).

Packaging.

Vial with powder. 1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer. ASTRAFARM LLC (packaging from in bulk form: Hebei Huamin Pharmaceutical Co., Ltd., China).

Manufacturer’s location and address of business operation. 6, Kyivska Street, city of Vyshneve, Bucha district, Kyiv region, 08132, Ukraine.