Cefoperazone/sulbactam

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Cefoperazone/Sulbactam

Composition:

Active substances: cefoperazone, sulbactam;

One vial contains: sodium cefoperazone equivalent to cefoperazone 500 mg, sodium sulbactam equivalent to sulbactam 500 mg, or

One vial contains: sodium cefoperazone equivalent to cefoperazone 1000 mg, sodium sulbactam equivalent to sulbactam 1000 mg.

Pharmaceutical form. Powder for preparation of solution for injection.

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

Pharmacotherapeutic group. Antibacterial agents 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 only by the 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 is cefoperazone—a third-generation cephalosporin that acts against susceptible microorganisms during the phase of 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 key 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 intact microorganisms and resistant strains, during which sulbactam demonstrated pronounced synergy with penicillins and cephalosporins. Since sulbactam also binds to certain penicillin-binding proteins, susceptible strains often become more vulnerable to the action of the medicinal product Cefoperazone/Sulbactam than to cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all microorganisms sensitive to cefoperazone. In addition, synergistic action is observed (reduction of inhibitory minimum concentrations of the combination by approximately 4-fold compared to each component alone) with the most pronounced effect 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/Sulbactam 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 species of Peptococcus, Peptostreptococcus, and Veillonella);
• Gram-positive bacilli (including species of Clostridium, Eubacterium, and Lactobacillus).

The following range of sensitivity to the drug Cefoperazone/Sulbactam has been established.

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

Disk diffusion method zone diameters (mm, Kirby-Bauer test):

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

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

Pharmacokinetics.

Distribution.

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

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

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

Elimination.

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose are excreted by the kidneys after administration of the drug. Most of the remaining cefoperazone dose is excreted via bile. After administration of the drug, 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 correspond to previously published results from pharmacokinetic studies of these components when administered separately.

After intramuscular administration of 1.5 g of the drug (0.5 g sulbactam and 1 g cefoperazone), peak plasma concentrations of sulbactam and cefoperazone were achieved between 15 minutes and 2 hours after administration. Mean peak plasma concentrations were 19 and 64.2 mcg/mL for sulbactam and cefoperazone, respectively.

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

Patients with hepatic impairment.

See section "Special instructions".

Patients with renal impairment.

In patients with various degrees of renal impairment who received the drug, total body clearance of sulbactam was strongly correlated with creatinine clearance. In patients with non-functioning kidneys, the elimination half-life of sulbactam was significantly prolonged (averaging 6.9 and 9.7 hours according to different studies). Hemodialysis significantly alters the elimination half-life, total body 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, exhibited a longer elimination half-life, lower clearance, and larger volume of distribution compared to values in 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 ranged 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 administered together in the form of the drug Cefoperazone/Sulbactam.

Cefoperazone does not displace bilirubin from plasma protein binding sites.

Clinical characteristics.

Indications.

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

• respiratory tract infections (upper and lower respiratory tract);
• cholecystitis, cholangitis, peritonitis and other intra-abdominal infections;
• urinary tract infections (upper and lower urinary tract);
• septicemia;
• meningitis;
• skin and soft tissue infections;
• bone and joint infections;
• inflammatory diseases of the pelvic organs, 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 types of interactions.

Combination therapy. Due to the broad spectrum of activity of the medicinal product, Cefoperazone/Sulbactam can be used as monotherapy for adequate treatment of most infections. However, under certain indications, the medicinal product may be used concomitantly with other antibiotics. When aminoglycosides are used simultaneously (see section "Method of administration and dosage"), renal function must be monitored throughout the course of therapy (see section "Incompatibilities").

Alcohol. Reactions such as facial flushing, sweating, headache, and tachycardia have been reported when alcohol is consumed during treatment and within 5 days after administration of cefoperazone. Similar reactions have also been observed with some other cephalosporins. Patients should be warned about possible adverse reactions that may occur when consuming alcoholic beverages during treatment with Cefoperazone/Sulbactam. When using artificial nutrition (oral or parenteral), solutions containing ethanol should not be used.

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

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 occurrence of such reactions is more likely in individuals with a history of hypersensitivity reactions to multiple allergens.

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

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

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

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

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

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

General warnings. Cases of hemorrhage, sometimes fatal, have been reported during treatment with sulbactam/cefoperazone. As with other antibiotics, vitamin K deficiency leading to coagulopathy has been observed in patients receiving sulbactam/cefoperazone. The mechanism is likely related to suppression of intestinal bacterial flora normally responsible for vitamin K synthesis. Patients at risk include those with restricted nutrition, malabsorption, or those receiving prolonged parenteral (intravenous) nutrition. In such patients and in patients taking oral anticoagulants, prothrombin time (or international normalized ratio) should be monitored to detect possible bleeding or thrombocytopenia, and vitamin K supplementation should be administered if indicated. If prolonged bleeding occurs in the absence of other causes, sulbactam/cefoperazone should be discontinued.

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

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

C. difficile produces toxins A and B, which contribute to the development of C. difficile-associated diarrhea. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as 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. A careful medical history is essential, as cases of C. difficile-associated diarrhea have been reported up to two months after completion of antibacterial treatment.

Children.

Cefoperazone/Sulbactam is 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 of the drug 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 — caution is advised when administering the drug to patients with impaired renal function or to those on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

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

Breastfeeding. Only a small portion of the administered doses of sulbactam and cefoperazone is excreted into breast milk. The drug should be administered with caution to nursing women, despite the fact that both components are excreted in breast milk in negligible amounts.

Ability to affect driving or operating machinery.

The effect of the medicinal product on the ability to drive or operate machinery is unlikely.

Method of administration and dosage.

The drug (sodium sulbactam/sodium cefoperazone combination) is supplied in vials and is intended for parenteral use only.

Adults. The usual dose of the drug 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., cefoperazone dose – 4 g), 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 of the drug should be adjusted in patients with significantly impaired renal function (creatinine clearance less than 30 mL/min) to compensate for reduced sulbactam clearance. In patients with creatinine clearance of 15–30 mL/min, sulbactam should be administered at a maximum dose of 1 g given every 12 hours (maximum daily sulbactam dose – 2 g). In patients with creatinine clearance less than 15 mL/min, sulbactam should be administered at a maximum dose of 500 mg given 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 pediatric patients.

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.

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

Use for treatment of newborns. Newborns during the first week of life should receive the drug every 12 hours. The maximum daily dose of sulbactam in children should not exceed 80 mg/kg body weight/day (160 mg/kg body weight/day of the medicinal product Cefoperazone/Sulbactam). If it is necessary to administer a dose of cefoperazone exceeding 80 mg/kg body weight/day, the additional dose of cefoperazone should be prescribed separately (see section "Special Instructions").

Method of administration.

Intravenous administration.

For infusion, the contents of each vial of the medicinal product Cefoperazone/Sulbactam should be reconstituted with an appropriate volume of 5% aqueous 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 injection, 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 injection should be used for reconstitution (see section "Incompatibilities"). A two-step dilution process using sterile water for injection is required (see table above); the resulting solution should then be further diluted with lactated Ringer's solution to achieve a sulbactam concentration of 5 mg/mL (add 2 mL or 4 mL of initially diluted solution to 50 mL or 100 mL of lactated Ringer's solution, respectively).

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

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

Children. The drug is administered to children (see section "Dosage and Administration").

Overdose.

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

Adverse Reactions

The drug is generally well tolerated. Most adverse reactions are of mild to moderate severity and have a favorable course during long-term treatment.

Listed below are adverse reactions observed during treatment with Cefoperazone/Sulbactam. The frequency of adverse reactions is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Adverse reactions are listed by organ systems according to MedDRA, in order of clinical significance.

* Adverse reactions reported during the post-marketing period.

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

Abnormalities in parameters such as 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.

Reports of suspected adverse reactions.

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

Shelf life. 2 years.

Storage conditions.

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

Incompatibilities.

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

Lactated Ringer's solution. Primary dilution with lactated Ringer's solution is not recommended, as these substances have been shown to be incompatible. However, a two-step dilution process, in which the primary solvent is water for injections, can avoid incompatibility when further dilution with lactated Ringer's solution is performed (see section "Dosage and administration").

Lidocaine. Primary dilution with 2% lidocaine solution is not recommended, as these substances are incompatible. However, using a two-step dilution process, where the primary solvent is water for injections, allows avoidance of incompatibility when subsequent dilution with 2% lidocaine hydrochloride solution is performed (see section "Dosage and administration").

Packaging.

Powder in glass vials. Packs of 1, 5, or 10 vials in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

NSPC Hebei Huamin Pharmaceutical Co., Ltd.

Manufacturer's address and place of business.

No. 98 Huan Road, Economic and Technological Development Zone, Shijiazhuang, Hebei 052165, China.