Sulcef

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SULCEF (SULCEF)

Composition:

Active substances: sulbactam and cefoperazone;

1 vial contains cefoperazone sodium equivalent to cefoperazone 1 g and sulbactam sodium equivalent to sulbactam 1 g;

Excipients: none.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical 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.

Sultsef is a combination of sulbactam sodium/cefoperazone sodium. Sulbactam sodium is a derivative of the basic penicillin nucleus. It is an irreversible inhibitor of beta-lactamase and is used only parenterally. Chemically, it is sodium sulphonate of penicillinate. It contains 92 mg of sodium (4 mEq) per 1 gram. Sulbactam is a highly water-soluble, crystalline, almost white powder. Molecular weight is 255.22.

Cefoperazone sodium is a broad-spectrum semisynthetic third-generation cephalosporin antibiotic used only parenterally. It contains 34 mg of sodium (1.5 mEq) per 1 gram. Cefoperazone is a water-soluble, white crystalline powder. Molecular weight is 667.65.

The antibacterial component of sulbactam/cefoperazone is cefoperazone—a third-generation cephalosporin that affects susceptible microorganisms during active multiplication by inhibiting the biosynthesis of the murein of the cell membrane. Sulbactam has no significant 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 destruction of penicillins and cephalosporins by resistant microorganisms has been confirmed in studies with resistant strains on intact microorganisms, where sulbactam demonstrated pronounced synergy with penicillins and cephalosporins. Since sulbactam also binds to certain penicillin-binding proteins, susceptible strains become more vulnerable to the action of Sultsef than to cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all microorganisms susceptible to cefoperazone. In addition, synergistic action is observed (reduction of the minimum inhibitory concentrations of the combination, approximately fourfold compared to the concentrations of each component alone) against various microorganisms, with the most pronounced effect against the following: 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.

Sultsef 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 streptococcus group A); Streptococcus agalactiae (beta-hemolytic streptococcus group B); 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 species of Pseudomonas; Acinetobacter calcoaceticus; Neisseria gonorrhoeae; Neisseria meningitidis; Bordetella pertussis; Yersinia enterocolitica.

Anaerobic microorganisms:

Gram-negative bacilli (including Bacteroides fragilis, other species of Bacteroides, and species of Fusobacterium); 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 effective concentration ranges have been established for Sultsef:

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

Disk diffusion zone diameter (mm, Kirby-Bauer)

To determine the MIC, serial dilutions of sulbactam/cefoperazone should be used by means of agar or broth dilution methods. The recommended susceptibility test using a disk containing 30 mcg sulbactam and 75 mcg cefoperazone is recommended. A laboratory report of "susceptible" indicates that the infecting microorganism is likely to respond effectively to therapy with Sulcef, while a report of "resistant" indicates that such effective response is unlikely. A report of "intermediate" indicates that the microorganism may be susceptible to Sulcef when the drug is administered at higher doses, or that the infection has developed in tissues or body fluids where high antibiotic concentrations are expected to be achieved.

Recommended quality control ranges for sulbactam/cefoperazone

30 mcg/75 mcg disks:

Pharmacokinetics.

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

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

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

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose administered as sulbactam/cefoperazone are excreted by the kidneys. Most of the remaining cefoperazone dose is excreted via bile. After administration of sulbactam/cefoperazone, the mean elimination half-life of sulbactam is 1 hour and that of cefoperazone is 1.7 hours. Plasma concentrations are proportional to the administered dose. These data correspond to previously published pharmacokinetic studies of these components when used separately.

After intramuscular administration of 1.5 g of Sulcef (0.5 g sulbactam and 1 g cefoperazone), maximum plasma concentrations of sulbactam and cefoperazone were achieved within 15 minutes to 2 hours after administration. Mean maximum concentrations were 19.0 and 64.2 \µg/mL for sulbactam and cefoperazone, respectively.

After repeated administration of the drug, no significant changes in the pharmacokinetics of Sulcef components were reported, and no accumulation was observed with administration every 8–12 hours.

Use in hepatic impairment.

See section "Special precautions".

Use in renal impairment.

In patients with renal impairment of varying severity receiving cefoperazone/sulbactam, total body clearance of sulbactam was highly correlated with creatinine clearance. In patients with non-functioning kidneys, the mean elimination half-life of sulbactam was significantly prolonged (on average 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.

Use in elderly patients.

The pharmacokinetics of cefoperazone/sulbactam have been studied in elderly patients with impaired renal and hepatic function. Both components of the drug, sulbactam and cefoperazone, demonstrated 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.

Use in children.

Studies conducted in children demonstrated no significant differences in the pharmacokinetics of cefoperazone/sulbactam 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 tissues and body fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, and uterus.

There is no evidence of any pharmacokinetic interaction between sulbactam and cefoperazone when co-administered as Sulcef.

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

Clinical characteristics.

Indications.

The drug is indicated for the treatment of the following infections caused by susceptible microbial strains:

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Combination therapy. Due to the broad spectrum of antibacterial activity of sulbactam/cefoperazone, Sulcef can be used as monotherapy for adequate treatment of most infections. However, under certain indications, sulbactam/cefoperazone may be administered concomitantly with other antibiotics. Renal function should be monitored throughout the course of therapy when aminoglycosides are used concurrently (see also section "Incompatibilities").

Alcohol. Reactions such as facial flushing, sweating, headache, and tachycardia have been reported when alcohol is consumed during treatment and for 5 days after cefoperazone administration. Similar reactions have also been observed with other cephalosporins. Patients should exercise caution when consuming alcoholic beverages during treatment with Sulcef. Solutions containing ethanol should not be used when artificial nutrition (oral or parenteral) is administered.

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

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 cefoperazone/sulbactam. Such reactions are more likely to occur in individuals with a history of multiple allergen sensitivity. If an allergic reaction occurs, the drug should be discontinued immediately and appropriate therapy initiated. Severe anaphylactic reactions require immediate administration of epinephrine. Oxygen therapy, intravenous corticosteroids, airway maintenance including intubation, may be required as indicated.

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, while renal excretion increases. Even in severe hepatic dysfunction, therapeutic concentrations of cefoperazone are achieved in bile, with only a 2- to 4-fold increase in serum half-life.

Dose 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 concentrations of cefoperazone should be monitored and dosage adjusted as needed. In such cases, without careful monitoring of serum concentrations, the dose of cefoperazone should not exceed 2 g/day.

General warnings. Serious bleeding events, including fatal cases, have been reported with the use of cefoperazone/sulbactam. As with other antibiotics, treatment with cefoperazone/sulbactam may lead to vitamin K deficiency in some patients. This is likely due to suppression of normal gut flora responsible for vitamin K synthesis. Thus, at-risk patients include those with poor nutrition, malabsorption (e.g., in cystic fibrosis), and those on long-term parenteral (intravenous) nutrition. In such patients, as well as in those receiving anticoagulants, prothrombin time (or International Normalized Ratio) should be monitored, and exogenous vitamin K supplementation should be administered if indicated. These patients should be closely monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. If prolonged bleeding occurs without other identifiable cause, the drug should be discontinued.

As with other antibiotics, prolonged use of Sulcef may result in overgrowth of non-susceptible microorganisms. Patients should be carefully observed during therapy. As with other potent systemic agents, periodic monitoring for signs of organ system toxicity—including renal, hepatic, and hematopoietic system dysfunction—is recommended, especially in premature infants and other neonates.

Clostridium difficile-associated diarrhea has been reported with almost all antibacterial agents, including sodium sulbactam/cefoperazone sodium. The severity may range from mild diarrhea to fatal colitis. Antibacterial agents alter normal gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of Clostridium difficile-associated diarrhea. Toxin-producing strains of C. difficile may lead to increased morbidity and mortality, as these infections may be resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in patients presenting with diarrhea following antibacterial therapy. Careful medical history is essential, as cases have been reported up to two months after completion of antibacterial treatment.

The medicinal product contains sodium: it may be unsuitable for patients who require sodium restriction.

Use during pregnancy or breastfeeding.

Pregnancy. Studies on reproductive function in rats 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 studies do not always predict human response, Sulcef should be used during pregnancy only if clearly needed.

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

Ability to influence reaction speed when driving or operating machinery.

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

Method of administration and dosage.

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

In severe or refractory infections, the daily dose of Sulcef can be increased up to 8 g with a 1:1 ratio of active ingredients (i.e., cefoperazone dose – 4 g), administered intravenously in evenly divided doses every 12 hours. In patients receiving sulbactam and cefoperazone in a 1:1 ratio, there may be a need for additional separate administration of cefoperazone. In such cases, it should be administered every 12 hours in equal doses. The recommended maximum daily dose of sulbactam is 4 g (8 g of Sulcef preparation).

Children. The usual dose of Sulcef preparation in children is 40 to 80 mg/kg/day (i.e., 20–40 mg/kg body weight/day of cefoperazone). The preparation should be administered every 6–12 hours in evenly divided doses.

In severe or refractory infections, the daily dose may be increased up to 160 mg/kg with a sulbactam to cefoperazone ratio of 1:1 (i.e., cefoperazone dose – 160 mg/kg/day), divided evenly into 2–4 doses.

Neonates. In neonates during the first week of life, the drug should be administered every 12 hours. The maximum daily dose of sulbactam in children should not exceed 80 mg/kg/day (160 mg/kg/day of Sulcef preparation). If a cefoperazone dose higher than 80 mg/kg/day is required, the additional cefoperazone dose should be administered separately.

Sulcef has been effectively used in children; however, comprehensive studies on its use in premature or full-term neonates have not been conducted. Therefore, a careful assessment of the potential benefits and risks should be performed before initiating treatment in premature or full-term neonates.

In neonates with bilirubin encephalopathy, cefoperazone does not displace bilirubin from its binding sites with plasma proteins.

Hepatic impairment. See section "Special precautions".

Renal impairment. Dosage regimen of Sulcef 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 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.

Elderly patients. See section "Pharmacokinetics".

Intravenous administration.

For infusion, the contents of each Sulcef vial should be dissolved in an appropriate volume of 5% dextrose in water, 0.9% sodium chloride injection solution, or sterile water for injection, then further diluted to 20 mL with the same diluent and administered over 15–60 minutes.

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

Lactated Ringer’s solution is an acceptable diluent for intravenous infusion but not for initial reconstitution (see section "Incompatibility").

Intramuscular administration.

2% lidocaine hydrochloride solution is an acceptable diluent for preparing the solution for intramuscular injection but not for initial reconstitution (see section "Incompatibility").

Reconstitution.

Sulcef is compatible with water for injections, 5 % glucose solution, 0.9 % sodium chloride solution, 5 % glucose in 0.225 % sodium chloride solution, and 5 % glucose in 0.9 % sodium chloride solution at concentrations up to 125 mg of cefoperazone and 125 mg of sulbactam per 1 ml.

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

Lidocaine. Sterile water for injections should be used for reconstitution (see section "Incompatibility"). For intramuscular injection, the drug should be diluted in two steps. First, prepare the primary solution in sterile water for injections (see table), followed by addition of 2 % lidocaine solution. The approximate concentration of lidocaine in the secondary solution is 0.5 %.

Reconstitution and administration of the vial contents must be performed under appropriate aseptic conditions. The reconstituted solution should be clear, colorless, and free from visible particulate matter. Any unused product or waste material should be disposed of in accordance with local requirements.

Children.

The drug can be used in children. However, comprehensive studies on the use of the drug 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. Cefoperazone does not displace bilirubin from plasma protein binding.

Overdose.

There is insufficient information regarding acute human intoxication with sodium cefoperazone and sodium sulbactam. Overdose is expected to produce manifestations primarily consisting of an intensification of its adverse effects. 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

Sulcef is generally well tolerated. Most adverse effects are mild to moderate in severity and resolve during treatment.

The adverse reactions listed below have been reported during administration of sulbactam/cefoperazone. The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

All adverse reactions listed below are classified according to MedRA system organ classes and are presented in order of clinical significance.

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: ≥ 1/1000 to < 1/100 (≥ 0.1% to < 1%), frequency not known: cannot be estimated from the 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 parameters such as leukocyte count, neutrophil count, platelet count, hemoglobin, and hematocrit were observed only during clinical trials. Increases and decreases were not differentiated.

§ Reports of fatal outcomes have been received.

Reporting of suspected adverse reactions. It is very important to report suspected adverse reactions after a medicinal product has been authorized. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legal requirements.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Reconstituted solutions are suitable for use when stored at 2–8 °C.

Incompatibilities.

Aminoglycosides. Solutions of Sulcef and aminoglycosides should not be mixed directly due to physical incompatibility. If combination therapy with Sulcef and aminoglycosides is required, they should be administered sequentially via separate intravenous infusion lines, using a separate secondary intravenous administration set. The primary intravenous line should be thoroughly flushed with an appropriate solution between infusions of the two agents. It is also advisable to maximize the time intervals between administration of Sulcef and aminoglycosides within a 24-hour period.

Lactated Ringer’s solution. Primary reconstitution with Lactated Ringer’s solution is not recommended, as this mixture is incompatible. However, a two-step dilution process, using water for injections as the primary solvent, allows avoidance of incompatibility when further dilution with Lactated Ringer’s solution is performed (see section "Dosage and administration").

Lidocaine. Primary reconstitution with 2% lidocaine solution is not recommended, as this mixture is incompatible. However, a two-step dilution process, using water for injections as the primary solvent, allows avoidance of incompatibility when further dilution with 2% lidocaine hydrochloride solution is performed (see section "Dos游戏副本 and administration").

Packaging. Powder in vials of 1 g/1 g, pack sizes of 1, 10, 50, and 100 in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie Limited / Medochemie Limited.

Manufacturer's address and place of business.
Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus /
Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.