Sanfazon plus - 1000

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SANFOZONE PLUS-500, SANFOZONE PLUS-1000 (SANFOZONE PLUS-500, SANFOZONE PLUS-1000)

Composition:

Active substances: sulbactam/cefoperazone;

One vial contains sodium cefoperazone equivalent to cefoperazone 500 mg, sodium sulbactam equivalent to sulbactam 500 mg;

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

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder from almost white to yellow in color.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. ATC code J01D D62.

Pharmacological properties.

Pharmacodynamics.

The medicinal product is a combination of sodium sulbactam and cefoperazone sodium.

Sodium sulbactam 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 very easily water-soluble crystalline powder, almost white in colour. Molecular weight is 255.22.

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

Mechanism of action.

The antibacterial component of the sulbactam/cefoperazone combination drug is cefoperazone—a third-generation cephalosporin that acts against susceptible microorganisms during active multiplication by inhibiting the biosynthesis of the mucopeptide of the cell wall. 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 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 whole 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 sulbactam/cefoperazone combination 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 minimum inhibitory concentrations of the combination, suppressing microorganisms approximately 4-fold compared to 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.

Sulbactam/cefoperazone exhibits 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 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 range of susceptibility to the sulbactam/cefoperazone drug has been established.

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

Susceptible ≤ 16

Intermediate 17–63

Resistant ≥ 64

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

Susceptible ≥ 21

Intermediate 16–20

Resistant ≤ 15

Serial dilutions of sulbactam/cefoperazone using agar or broth dilution methods can be used to determine MIC. It is recommended to use a disk diffusion test containing 30 μg of sulbactam and 75 μg of cefoperazone. A laboratory result of "susceptible" indicates that therapy with sulbactam/cefoperazone is likely to be effective against the infecting microorganism, while a "resistant" result indicates that such effective action is unlikely. An "intermediate" result means that the microorganism may be susceptible to sulbactam/cefoperazone when administered at higher doses or if the infection has developed in tissues or body fluids where high antibiotic concentrations are achieved.

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

Pharmacokinetics.

When sulbactam/cefoperazone is administered, approximately 84% of the sulbactam dose and 25% of the cefoperazone dose 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 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.

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

Mean peak plasma concentrations were 19 and 64.2 µg/mL for sulbactam and cefoperazone, respectively. Sulbactam and cefoperazone are well distributed into various body tissues and fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, and others.

There is no evidence of any pharmacokinetic interaction between sulbactam and cefoperazone when administered together in the form of the sulbactam/cefoperazone combination.

After repeated administration of the drug, no significant changes in the pharmacokinetics of sulbactam/cefoperazone components have been reported, and no accumulation was observed with dosing every 8–12 hours.

Patients with hepatic impairment

See section "Dosage and administration and precautions".

Patients with renal impairment

In patients with renal impairment of varying severity who received sulbactam/cefoperazone, total body clearance of sulbactam correlated strongly 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 the pharmacokinetics of cefoperazone were observed in patients with renal insufficiency.

Elderly patients

The pharmacokinetics of sulbactam/cefoperazone have been studied in elderly patients with impaired renal and hepatic function. Both drug components, 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 body tissues and fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, and others.

There is no evidence of any pharmacokinetic interaction between sulbactam and cefoperazone when administered together in the form of the medicinal product.

Cefoperazone does not displace bilirubin from plasma protein binding sites.

Clinical characteristics.

Indications.

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

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

Contraindications.

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.

Combination therapy. Due to the broad spectrum of activity of the drug, it can be used as monotherapy for adequate treatment of most infections. However, under certain indications, the drug may be used concomitantly with other antibiotics. When aminoglycosides are used simultaneously, renal function should be monitored throughout the course of therapy (see sections "Method of administration and dosage" and "Incompatibility").

Alcohol. During and for 5 days after cefoperazone administration, reactions such as facial flushing, sweating, headache, and tachycardia have been reported upon alcohol consumption. Similar reactions have also been observed with some other cephalosporins. Patients should be warned about possible adverse reactions occurring with alcoholic beverage consumption during treatment. Patients requiring artificial nutrition (oral or parenteral) should not be administered solutions containing ethanol.

Interaction with substances used in laboratory tests. A false-positive urine glucose reaction 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 therapy with beta-lactam or cephalosporin antibiotics, including sulbactam/cefoperazone. The likelihood of such reactions is higher 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 form of allergy, particularly to drugs.

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

Cases of severe, sometimes fatal, skin reactions 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 typically prolonged, while renal excretion increases. Even in cases of severe hepatic dysfunction, therapeutic concentrations of cefoperazone are observed in bile, with only a 2- to 4-fold prolongation of the elimination 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, sometimes fatal, bleeding events have been reported with the use of 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 responsible for the synthesis of this vitamin. Patients at risk include those with poor 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 signs of bleeding, thrombocytopenia, and hypoprothrombinemia, and vitamin K supplementation should be administered if indicated. If prolonged bleeding occurs and no other cause is identified, sulbactam/cefoperazone should be discontinued.

As with other antibiotics, prolonged use of the drug 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 function—should be performed during prolonged therapy, especially 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 may range from mild diarrhea to fatal colitis. Antibacterial agents alter 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. Hypertoxin-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.

Pediatric use.

The drug can be effectively used in infants; however, comprehensive studies on the use of the drug in premature or full-term neonates have not been conducted. Therefore, the potential benefits and risks of using 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.

One vial containing 1 g of the medicinal product Sanfozon Plus (500 mg/500 mg) contains 2.9 mmol (or 67.06 mg) of sodium. One vial containing 2 g of the medicinal product Sanfozon Plus (1000 mg/1000 mg) contains 5.8 mmol (or 134.14 mg) of sodium. This information should be taken into account when administering the drug to patients with impaired renal function or to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy. Reproductive function studies conducted 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 reproductive study results may not always predict human responses, sulbactam and cefoperazone should be used during pregnancy only if clearly indicated.

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

Ability to affect reaction rate when driving or operating machinery.

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

Method of Administration and Dosage

The medicinal product (sodium sulbactam/sodium cefoperazone combination) is supplied in vials and must be administered only by the parenteral route.

The sodium sulbactam/sodium cefoperazone combination is available as a dry powder for reconstitution in a 1:1 ratio, calculated as free sulbactam and cefoperazone. Vials in a 1:1 ratio contain 500 mg + 500 mg and 1000 mg + 1000 mg of sulbactam and cefoperazone, respectively.

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., the cefoperazone dose is 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".

Renal impairment. The dosing 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 dose not exceeding 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 dose not exceeding 500 mg given every 12 hours (maximum daily sulbactam dose – 1 g). In severe infections, additional administration of cefoperazone alone 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".

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, this 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").

Neonates. For neonates during the first week of life, the drug should be administered every 12 hours. The maximum daily dose of sulbactam for children should not exceed 80 mg/kg body weight/day (160 mg/kg body weight/day of the drug). When a dose of cefoperazone exceeding 80 mg/kg body weight/day is required, the additional dose of cefoperazone should be administered separately (see section "Special Instructions").

Method of administration.

Intravenous administration.

For infusion, the contents of each vial 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 diluent for intravenous infusion, but not for primary reconstitution (see section "Incompatibility").

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

Intramuscular administration.

2% lidocaine hydrochloride solution is an acceptable solvent for preparing a solution for intramuscular administration, but not for primary dilution (see section "Incompatibility").

The medicinal product has been shown to be 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 mg to 250 mg per 1 mL of diluent. Sulbactam is compatible at concentrations ranging from 5 mg to 125 mg per 1 mL of diluent.

Lactated Ringer's solution. Sterile water for injection should be used for reconstitution (see section "Incompatibility"). 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. Sterile water for injection should be used for reconstitution (see section "Incompatibility").

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

Children. The medicinal product may be administered to children (see above).

Overdose.

There is insufficient information regarding acute toxicity of sodium cefoperazone and sodium sulbactam in humans. Overdose of the drug is expected to cause manifestations that are primarily an intensification of its known adverse effects. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may lead to 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

Sulbactam/cefoperazone is generally well tolerated. Most adverse reactions are of mild to moderate severity and have a favorable course during prolonged treatment.

The following adverse reactions have been reported during use of the drug. 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 (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

All adverse reactions listed below are categorized by MedRA system organ classes.

The 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 calculation of the frequency of adverse reactions regarding deviations of laboratory parameters from normal included all available laboratory values, including those from patients with abnormalities at baseline. 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 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

Reporting of adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all 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.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

Aminoglycosides. Solutions of this medicinal product and aminoglycosides should not be mixed directly due to physical incompatibility. If combination therapy with this medicinal product and aminoglycosides is required, they should be administered sequentially via separate intravenous infusion lines. The primary intravenous infusion line must be thoroughly flushed with an approved solution between infusions of the respective medicinal products. It is also advisable to maximize the time intervals between administration of this medicinal product 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 initial diluent 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 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 “Dosage and administration”).

Packaging.

1 or 25 vials per cardboard pack.

Prescription status.

Prescription-only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer’s address and location of operations.

VI/51B, P.O. Box No. 2, Kothuvanallur, Pala, Kottayam – 686 573, Kerala, India.