Faitobakt 1 g

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FYTOBACT 1 g, FYTOBACT 2 g (FYTOBACT 1 g, FYTOBACT 2 g)

Composition:

Active substances: cefoperazone, sulbactam;

FYTOBACT 1 g: 1 vial contains sodium sulbactam equivalent to sulbactam 0.5 g and sodium cefoperazone equivalent to cefoperazone 0.5 g;

FYTOBACT 2 g: 1 vial contains sodium sulbactam equivalent to sulbactam 1 g and sodium cefoperazone equivalent to cefoperazone 1 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline hygroscopic powder, white to almost white.

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

Pharmacological Properties

Pharmacodynamics

The medicinal product contains cefoperazone (a third-generation cephalosporin antibiotic) and sulbactam (an irreversible inhibitor of most major β-lactamases produced by penicillin-resistant microorganisms).

The antibacterial component of the drug is cefoperazone, which acts on susceptible microorganisms during active replication by inhibiting the biosynthesis of the peptidoglycan layer of the bacterial cell wall.

Sulbactam has no significant intrinsic antibacterial activity, except against Neisseriaceae and Acinetobacter. However, biochemical studies on cell-free bacterial systems have demonstrated sulbactam's ability to irreversibly inhibit the most important β-lactamases produced by penicillin-resistant microorganisms.

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

The combination of sulbactam and cefoperazone is active against all microorganisms susceptible to cefoperazone. In addition, synergistic effects of the components have been observed with the following microorganisms: Haemophilus influenzae, Bacteroides spp., Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Sulbactam/cefoperazone is in vitro active against a broad spectrum of clinically significant microorganisms.

Gram-positive microorganisms: Staphylococcus aureus (strains producing or not producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae (predominantly Diplococcus pneumoniae), Streptococcus pyogenes (β-hemolytic streptococcus group A); Streptococcus agalactiae (β-hemolytic streptococcus group B), most other strains of β-hemolytic streptococci; most strains of Streptococcus faecalis (enterococci). Gram-negative microorganisms: Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (predominantly Proteus morganii), Providencia rettgeri (predominantly Proteus rettgeri), Providencia spp., Serratia spp. (including S. marcescens), Salmonella spp. and Shigella spp., 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 Bacteroides species, and Fusobacterium spp.); gram-positive and gram-negative cocci (including Peptococcus spp., Peptostreptococcus spp., and Veillonella spp.); gram-positive bacilli (including Clostridium spp., Eubacterium spp., and Lactobacillus spp.).

The following effective concentration ranges (MIC [minimum inhibitory concentration], mcg/mL based on cefoperazone concentration) have been established for the drug: susceptible — less than 16, intermediate — 17–36, resistant — more than 64.

Pharmacokinetics

After administration of the drug, approximately 84% of sulbactam and 25% of cefoperazone are excreted by the kidneys. The majority of cefoperazone 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 the pharmacokinetic parameters of the components when administered separately.

Mean peak plasma concentrations of sulbactam and cefoperazone after intravenous administration of 2 g of the drug (1 g sulbactam, 1 g cefoperazone) over 5 minutes are 130.2 and 236.8 mcg/mL, respectively. This indicates a larger volume of distribution for sulbactam (Vα = 18.0–27.6 L) compared to cefoperazone (Vα = 10.2–11.3 L). Sulbactam and cefoperazone are extensively distributed into tissues and body fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, and uterus. In children, the elimination half-life of sulbactam ranges from 0.91 to 1.42 hours and that of cefoperazone from 1.44 to 1.88 hours. Data on pharmacokinetic interaction between sulbactam and cefoperazone when administered simultaneously in combination form are lacking.

Repeated administration did not reveal any significant changes in the pharmacokinetics of the drug components or their accumulation when administered every 8–12 hours.

Hepatic impairment. See section "Special precautions".

Renal impairment. In patients with varying degrees of renal dysfunction receiving sulbactam/cefoperazone, total clearance of sulbactam closely correlates with creatinine clearance. In patients with severe renal impairment, a significant prolongation of the elimination half-life of sulbactam is observed (on average 6.9 and 9.7 hours according to different studies). Hemodialysis significantly affects the elimination half-life, total clearance, and volume of distribution of sulbactam. No significant changes in the pharmacokinetics of cefoperazone have been observed in patients with renal insufficiency.

Cefoperazone does not displace bilirubin from its binding to serum albumin.

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to the drug:

• 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 pelvic organs, endometritis, gonorrhea, and other genital infections.

Contraindications.

The use of the drug is contraindicated in patients with a history of allergy to sulbactam, penicillins, or cephalosporins.

Interaction with other medicinal products and other forms of interactions.

Aminoglycosides. Mixing the drug with aminoglycosides in the same syringe leads to mutual inactivation; if these groups of antibacterial agents are to be administered simultaneously, they should be injected at different sites with an interval of 1 hour. The drug increases the risk of nephrotoxicity associated with aminoglycosides and furosemide. Bacteriostatic agents (chloramphenicol, erythromycin, sulfonamides, tetracyclines) reduce the activity of the drug.

Probenecid decreases tubular secretion of sulbactam; this results in increased plasma concentration and prolonged elimination half-life of the drugs, as well as an increased risk of intoxication. It enhances the risk of bleeding when used concomitantly with nonsteroidal anti-inflammatory drugs.

Alcohol. Reactions such as facial flushing, sweating, headache, and tachycardia have been reported when alcohol is consumed during and within 5 days after treatment with cefoperazone. Similar reactions have also been observed with other cephalosporins. Patients should be cautious about consuming alcoholic beverages during treatment with the drug. When using artificial nutrition (oral or parenteral), solutions containing ethanol must not be used. Combination therapy. Due to the broad spectrum of antibacterial activity of sulbactam/cefoperazone, most infections can be adequately treated with this antibiotic as monotherapy. However, under certain indications, sulbactam/cefoperazone may be used in combination with other antibiotics. If aminoglycosides are used concomitantly, renal function should be monitored throughout the course of therapy (see also section "Incompatibility").

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

Special precautions for use.

Hypersensitivity. There have been reports of severe, and sometimes fatal, anaphylactic reactions in patients receiving therapy with β-lactams or cephalosporins. Such reactions are more likely to occur in individuals with a history of hypersensitivity to multiple allergens. Before initiating therapy with sulbactam/cefoperazone, the patient's history of allergic reactions to cephalosporins, penicillins, or other drugs should be carefully evaluated (see section "Contraindications"). Antibiotics should be prescribed with caution in patients with any form of allergy, especially to drugs.

In case of allergic reactions, the drug must be discontinued immediately and appropriate treatment initiated. Severe anaphylactic reactions require immediate emergency therapy, including administration of epinephrine. Oxygen therapy, intravenous corticosteroids, airway maintenance, including intubation, may be indicated as needed. 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").

General warnings. As with other antibiotics, treatment with cefoperazone may lead to vitamin K deficiency in some patients. The mechanism is likely related to suppression of intestinal flora normally responsible for synthesizing this vitamin. Thus, at-risk patients include those with restricted nutrition, malabsorption (e.g., due to biliary fibrosis), and those on long-term parenteral (intravenous) nutrition. Prothrombin time should be monitored in these patients. Similarly, monitoring is recommended in patients receiving anticoagulant therapy. Exogenous vitamin K supplementation should be administered in these cases.

As with other antibiotics, prolonged treatment may lead to overgrowth of resistant microorganisms. Patients should be closely monitored during therapy. Clinicians should be alert to possible periodic disturbances in kidney, liver, and hematopoietic system function, as seen with other systemic agents. This is particularly important in newborns, especially premature infants, and other infants.

During prolonged therapy, periodic monitoring for organ system dysfunction, including renal, hepatic, and hematopoietic function, is necessary.

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including sodium sulbactam/sodium cefoperazone. The severity of symptoms may range from mild diarrhea to fatal colitis. Antibacterial therapy suppresses normal colonic flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which are important in the development of CDAD. A hyper-toxigenic strain of C. difficile can cause increased morbidity and mortality, as these organisms may be refractory to antimicrobial therapy, potentially necessitating colectomy. CDAD should be considered in any patient who develops diarrhea after antibiotic use. A careful medical history is essential, as CDAD has been reported up to two months after antibiotic administration.

Appropriate therapy should be initiated if superinfection occurs.

Use in renal impairment. In patients with varying degrees of renal dysfunction, the total clearance of sulbactam closely correlates with creatinine clearance. In patients with severe renal impairment, the elimination half-life of sulbactam is significantly prolonged. Hemodialysis significantly affects the half-life, total clearance, and volume of distribution of sulbactam. No changes in the pharmacokinetics of cefoperazone have been observed in patients with renal insufficiency.

Use in hepatic impairment. Cefoperazone is primarily excreted via bile. In patients with liver disease and/or biliary obstruction, the plasma elimination half-life of cefoperazone is usually prolonged, and urinary excretion increases. Even in severe hepatic impairment, therapeutic concentrations of cefoperazone are found in bile, and the plasma half-life is prolonged by 2–4 times.

Dose adjustment may be necessary in cases of severe biliary obstruction, severe liver disease, or concomitant renal impairment. Dose modification may be required in cases of severe biliary obstruction, severe liver disease, or renal dysfunction associated with any of these conditions. In patients with both hepatic and concomitant renal impairment, serum cefoperazone concentrations should be monitored, and dosage adjusted accordingly. In such cases, the cefoperazone dose should not exceed 2 g/day without careful monitoring of serum concentrations.

Use in elderly patients. With administration of both sulbactam and cefoperazone, prolonged elimination half-life, reduced total clearance, and increased volume of distribution have been observed compared to young volunteers. Sulbactam pharmacokinetics directly correlate with renal function, while cefoperazone pharmacokinetics correlate well with hepatic impairment.

Children. Studies in the pediatric population have shown no significant differences in the pharmacokinetics of the drug components compared to adults. The drug can be effectively used in infants. However, adequate studies on use in premature infants or newborns have not been conducted. Therefore, the potential benefits and risks of therapy should be carefully evaluated before initiating treatment in premature infants or newborns. In newborns with bilirubin encephalopathy, cefoperazone does not displace bilirubin from its binding sites on plasma proteins.

Important information about excipients. This medicinal product contains sodium and may be unsuitable for patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

The drug crosses the placental barrier. It should be administered to pregnant women only when the potential benefit justifies the potential risk to the fetus.

Only a small fraction of the administered dose of sulbactam and cefoperazone passes into breast milk. Although both components of the drug are present in breast milk in small amounts, it should be used with caution in breastfeeding women.

Ability to affect the speed of reactions when driving or operating machinery.

Effect is unlikely.

Administration and Dosage.

The drug solution can be administered intravenously and intramuscularly. Before initiating therapy, hypersensitivity to Phytobact must be ruled out (perform a skin sensitivity test for antibiotic tolerance). Adults should receive a daily dose of 2–4 g (administered every 12 hours). In severe infections, the dose may be increased up to 8 g per day with a 1:1 ratio of active ingredients (i.e., cefoperazone content — 4 g). In patients receiving sulbactam and cefoperazone in a 1:1 ratio, additional separate administration of cefoperazone may be required. In such cases, it should be administered every 12 hours in equal doses. The recommended maximum daily dose of sulbactam is 4 g. Use in patients with impaired renal function. The dosage regimen for patients with significantly reduced kidney function (creatinine clearance less than 30 mL/min) should be adjusted to compensate for reduced sulbactam clearance. For patients with creatinine clearance of 15–30 mL/min, sulbactam should be administered at a maximum dose of 1 g every 12 hours (maximum daily dose — 2 g of sulbactam). For 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 dose — 1 g of sulbactam). In severe infections, additional administration of cefoperazone may be necessary.

The pharmacokinetic profile of sulbactam is significantly altered during hemodialysis. The elimination half-life of cefoperazone in plasma is slightly reduced during hemodialysis. Therefore, the dosage regimen should be adjusted when dialysis is performed.

Combination therapy. Since the sulbactam/cefoperazone combination has a broad spectrum of antibacterial activity, most infections are effectively treated with monotherapy using this drug. However, in some cases, sulbactam/cefoperazone may be used in combination with other antibiotics. When aminoglycosides are used concomitantly, renal and hepatic functions should be monitored throughout the treatment course.

Use in patients with impaired liver function. Dose adjustment may be necessary in cases of severe obstructive jaundice, severe liver disease, or when both conditions are accompanied by impaired renal function. Patients with impaired liver function and concomitant renal dysfunction require monitoring of cefoperazone plasma concentrations and, if necessary, appropriate dose adjustment. In the absence of careful monitoring of drug plasma concentrations, the cefoperazone dose should not exceed 2 g per day.

For children, the drug dosage is 40–80 mg/kg per day. The drug should be administered every 6–12 hours in evenly divided doses.

In severe infections, these doses may be increased up to 160 mg/kg per day with a 1:1 ratio of sulbactam to cefoperazone. The dose should be administered in 2–4 equal portions.

Treatment of neonates. Neonates during the first week of life should receive the drug every 12 hours. The maximum daily dose of sulbactam for children should not exceed 80 mg/kg per day. If a cefoperazone dose exceeding 80 mg/kg/day is required, cefoperazone should be additionally administered separately.

Intravenous administration.

Reconstitution method.

Step 1. Preparation of the primary solution.

The contents of the vial should be dissolved in an appropriate volume of 5% glucose injection solution, 0.9% sodium chloride injection solution, or sterile water for injection, according to the ratios specified in the table.

2nd stage. Preparation of the secondary solution.

For intravenous infusion, add the obtained primary solution to a suitable diluent to achieve a final concentration of the drug Fitobact of 10–20 mg/mL in the total volume of the solution. The prepared secondary solution should be administered intravenously by drip infusion over 15–60 minutes.

For intravenous bolus injections, dilute the obtained primary solution of the drug Fitobact with diluent to a volume of 20 mL and administer slowly over no less than 3 minutes.

Fitobact is compatible with the following solutions:

• Sterile water for injection;
• 5% glucose solution;
• 0.9% sodium chloride solution;
• 5% glucose solution in 0.225% sodium chloride solution;
• 5% glucose solution in 0.9% sodium chloride solution.

Ringer's lactate solution is acceptable as a diluent for intravenous infusion, but not for primary dilution (see section "Incompatibility"). A two-stage dilution is required. For reconstitution, use sterile water for injection (see table above); then dilute the obtained solution with Ringer's lactate solution to achieve a sulbactam concentration of 5 mg/mL (using 2 mL or 4 mL of the initially reconstituted solution). Intramuscular administration. 2% lidocaine solution is acceptable as a diluent for preparing a solution for intramuscular injection, but not for primary dilution (see section "Incompatibility").

Lidocaine. When using lidocaine, a skin sensitivity test should be performed. For intramuscular injection, dilution of the drug should be performed in two stages. First, prepare the primary solution using sterile water for injection (see table above), followed by addition of 2% lidocaine solution. The approximate concentration of lidocaine in the secondary solution is 0.5%.

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

Children.

Fitobact can be used in children. However, comprehensive studies on the use of the drug in premature infants or newborns have not been conducted. Therefore, before initiating treatment in premature infants or newborns, the potential benefits and possible risks of therapy should be carefully evaluated.

Overdose.

Symptoms. Overdose of the drug may manifest as an intensification of adverse effects. It should be noted that high concentrations of β-lactam antibiotics in cerebrospinal fluid may cause neurological reactions, including seizures.

Treatment. Since cefoperazone and sulbactam are removed from the 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 have a favorable course during long-term treatment. The adverse reactions listed below were observed during administration of sulbactam/cefoperazone. The frequency of adverse reactions is specified as follows: 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 the available data). Adverse reactions are listed by organ systems according to MedDRA [Medical Dictionary for Regulatory Activities] in order of clinical significance.

* Adverse reactions reported during the post-marketing period.

† The calculation of the frequency of laboratory parameter deviations 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, neutrophil, platelet, hemoglobin, and hematocrit levels were observed only during clinical studies. Increases and decreases in levels were not differentiated.

§ Reports of fatal outcomes have been received.

Reporting suspected adverse reactions

Reporting adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical 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 in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibilities. Fitobact and aminoglycosides should not be mixed directly due to physical incompatibility. If combination therapy with Fitobact and aminoglycosides is necessary, they should be administered sequentially via separate intravenous infusions using separate secondary intravenous tubing systems. The primary intravenous line must be thoroughly flushed with an appropriate solution between infusions of these agents. It is also advisable to maximize the time intervals between administration of Fitobact and aminoglycosides within a 24-hour period. Primary dilution with Ringer's lactate solution is not recommended, as this mixture is incompatible with Fitobact (see section "Instructions for use and dosage"). Primary dilution with 2% lidocaine solution is not recommended, as this mixture is incompatible (see section "Instructions for use and dosage").

Cefoperazone is physically incompatible with perphenazine and promethazine.

Packaging. 1 vial of powder in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Cadila Pharmaceuticals Limited, India / Cadila Pharmaceuticals Limited, India.

Manufacturer's address and location of manufacturing site. Plot No. 1389, Trasad Road, Dholka, Dist: Ahmedabad, India.