Cefobocid

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

Composition:

Active substance: cefoperazone;

1 vial contains 1 g of cefoperazone in the form of sterile cefoperazone sodium salt.

Dosage form. Powder for solution for injection.

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

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Cefoperazone. ATC code J01D D12.

Pharmacological properties.

Pharmacodynamics.

Cefoperazone is a semi-synthetic third-generation cephalosporin antibiotic with a broad spectrum of activity intended for parenteral administration.

The bactericidal action of cefoperazone is due to inhibition of bacterial cell wall synthesis. Cefoperazone is active in vitro against a wide range of clinically significant microorganisms. At the same time, it demonstrates resistance to the action of many β-lactamases.

The following microorganisms are susceptible to cefoperazone.

Gram-positive microorganisms

Staphylococcus aureus (strains producing and not producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae (formerly Diplococcus pneumoniae), Streptococcus pyogenes (β-hemolytic streptococcus group A), Streptococcus agalactiae (β-hemolytic streptococcus group B), many strains of Streptococcus faecalis (enterococci), other strains of β-hemolytic streptococci.

Gram-negative microorganisms

Escherichia coli, genus Klebsiella, genus Enterobacter, genus Citrobacter, Haemophilus influenzae (strains producing and not producing β-lactamases), Proteus mirabilis, Proteus vulgaris, Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri), genus Providencia, genus Serratia (including S. marcescens), genus Salmonella and Shigella, Pseudomonas aeruginosa and some other Pseudomonas species, Acinetobacter calcoaceticus, Neisseria gonorrhoeae (strains producing and not producing β-lactamases), Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.

Anaerobic microorganisms

Gram-positive and gram-negative cocci (including genera Peptococcus, Peptostreptococcus, and Veillonella); gram-positive bacilli (including Clostridium, Eubacterium, and genus Lactobacillus); gram-negative bacilli (including genus Fusobacterium, many strains of Bacteroides fragilis and other representatives of the genus Bacteroides).

Pharmacokinetics.

High levels of cefoperazone are achieved in blood, bile, and urine after a single dose of the drug.

Below (Table 1) are the concentrations of the drug in serum of healthy adult individuals after a 15-minute intravenous administration of 1, 2, 3, or 4 g of the drug or a single intramuscular injection of 1 or 2 g of the drug.

Table 1

Cefoperazone serum concentrations

* Time elapsed after administration of the drug.

** Results obtained 15 minutes after administration of the drug.

The elimination half-life of cefoperazone from blood serum is approximately 2 hours, regardless of the route of administration.

Cefoperazone achieves therapeutic levels in all body fluids and tissues (peritoneal, ascitic, and cerebrospinal fluid [during meningitis], urine, bile, and gallbladder wall, sputum and lungs, palatine tonsils and sinus mucosa, atria, kidneys, ureter, prostate, testes, uterus and fallopian tubes, bones, umbilical cord blood, and amniotic fluid).

Cefoperazone is excreted via bile and urine. The concentration of the drug in bile reaches very high levels (usually within 1–3 hours after administration) and exceeds serum concentrations by 100-fold.

Biliary concentrations have been recorded as follows: from 66 mcg/mL at 30 minutes to 6000 mcg/mL at 3 hours after intravenous administration of 2 g of cefoperazone to patients without biliary obstruction.

Twelve hours after administration at various doses and by different routes, the concentration of cefoperazone in the urine of individuals with normal renal function averages between 20% and 30%. Drug concentrations in urine exceeding 2200 mcg/mL are achieved within 15 minutes after intravenous administration of 2 g of cefoperazone. After intramuscular administration of 2 g of the drug, maximum urinary concentrations are approximately 1000 mcg/mL.

Repeated administration of cefoperazone does not lead to drug accumulation in healthy volunteers. In patients with renal impairment, maximum serum concentration, area under the pharmacokinetic curve, and elimination half-life from serum are similar to those in healthy volunteers.

In patients with impaired liver function, the elimination half-life of the drug from serum is prolonged, but urinary excretion increases. In patients with both renal and hepatic impairment, cefoperazone may accumulate in serum. However, therapeutic concentrations of cefoperazone are still achieved even in severe liver disease, and the half-life is prolonged only 2- to 4-fold.

Clinical characteristics.

Indications.

Treatment of infectious processes caused by microorganisms sensitive to Cefobutin:

• infections of upper and lower respiratory tract;
• infections of 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 tract infections.

Prophylaxis of postoperative infectious complications during abdominal, gynecological, cardiovascular, and orthopedic surgeries.

Contraindications.

Hypersensitivity to cephalosporins and to other β-lactam antibiotics.

Interaction with other medicinal products and other types of interactions.

Cefoperazone has the following interactions typical for antibiotics of the cephalosporin group.

Nephrotoxic drugs: concomitant treatment with high doses of cephalosporins and nephrotoxic medicinal agents such as aminoglycosides or potent diuretics (e.g., furosemide) may adversely affect kidney function. If combination therapy is necessary, renal function should be monitored throughout the treatment course (see also section “Incompatibilities”).

Alcohol (ethanol): due to the risk of disulfiram-like reactions (flushing, sweating, headache, tachycardia), patients should avoid consumption of alcohol and alcohol-containing medicinal products during treatment and for 5 days after its completion. In artificial nutrition (oral or parenteral), solutions containing ethanol should not be used.

Nonsteroidal anti-inflammatory drugs, antiplatelet agents, vitamin K antagonists (e.g., warfarin), heparin: increased risk of bleeding.

Allopurinol, ampicillin: significant increase in the frequency of skin rashes.

Bacteriostatic antibacterial agents (e.g., chloramphenicol, tetracyclines): reduce the bactericidal effect of cefoperazone.

Probenecid: reduction of tubular excretion of cefoperazone, leading to its accumulation and prolonged elevation of drug concentration in blood.

Like other antibiotics, cefoperazone may reduce the therapeutic effect of the oral typhoid vaccine.

Laboratory tests: a false-positive result may occur when testing for glucose in urine using Benedict’s or Fehling’s solution.

Special precautions.

Hypersensitivity. Before each new course of treatment with cefoperazone, it is necessary to determine whether the patient has a history of hypersensitivity reactions to cephalosporins, penicillins, other beta-lactam antibiotics, or other drugs. Cross-allergic reactions between penicillins and cephalosporins are possible. This drug should be prescribed with caution to patients with hypersensitivity to penicillin. Antibiotics should be administered cautiously to any patient who has previously experienced any allergic manifestations, especially drug allergies.

Severe, and sometimes fatal, hypersensitivity reactions (anaphylactic reactions) have been reported with the use of beta-lactam or cephalosporin antibiotics, including cefoperazone. Hypersensitivity reactions occur more frequently in patients with a history of any type of allergy, particularly drug allergy. If allergic reactions occur, the drug should be discontinued immediately and appropriate therapy initiated. In the event of severe anaphylactic reactions, epinephrine should be administered immediately, along with glucocorticoids, airway maintenance (including intubation if necessary), oxygen, and other emergency measures.

Cases of severe skin reactions, sometimes fatal, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis, have been reported in patients receiving cefoperazone. If a skin reaction occurs, cefoperazone therapy should be discontinued and appropriate treatment initiated.

Use in hepatic impairment.

Cefoperazone is actively excreted in bile. In patients with liver disease and/or biliary obstruction, the elimination half-life of cefoperazone is usually prolonged, and renal excretion increases. Dose adjustment may be required. In cases of hepatic impairment with concomitant severe renal dysfunction, the daily dose should not exceed 2 g in the absence of regular monitoring of cefoperazone blood concentrations. Even in severe hepatic impairment, therapeutic concentrations of cefoperazone are achieved in bile, and the elimination half-life increases only 2- to 4-fold.

General warnings.

As with other antibiotics, cefoperazone therapy, especially prolonged treatment:

• may cause vitamin K deficiency due to suppression of intestinal flora normally responsible for synthesizing this vitamin. Cases of severe bleeding, including fatal outcomes, have been reported. Patients at risk include those with poor nutrition, malabsorption syndrome (e.g., in cystic fibrosis, biliary fibrosis), and those on long-term parenteral (intravenous) nutrition. These patients, as well as those who have received prolonged anticoagulant therapy prior to cefoperazone administration, should have prothrombin time (or International Normalized Ratio) monitored regularly at the beginning and throughout treatment. Such patients should be closely monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. If prolonged bleeding occurs without other identifiable cause, cefoperazone should be discontinued. Exogenous vitamin K should be administered if indicated;
• may lead to overgrowth of resistant microorganisms;
• may suppress normal colonic flora and promote overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of C. difficile-associated diarrhea (CDAD). The severity of symptoms may range from mild diarrhea to fatal colitis. Strains of C. difficile with hyperproduction of toxins are associated with increased morbidity and mortality, as the resulting infections may be resistant to antibacterial therapy and may require colectomy. CDAD should be considered in all patients who develop diarrhea during or after antibiotic use. A careful medical history is essential, as CDAD has been reported up to 2 months after antibiotic treatment. In cases of severe and persistent diarrhea, the drug should be discontinued immediately and appropriate therapy initiated (e.g., oral vancomycin). The use of agents that inhibit peristalsis is contraindicated. Without appropriate treatment, toxic megacolon, peritonitis, and shock may develop.

Alcohol consumption during treatment and for 5 days after completion of cefoperazone therapy has been associated with reactions such as facial flushing, sweating, headache, and tachycardia. Therefore, alcohol should be avoided during treatment and for at least 5 days after discontinuation of the drug.

The elimination half-life of cefoperazone in serum is slightly reduced during hemodialysis. The drug should be administered after completion of the dialysis procedure.

Cefoperazone should be used with caution in patients with a history of gastrointestinal disorders, particularly colitis.

During treatment, patients should be closely monitored, with periodic assessment of renal, hepatic, and hematopoietic function. This is especially important for neonates, particularly premature infants, and other infants.

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

Pseudopositive results may occur in tests for urinary glucose using non-enzymatic methods and in the Coombs test.

Each 1 g of cefoperazone contains 34.4 mg of sodium, which should be considered when prescribing the drug to patients on a sodium-restricted diet.

Storage of solutions.

Stability.

The parenteral diluents and approximate cefoperazone concentrations listed below ensure solution stability under the specified conditions and time periods (Table 2). After the specified storage period, any unused solution should be discarded.

Table 2

Ready-to-use solutions of Cefobosid are stored in glass or plastic syringes, glass or flexible plastic containers intended for parenteral solutions.

The drug should be thawed at room temperature prior to administration. After thawing, any unused solution must be discarded. The solution must not be refrozen.

Use during pregnancy or breastfeeding.

The drug should be used during pregnancy only if absolutely necessary and after careful assessment of the risk/benefit ratio.

The drug passes into breast milk; therefore, breastfeeding should be discontinued during treatment.

Ability to affect reaction rate when driving or operating machinery.

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

Method of Administration and Dosage

In the absence of contraindications, perform an intradermal test for hypersensitivity to cefoperazone prior to initiating treatment with the drug. When lidocaine is used as a solvent (for intramuscular administration), safety information regarding lidocaine must be taken into account, and a skin test for hypersensitivity to lidocaine should be performed.

Administer intravenously and intramuscularly.

Adults. The usual daily dose is 2–4 g/day, divided into equal parts administered every 12 hours. For severe infections, the daily dose may be increased up to 8 g; equal portions of this dose should be administered every 12 hours. If further increase of the daily dose to 12–16 g is required, it should be divided into 3 doses (every 8 hours).

Treatment with the drug may be initiated before obtaining results of microbial sensitivity testing.

Children. The recommended daily dose is 50–200 mg/kg body weight, depending on the severity of infection; the dose should be administered in two divided doses (every 12 hours). The maximum daily dose should not exceed 12 g. Daily doses up to 300 mg/kg body weight have been used without complications in the treatment of infants and children with severe infections, including bacterial meningitis.

Neonates under 8 days of age: administer the drug every 12 hours; however, potential risks should be considered when prescribing.

For uncomplicated gonococcal urethritis, a single intramuscular dose of 500 mg is recommended.

For prophylaxis of postoperative infectious complications, administer 1–2 g intravenously 30–90 minutes before the start of surgery, followed by doses every 12 hours (in most cases, for no more than 24 hours). In surgeries with a high risk of infection (e.g., colorectal surgery) or when infection could lead to particularly severe consequences (e.g., open-heart surgery or joint prosthesis implantation), prophylactic use of the drug may continue for up to 72 hours after surgery.

Combination Therapy

The broad spectrum of activity of Cefobocide allows monotherapy for most infections. However, when indicated, Cefobocide may be used in combination with other antibiotics. When used concomitantly with aminoglycosides, renal function should be monitored.

Renal Impairment

Since the kidneys are not the primary route of elimination for Cefobocide, the usual daily dose (2–4 g) may be administered without dose adjustment. In patients with a glomerular filtration rate below 18 mL/min or serum creatinine levels exceeding 3.5 mg/100 mL, the daily dose should not exceed 4 g. The serum half-life of cefoperazone is slightly reduced during hemodialysis. The drug should be administered to patients undergoing hemodialysis after completion of the dialysis procedure.

Hepatic Impairment

Dose adjustment may be necessary in cases of biliary obstruction or severe liver disease with concomitant renal impairment. If serum drug concentration monitoring is not performed, the dose should not exceed 2 g/day.

Patients with hepatic impairment and concomitant renal impairment should have serum drug concentrations monitored, and dosage should be adjusted as needed.

In the absence of regular monitoring of serum cefoperazone concentrations, the dose should not exceed 2 g/day.

Solutions should be prepared immediately before administration.

Preparation of Solutions

Intravenous Administration

Sterile Cefobocide powder should first be reconstituted with any compatible intravenous solvent (minimum 2.8 mL per 1 g of cefoperazone) (Table 3). To facilitate dissolution, it is recommended to use 5 mL of solvent per 1 g of Cefobocide. During reconstitution, vials should be shaken vigorously until the powder is completely dissolved; this solution should then be added to an appropriate intravenous infusion solution.

Table 3

Solutions Recommended for Initial Reconstitution of Cefobocide Powder

For intravenous infusion, the reconstituted solution should be further diluted in 20–100 mL of one of the compatible sterile diluents for intravenous administration (Table 4) and administered over 15–60 minutes. If sterile water for injection is used as diluent, no more than 20 mL should be added to the vial.

For continuous intravenous infusion, each gram of cefbocin should be dissolved in 5 mL of sterile water for injection; this solution should then be added to an appropriate intravenous diluent.

For intravenous bolus injection, the maximum single dose of cefbocin is 2 g for adults and 50 mg/kg body weight for children. The drug should be dissolved in a compatible diluent (Table 4) to a final concentration of 100 mg/mL and administered over at least 3–5 minutes.

Table 4

Diluents for intravenous administration

Intramuscular administration.

Sterile water for injections may be used to prepare the solution. If a solution with a concentration exceeding 250 mg/mL is intended for administration, then a lidocaine solution should be used to prepare the solution, with the final concentration of lidocaine being 0.5%. Such a solution is prepared using sterile water for injections and a 2% lidocaine solution.

A two-step reconstitution with the specified component ratio is recommended (Table 5): first, add the required amount of sterile water for injections to the vial, shaking until the cefoperazone powder is completely dissolved; then add the appropriate amount of 2% lidocaine solution and mix. Administer deeply into the upper outer quadrant of the gluteal muscle or into the anterior thigh.

Table 5

* The excess volume allows complete filling of the syringe of the specified volume.

Children.

Cefobocid can be used for the treatment of children of all age groups. The use of the drug in premature infants, newborns, and infants is possible; however, since there are insufficient data on the safety of the drug in this age group, the potential benefits and possible risks should be carefully weighed before prescribing the drug.

In newborns with kernicterus, cefoperazone does not displace bilirubin from its binding sites to plasma proteins.

When using lidocaine as a solvent, information on lidocaine safety should be taken into account.

Overdose.

Data on acute toxicity of sodium cefoperazone are limited.

Symptoms: the expected manifestations of overdose are primarily an intensification of adverse effects. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may cause neurological effects and seizures.

Treatment: discontinue the drug, symptomatic and supportive therapy. In case of seizures, sedative therapy is required. Hemodialysis may be used to accelerate drug elimination, especially in patients with impaired renal function.

Side effects.

Immune system (these reactions are more common in patients with allergies, especially to penicillin): hypersensitivity reactions, anaphylactic reactions (including laryngospasm, bronchospasm, dyspnea, anaphylactic shock), anaphylactoid reactions (including shock), drug fever, chills.

Skin and subcutaneous tissue: allergic skin reactions (including maculopapular rash, urticaria, erythema, exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome), pruritus.

Blood and lymphatic system: leukopenia, lymphopenia, neutropenia (reversible, especially with prolonged use), eosinophilia, thrombocytopenia, bleeding, decreased hemoglobin levels, hematocrit, anemia, hypoprothrombinemia, prolonged prothrombin time, coagulopathy.

Gastrointestinal tract: nausea, vomiting, loose stools/diarrhea. These reactions are usually mild or moderate in severity.

Hepatobiliary system: increased levels of ALT, AST, alkaline phosphatase, bilirubin; jaundice.

Cardiovascular system: arterial hypotension, flushing, bradycardia/tachycardia, cardiogenic shock, cardiac arrest.

Nervous system: oral mucosa hyperesthesia, restlessness, headache, dizziness.

Renal system: hypercreatininemia, transient increase in blood urea nitrogen, hematuria.

Effects due to biological activity: possible development of superinfection (including candidiasis, genital mycosis) caused by resistant microorganisms, pseudomembranous colitis.

Local reactions: pain at the site of intramuscular injection. Phlebitis at the infusion site may occur with intravenous infusion.

Other: vitamin K deficiency, pseudopositive results in non-enzymatic glucose testing in urine and in the Coombs test.

Shelf life.

2 years.

Storage conditions.

In the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

Solutions of Cefobosidum and aminoglycosides should not be mixed in the same container due to physicochemical incompatibility. If combined therapy with Cefobosidum and an aminoglycoside is intended, administration may be performed by alternating intravenous infusions. It is recommended to administer Cefobosidum before aminoglycosides. The infusion system should be flushed with an appropriate solution before administering the aminoglycoside.

It is also advisable to maximize the time intervals between doses of Cefobosidum and aminoglycosides within a 24-hour period.

Cefobosidum solution should not be mixed in the same container with other antibiotics.

Packaging.

1 g in a vial. 1 vial per pack; 1 vial per carton; 5 vials in a cassette, 1 cassette in a case.

Prescription category. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and place of business.

17 Myru Street, Kyiv, 03134, Ukraine.