CEFOPERAZONE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFOPERAZONE (Cefoperazone)

Composition:
Active substance: cefoperazone;
1 vial contains sodium cefoperazone equivalent to cefoperazone 1000 mg.

Medicinal form:
Powder for solution for injection.

Basic physical and chemical properties:
White to yellowish-brown crystalline powder.

Pharmacotherapeutic group:
Antibacterials for systemic use.
Antibiotics for systemic use.
Other beta-lactam antibiotics.
Cephalosporins of the third generation.
Cefoperazone.
ATC code: J01D D12.

Pharmacological properties:
Pharmacodynamics:
The bactericidal effect 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 beta-lactamases. The following microorganisms are susceptible to cefoperazone:

Gram-positive microorganisms:
Staphylococcus aureus (strains producing and 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),
Streptococcus faecalis (enterococcus),
other beta-hemolytic streptococci.

Gram-negative microorganisms:
Escherichia coli,
genus Klebsiella,
genus Enterobacter,
genus Citrobacter,
Haemophilus influenzae,
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 beta-lactamases),
Neisseria meningitidis,
Bordetella pertussis,
Yersinia enterocolitica.

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

Pharmacokinetics:
High levels of cefoperazone in blood, bile, and urine are achieved after a single dose of the drug. Table 1 shows the concentrations of the drug in blood plasma of healthy adult volunteers. These data were obtained after 15-minute intravenous administration of 1, 2, 3, or 4 g of the drug or single intramuscular injection of 1 or 2 g of the drug. Probenecid does not affect the plasma concentration levels of cefoperazone.

Table 1. Mean plasma concentrations of cefoperazone (µg/mL)

* Time after administration of the drug (measured from the end of the infusion). ** Results obtained 15 minutes after administration of the drug. The elimination half-life of ceftazidime from blood plasma is approximately 2 hours, regardless of the route of administration. Ceftazidime achieves therapeutic concentrations in all body fluids and tissues, including ascitic and cerebrospinal fluid (during meningitis), urine, bile, gallbladder wall, sputum and lungs, palatine tonsils and sinus mucosa, pericardium, kidneys, ureters, prostate, seminal vesicles, uterus and fallopian tubes, bones, umbilical cord blood, and amniotic fluid. Ceftazidime is excreted via bile and urine. The concentration of the drug in bile reaches very high levels (usually 1–3 hours after administration) and exceeds corresponding concentrations in blood plasma by 100-fold. Documented bile concentrations include: from 66 mcg/mL at 30 minutes to 6000 mcg/mL at 3 hours after intravenous administration of 2 g of the drug to patients without biliary tract obstruction. Twelve hours after administration in various doses and by different routes, elevated concentrations of ceftazidime in the urine of patients with normal renal function reach on average 20–30%. A concentration of the drug exceeding 2200 mcg/mL in urine was achieved 15 minutes after intravenous administration of 2 g of ceftazidime. After intramuscular administration of 2 g of the drug, the maximum concentration in urine was approximately 1000 mcg/mL. Repeated administration of ceftazidime does not lead to drug accumulation in healthy volunteers. Patients with hepatic impairment — in patients with impaired liver function, the elimination half-life of the drug from plasma increases, but so does renal excretion. In patients with both renal and hepatic insufficiency, ceftazidime may accumulate in plasma. Patients with renal impairment — in patients with renal insufficiency, maximum plasma concentration, area under the pharmacokinetic curve, and elimination half-life from plasma are similar to those in healthy volunteers. Clinical characteristics. Indications. Treatment of infections caused by microorganisms sensitive to ceftazidime:

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

Prophylaxis of postoperative complications during abdominal, gynecological, cardiovascular, and orthopedic surgeries. Contraindications. Hypersensitivity to ceftazidime or to any cephalosporin antibiotics. Interaction with other medicinal products and other forms of interaction. Alcohol It has been reported that consumption of alcohol during treatment with ceftazidime and even up to 5 days after the last administration of ceftazidime may cause a disulfiram-like reaction characterized by flushing, nausea, headache, and tachycardia. Similar reactions have also occurred after intake of other cephalosporins; therefore, patients should be warned against consuming alcoholic beverages during ceftazidime therapy. Patients requiring oral or parenteral artificial nutrition should avoid using solutions containing ethanol. Interactions affecting laboratory test results False-positive urine glucose reactions may occur when testing with Benedict's or Fehling's solutions. Aminoglycosides Cephalosporins may increase the risk of nephrotoxicity of aminoglycosides. Therefore, careful monitoring of patients receiving concomitant aminoglycosides and cephalosporins is necessary. Anticoagulant (vitamin K antagonists) Ceftazidime may enhance the anticoagulant effect of vitamin K antagonists, including warfarin. INR values and bleeding parameters should be monitored if vitamin K antagonists are used in combination with ceftazidime. Live vaccines Antibiotics may interfere with the replication of vaccine strains necessary for immune response and thus may reduce the therapeutic efficacy of vaccines. Concomitant use of live attenuated vaccines and antibiotics should be avoided. Clostridium difficile-associated diarrhea (CDAD) has been reported following the use of almost all antibacterial agents, including ceftazidime. The therapeutic efficacy of oral and rectal drugs may be reduced due to the development of diarrhea caused by ceftazidime. Special precautions. Hypersensitivity Serious hypersensitivity reactions (anaphylactic reactions), sometimes fatal, have been reported in patients receiving beta-lactam drugs or cephalosporin drugs, including ceftazidime. These reactions occur more frequently in patients with a history of hypersensitivity reactions to multiple allergens. Before prescribing ceftazidime, a careful history should be taken to determine whether the patient has previously experienced hypersensitivity reactions to cephalosporins, penicillins, or other drugs. This drug should be prescribed with caution to patients hypersensitive to penicillin. Antibiotics should be prescribed with caution to patients who have previously experienced any form of allergic reaction, especially to drugs. If an allergic reaction occurs, the drug should be discontinued and appropriate treatment initiated. Serious anaphylactic reactions require immediate emergency administration of epinephrine. Oxygen, intravenous corticosteroids, and maintenance of airway patency, including with the help of intubation, should be used if necessary. Cases of severe skin reactions, sometimes fatal, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis, have been reported in patients using ceftazidime. In the event of severe skin reactions, ceftazidime therapy should be discontinued and appropriate treatment initiated (see section "Adverse reactions"). Use in patients with hepatic impairment Ceftazidime is excreted predominantly via bile. In patients with liver disease and/or biliary tract obstruction, the elimination half-life of ceftazidime from plasma is prolonged, and renal excretion of the drug in urine increases. Even in severe hepatic impairment, therapeutic concentrations of ceftazidime are achieved in bile, and the elimination half-life increases only 2–4 times. General warnings Serious bleeding events, including fatal cases, have been reported with the use of ceftazidime. Patients at risk include those with limited nutrition, malabsorption, and patients on prolonged parenteral (intravenous) nutrition. Such patients should be monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. In the event of prolonged bleeding without identification of other causes, ceftazidime use should be discontinued. Like other antibiotics, prolonged use of ceftazidime may lead to overgrowth of resistant microflora; therefore, careful monitoring of patients during treatment is necessary. As with treatment with any potent systemic drug, periodic examinations to detect possible functional disorders of organ systems, particularly kidneys, liver, and hematopoietic system, are recommended during prolonged ceftazidime therapy. Such examinations are especially important in newborns, particularly premature infants, and other infants. During use of almost all antibacterial drugs, including ceftazidime, cases of diarrhea caused by Clostridium difficile [Clostridium difficile associated diarrhea] (CDAD) have been documented, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy disrupts the normal microflora of the large intestine, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Strains of C. difficile with hyperproduction of toxins lead to increased morbidity and mortality, as the infections they cause may be resistant to antimicrobial therapy and may require colectomy. CDAD should be suspected in all patients who develop diarrhea following antibacterial drug use. Careful history review is necessary, as CDAD has been reported to occur more than 2 months after antibacterial drug use. If the patient follows a low-sodium diet, it should be noted that ceftazidime contains 34 mg of sodium (1.5 mmol). Use during pregnancy or breastfeeding. Pregnancy Animal studies on the effect of the drug on reproductive function, conducted at doses 10 times higher than the human dose, did not reveal evidence of impaired fertility or teratogenic effects. However, adequate and well-controlled studies in pregnant women have not been conducted. Given that animal studies on the effect of the drug on reproductive function do not always predict human response, the drug should be used during pregnancy only if clearly indicated. Breastfeeding Only small amounts of ceftazidime pass into breast milk. Although ceftazidime poorly penetrates into breast milk, the drug should be prescribed with caution during breastfeeding. Ability to affect reaction speed when driving or operating machinery Clinical experience with ceftazidime indicates that its effect on the patient's ability to drive or operate machinery is unlikely. Method of administration and dosage. The drug should be administered intravenously or intramuscularly. Adults. The usual dose for adults is 2–4 g per day, administered every 12 hours in equal divided doses. In particularly severe infections, the dose may be increased to 8 g per day, administered every 12 hours in equal divided doses. When administering ceftazidime at a daily dose of 12–16 g, divided into 3 equal doses (with an 8-hour interval between administrations), no complications were observed. Treatment with the drug may be initiated before obtaining results of microbial sensitivity testing. The recommended dose for uncomplicated gonococcal urethritis is 500 mg as a single dose, administered intramuscularly. Intramuscular administration is performed deeply into the large gluteal muscle or the anterior surface of the thigh. Combination therapy. The broad spectrum of activity of ceftazidime allows monotherapy for most infections. However, ceftazidime may also be used in combination therapy with other antibiotics if indicated. When used concomitantly with aminoglycosides, renal function should be monitored. Official recommendations for antibiotic use should be considered. Use in patients with hepatic impairment Dose adjustment may be necessary in cases of biliary tract obstruction, severe liver disease, or concomitant kidney damage. If the drug concentration in plasma is not monitored, the dose should not exceed 2 g per day. Use in patients with renal impairment. Since kidneys are not the primary route of ceftazidime elimination, patients with kidney damage may be prescribed the usual daily dose (2–4 g) without dose adjustment. For patients with glomerular filtration rate below 18 mL/min or serum creatinine level exceeding 3.5 mg/100 mL, the maximum daily dose is 4 g. The elimination half-life of ceftazidime from plasma is slightly reduced during hemodialysis. Administration of the drug should be performed after completion of dialysis. Use in patients with hepatic impairment and concomitant renal impairment. In patients with hepatic impairment and concomitant kidney damage, drug concentration in plasma should be monitored and dose adjusted if necessary. If the drug concentration in plasma is not monitored, the dose should not exceed 2 g per day. Children. For treatment of children, ceftazidime should be prescribed at daily doses of 200 mg per 1 kg body weight; the dose should be administered in 2 doses (every 8–12 hours). The maximum dose should not exceed 12 g per day (see section "Special precautions"). Daily doses up to 300 mg/kg have been used for treatment of children with severe infections, including several patients with bacterial meningitis, without causing complications. Use in newborns. In newborns (up to 8 days), the drug should be administered every 12 hours. Intravenous administration to children and adults. For intermittent intravenous infusion, 1000 mg of ceftazidime (contents of 1 vial) should be dissolved in 20–100 mL of compatible sterile solution for intravenous injection and administered over 15 minutes to 1 hour. If the solvent is sterile water, no more than 20 mL should be added to the vial with the drug. For continuous intravenous infusion, 1000 mg of ceftazidime should be reconstituted or in 5 mL of sterile water for injection, or in 5 mL of bacteriostatic water for injection; this solution should be added to an appropriate solvent for intravenous administration. For direct intravenous injection, the maximum single dose of ceftazidime for adult patients is 2000 mg, for children — 50 mg/kg body weight. The drug should be dissolved in an appropriate solvent to achieve a final concentration of 100 mg/mL and administered over no less than 3–5 minutes. For antibacterial prophylaxis of postoperative complications, administer 1000 mg or 2000 mg of the drug intravenously 30–90 minutes before the start of surgery. The dose may be repeated every 12 hours, but in most cases — for no more than 24 hours. In surgeries with increased risk of infection (e.g., surgeries in the colorectal area) and when infection may be accompanied by severe complications (e.g., surgeries on open heart or joint prostheses), prophylactic use of ceftazidime may last up to 72 hours after completion of surgery. Intravenous administration. Sterile powder of ceftazidime may initially be dissolved using any compatible solvent (at least 2.8 mL/g of ceftazidime), suitable for intravenous administration. To facilitate reconstitution, it is recommended to use 5 mL of solvent per 1000 mg of ceftazidime. Solutions recommended for reconstitution of sodium ceftazidime powder: 5% glucose for injection; 10% glucose for injection; 5% glucose and 0.9% sodium chloride for injection; 0.9% sodium chloride for injection; Normosol-M and 5% glucose for injection; 5% glucose and 0.2% sodium chloride for injection; Normosol-R; sterile water for injection. After reconstitution, the obtained solution should be diluted with one of the standard solvents for intravenous administration: 5% glucose for injection; 10% glucose for injection; 5% glucose and Ringer's lactate solution for injection; Ringer's lactate solution for injection; 0.9% sodium chloride for injection; 5% glucose and 0.9% sodium chloride; Normosol-M and 5% glucose for injection; Normosol-R; 5% glucose and 0.2% sodium chloride for injection. Intramuscular administration For preparing a solution intended for intramuscular administration, sterile or bacteriostatic water for injection may be used. If administration of a solution with a concentration of 250 mg/mL or higher is anticipated, lidocaine solution is recommended for preparing the solution. Such a solution can be prepared using a combination of sterile water for injection and 2% lidocaine hydrochloride solution, nearly equivalent to a 0.5% lidocaine solution concentration. A two-step dissolution method is recommended: first, add the required amount of sterile water for injection and shake until complete dissolution of ceftazidime powder, then add the required amount of 2% lidocaine solution and mix. Table 2

* A slight excess may be drawn and administered in the specified volumes. Intramuscular administration should be performed deeply into the large gluteal muscle or the anterior surface of the thigh. Stability of Solutions The chemical and physical stability of ceftoperazone solutions prepared using the parenteral solvents listed below, with the approximate ceftoperazone concentrations indicated, ensures solution stability provided the specified storage temperatures and time limits are observed. After the expiration of the indicated period, any unused solution must be discarded. At room temperature (15–25 °C), ceftoperazone solutions may be stored for 24 hours in the following solvents (approximate ceftoperazone concentrations are given in parentheses): bacteriostatic water for injection (300 mg/mL); 5% glucose for injection (2 mg to 50 mg/mL); 5% glucose for injection and Ringer's lactate solution for injection (2 mg to 50 mg/mL); 5% glucose and 0.9% sodium chloride for injection (2 mg to 50 mg/mL); 5% glucose and 0.2% sodium chloride for injection (2 mg to 50 mg/mL); 10% glucose for injection (2 mg to 50 mg/mL); Ringer's lactate solution for injection (2 mg/mL); 0.5% lidocaine hydrochloride for injection (300 mg/mL); 0.9% sodium chloride for injection (2 mg to 300 mg/mL); Normosol-M and 5% glucose for injection (2 mg to 50 mg/mL); Normosol-R (2 mg to 50 mg/mL); sterile water for injection (300 mg/mL). Reconstituted ceftoperazone solutions may be stored in glass or plastic syringes, or in glass or flexible plastic containers intended for parenteral solutions. For 5 days in a refrigerator (2–8 °C), the following solvents (approximate ceftoperazone concentrations in parentheses) are suitable: bacteriostatic water for injection (300 mg/mL); 5% glucose for injection (2 mg to 50 mg/mL); 5% glucose and 0.9% sodium chloride for injection (2 mg to 50 mg/mL); 5% glucose and 0.2% sodium chloride for injection (2 mg to 50 mg/mL); Ringer's lactate solution for injection (2 mg/mL); 0.5% lidocaine hydrochloride for injection (300 mg/mL); 0.9% sodium chloride for injection (2 mg to 300 mg/mL); Normosol-M and 5% glucose for injection (2 mg to 50 mg/mL); Normosol-R (2 mg to 50 mg/mL); sterile water for injection (300 mg/mL). Reconstituted ceftoperazone solutions may be stored in glass or plastic syringes, or in glass or flexible plastic containers intended for parenteral solutions. Ceftoperazone solutions in the following solvents (approximate ceftoperazone concentrations in parentheses) may be stored in a freezer (from -20 to -10 °C) for 3 weeks: 5% glucose for injection (50 mg/mL); 5% glucose and 0.9% sodium chloride for injection (2 mg/mL); 5% glucose and 0.2% sodium chloride for injection (2 mg/mL), or for 5 weeks: 0.9% sodium chloride for injection (300 mg/mL); sterile water for injection (300 mg/mL). Reconstituted solutions may be stored in plastic syringes or flexible plastic containers intended for parenteral solutions. The drug should be thawed before use at room temperature. After thawing, any unused solution must be discarded. The solution must not be refrozen. From a microbiological standpoint, the drug should be used immediately. If not used immediately, the storage time and conditions prior to use are the responsibility of the user and should not usually exceed 24 hours at 2–8 °C, provided reconstitution/dilution was performed under controlled and validated aseptic conditions. Paediatric population. See section "Dosage and administration". Ceftoperazone has been effectively used in children from birth. Large-scale studies involving preterm infants and newborns have not been conducted. Therefore, before prescribing ceftoperazone to preterm infants and newborns, the potential benefits and possible risks of therapy with this drug should be carefully weighed. In newborns with kernicterus, ceftoperazone does not displace bilirubin from its binding to plasma proteins. Overdose. Data on acute toxicity of sodium ceftoperazone are limited. Expected manifestations of overdose include, primarily, intensification of the drug's characteristic adverse reactions. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may cause certain neurological effects and increase the likelihood of seizures. Careful adherence to dosage recommendations is necessary to avoid overdose. Treatment should be supportive and symptomatic, based on the patient's clinical condition. No specific antidote is known. Since ceftoperazone is eliminated from the body during hemodialysis, this procedure may accelerate the elimination of the drug in cases of overdose in patients with impaired renal function. Adverse reactions. Listed below are adverse reactions that have been identified and reported during ceftoperazone therapy. Blood and lymphatic system disorders: very common: decreased hemoglobin levels, decreased hematocrit levels; common: neutropenia, positive direct Coombs test, thrombocytopenia, eosinophilia; rare: hypoprothrombinemia; frequency not known: coagulopathy. Immune system disorders: frequency not known: anaphylactic shock*, anaphylactic reaction*, anaphylactoid reaction (including shock), hypersensitivity. Vascular disorders: common: phlebitis at the catheter site; rare: hemorrhage*. Gastrointestinal disorders: common: diarrhea; uncommon: vomiting*; frequency not known: pseudomembranous colitis*. Hepatobiliary disorders: common: increased levels of AST, ALT, increased levels of alkaline phosphatase in blood, jaundice. Skin and subcutaneous tissue disorders: common: pruritus*, urticaria, maculopapular rash; frequency not known: toxic epidermal necrolysis*, Stevens-Johnson syndrome, exfoliative dermatitis*. Renal and urinary disorders: frequency not known: hematuria. General disorders and administration site conditions: uncommon: pain at injection site, fever. * Adverse reactions reported during the post-marketing period. Reporting suspected adverse reactions. Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua. Shelf life. 2 years. Storage conditions. Store in the original packaging, in a place inaccessible to children, at a temperature not exceeding 25 °C. Incompatibility. Ceftoperazone solutions and aminoglycosides should not be mixed, as physical incompatibility exists between them. If combined therapy with ceftoperazone and an aminoglycoside is planned, this can be achieved by alternating intravenous infusions, provided a separate secondary intravenous administration system is used and the primary intravenous system is flushed with the appropriate solution between infusions. It is recommended to administer ceftoperazone before aminoglycosides. Packaging. Powder in vials; 10 vials per cardboard box. Prescription category. By prescription only. Manufacturer. NBP Pharmaceutical Huamin Pharmaceutical Company Limited. Address of manufacturer and location of its business activities: No. 98 Huan Road, Economic and Technological Development Zone, Huangshi, Hubei, 435165, China.