Medoceff

INSTRUCTIONS for medical use of the medicinal product Medocef (MEDOCEF)

Composition:

Active substance: cefoperazone;

1 vial contains cefoperazone sodium equivalent to cefoperazone 1 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or yellowish powder, hygroscopic.

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

Pharmacological Properties

Pharmacodynamics

The bactericidal activity of Medoceff is due to inhibition of bacterial cell wall synthesis.

Medoceff is active in vitro against a wide range of clinically significant microorganisms. At the same time, it is resistant to the action of many β-lactamases.

The following microorganisms are susceptible to Medoceff:

Gram-positive microorganisms:

Staphylococcus aureus (strains producing and non-producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae (former name – Diplococcus pneumoniae), Streptococcus pyogenes (β-hemolytic streptococcus group A), Streptococcus agalactiae (β-hemolytic streptococcus group B), Streptococcus faecalis (enterococcus), β-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, Acinetobacter calcoaceticus, Neisseria gonorrhoeae (strains producing and non-producing β-lactamases), Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.

Anaerobic microorganisms:

Gram-positive and gram-negative cocci (including genus Peptococcus, Peptostreptococcus, and Veillonella);

Gram-positive bacilli (including genus Clostridium, Eubacterium, and Lactobacillus);

Gram-negative bacilli (including genus Fusobacterium, many strains of Bacteroides fragilis, and other representatives of the genus Bacteroides).

Pharmacokinetics

High concentrations in blood, bile, and urine are achieved after single administration of the drug. Table 1 shows the serum concentrations of the drug in healthy adult individuals. These data were obtained after 15-minute intravenous administration of 1, 2, 3, or 4 g of the drug or single intramuscular administration of 1 or 2 g of the drug. Probenecid has no effect on the serum concentration levels of cefoperazone.

Serum concentrations of cefoperazone. Table 1

* Time elapsed after administration of the drug (counting starts immediately after completion of infusion).

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

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

Medocef reaches therapeutic levels in all body fluids and tissues that have been studied. These include ascitic and cerebrospinal fluid (during meningitis), urine, bile, gallbladder wall, sputum and lungs, palatine tonsils and sinus mucosa, atria, kidneys, ureters, prostate, testes, uterus and fallopian tubes, bones, umbilical cord blood, and amniotic fluid.

Medocef is excreted via bile and urine. Drug concentrations in bile reach very high levels (typically within 1–3 hours after administration) and exceed corresponding serum concentrations by 100-fold.

Bile 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 the drug to patients without biliary obstruction.

Twelve hours after administration at various doses and by different routes, urinary excretion of cefoperazone in patients with normal renal function reaches on average between 20% and 30%. Drug concentrations in urine exceeding 2200 mcg/mL were achieved 15 minutes after intravenous administration of 2 g of Medocef. After intramuscular administration of 2 g of the drug, maximum urinary concentrations were approximately 1000 mcg/mL.

Repeated administration of Medocef does not lead to drug accumulation in healthy volunteers.

In patients with impaired liver function, the elimination half-life of the drug from serum increases, but urinary excretion also increases. In patients with both renal and hepatic insufficiency, Medocef may accumulate in blood serum.

In patients with renal insufficiency, maximum serum concentration, area under the pharmacokinetic curve, and elimination half-life from serum are comparable to those in healthy volunteers.

Clinical characteristics.

Indications.

For the treatment of infections caused by microorganisms sensitive to Medoceph:

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

Prophylaxis.

Medoceph may be administered for prophylaxis of postoperative complications during abdominal, gynecological, cardiovascular, and orthopedic surgeries.

Contraindications.

Cefoperazone is contraindicated in patients with a known allergy to cephalosporin antibiotics.

Interaction with other medicinal products and other forms of interaction.

Aminoglycoside antibiotics

Concomitant use may have an additive nephrotoxic effect. Avoid simultaneous administration of cefoperazone and aminoglycoside antibiotics in patients with existing renal impairment. If concomitant use is necessary, patients should be monitored for signs of nephrotoxicity.

Anticoagulants

Concomitant use of coumarin or indandione derivatives, heparin, or thrombolytic agents may increase the risk of bleeding. Such therapy should be closely monitored, including prothrombin time. If necessary, the dose of anticoagulant agents should be adjusted during and after cefoperazone therapy to maintain appropriate anticoagulation levels.

Loop diuretics

The combination of cephalosporins and loop diuretics may lead to nephrotoxicity. Simultaneous use of these agents should be avoided in patients with existing renal impairment.

Alcohol

Disulfiram-like reactions, characterized by flushing, increased sweating, headache, and tachycardia, have been reported when alcohol is consumed during treatment with this drug and even up to 5 days after the last dose of cefoperazone. Similar reactions have also occurred with other cephalosporins; therefore, patients should be warned against consuming alcoholic beverages during cefoperazone therapy. Patients requiring oral or parenteral nutritional support should avoid solutions containing ethanol.

Interactions affecting laboratory test results

False-positive urine glucose reactions may occur when testing with Benedict's or Fehling's solutions.

Special precautions for use.

Hypersensitivity

Severe hypersensitivity reactions (anaphylactic reactions), sometimes fatal, have been reported in patients receiving β-lactam agents or cephalosporin drugs, including cefoperazone. Such reactions are more likely to occur in patients with a history of hypersensitivity to multiple allergens.

A careful medical history should be obtained prior to initiating therapy with cefoperazone to determine whether the patient has previously experienced hypersensitivity reactions to cephalosporins, penicillins, or other drugs. This drug should be administered with caution to patients who are sensitive to penicillins. Antibiotics should be used cautiously in patients who have previously exhibited any type of allergic reaction, especially drug allergies.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy initiated. Serious anaphylactic reactions require immediate emergency treatment with adrenaline (epinephrine). If necessary, oxygen, intravenous corticosteroids, and airway maintenance, including intubation, should be administered.

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 severe skin reaction occurs, cefoperazone therapy should be discontinued and appropriate treatment initiated (see section "Adverse reactions").

Use in patients with impaired liver function

Cefoperazone is predominantly excreted via bile. In patients with liver disease and/or biliary obstruction, the serum half-life of cefoperazone is prolonged and renal excretion of the drug in urine is increased. Even in cases of severe liver dysfunction, therapeutic concentrations of cefoperazone are achieved in bile, and the half-life increases only 2- to 4-fold.

General warnings

Cases of severe bleeding, including fatal events, have been reported during cefoperazone use. Patients at risk include those with poor nutrition, malabsorption, and those receiving prolonged parenteral nutrition. Such patients should be monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. If prolonged bleeding occurs without other identifiable causes, cefoperazone should be discontinued. As with other antibiotics, prolonged use of cefoperazone may result in overgrowth of resistant microorganisms; therefore, patients should be closely monitored during therapy. As with any potent systemic agent, periodic laboratory tests to monitor possible organ system dysfunction (particularly kidneys, liver, and hematopoietic system) are recommended during prolonged therapy with cefoperazone. Such monitoring is especially important in newborns, particularly premature infants, and other infants.

During treatment with nearly all antibacterial agents, including cefoperazone, cases of diarrhea associated with Clostridium difficile (Clostridium difficile associated diarrhea, CDAD) have been reported, ranging in severity from mild diarrhea to fatal colitis. Antibiotic therapy alters the normal gut flora, 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 are associated with increased morbidity and mortality, as the infections they cause may be refractory to antimicrobial therapy and may require colectomy. CDAD should be suspected in all patients who develop diarrhea following antibiotic use. Careful medical history is essential, as CDAD has been reported to occur more than two months after administration of antibacterial agents.

Patients on a low-sodium diet should be advised that 1 g of cefoperazone contains 34 mg of sodium.

Use during pregnancy or breastfeeding.

Pregnancy

Adequate and well-controlled studies in pregnant women have not been conducted; therefore, this medicinal product should be used during pregnancy only if clearly needed.

Breastfeeding period

Cefoperazone is excreted in small amounts into breast milk; therefore, the drug should be used with caution during breastfeeding.

Ability to affect reaction speed when driving vehicles or operating machinery.

Clinical experience with cefoperazone suggests that its effect on a patient's ability to drive vehicles or operate machinery is unlikely.

Administration and Dosage

The drug is intended for intravenous or intramuscular administration.

Before initiating therapy with this drug, hypersensitivity to the antibiotic and to lidocaine must be ruled out in the patient.

Adults.

The usual adult dose is 2–4 g per day, administered every 12 hours in equally divided doses. In particularly severe infections, the dose may be increased to 8 g/day, administered every 12 hours in equally divided doses. Administration of Medoceff in daily doses of 12–16 g, divided into 3 equal doses (at 8-hour intervals), has not been associated with complications. Treatment with the drug may be initiated before the results of microbial susceptibility testing are available.

The recommended dose for uncomplicated gonococcal urethritis is a single intramuscular dose of 500 mg.

Combination therapy.

Due to the broad spectrum of activity of Medoceff, monotherapy is feasible for most infections. However, Medoceff may also be used in combination with other antibiotics when indicated. When used concomitantly with aminoglycosides, renal function should be monitored.

Use in patients with hepatic impairment.

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

Use in patients with renal impairment.

Since the kidneys are not the primary route of elimination of Medoceff, patients with renal impairment may receive the usual daily dose (2–4 g) without dosage adjustment. For patients with a glomerular filtration rate below 18 ml/min or serum creatinine levels exceeding 3.5 mg/100 ml, the maximum daily dose is 4 g.

The serum half-life of Medoceff 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 renal dysfunction, serum drug concentration monitoring should be performed, and dosage adjusted as necessary. If serum drug concentration monitoring is not performed, the daily dose should not exceed 2 g.

Children.

When treating children, including infants, Medoceff should be administered at daily doses of 50–200 mg per kg of body weight, given in two divided doses (every 8–12 hours). The maximum daily dose should not exceed 12 g. Daily doses up to 300 mg/kg have been used in the treatment of infants and children with severe infections, including several patients with bacterial meningitis, without causing complications.

Use in newborns.

In newborns (up to 8 days of age), the drug should be administered every 12 hours.

Intravenous administration in children and adults.

For intermittent intravenous infusion, 1 g of Medoceff (contents of one vial) should be dissolved in 20–100 ml of a compatible sterile intravenous solution and infused over 15 minutes to 1 hour. If sterile water is used as the solvent, no more than 20 ml should be added to the vial.

For continuous intravenous infusion, one gram of Medoceff should be dissolved either in 5 ml of sterile water for injection or in 5 ml of bacteriostatic water for injection; this solution should then be added to an appropriate intravenous diluent.

For direct intravenous injection, the maximum single dose of Medoceff is 2 g for adult patients and 50 mg/kg body weight for children. The drug should be dissolved in an appropriate diluent to achieve a final concentration of 100 mg/ml and administered over at least 3–5 minutes.

For prophylaxis of postoperative bacterial complications, 1 g or 2 g of the drug should be administered intravenously 30–90 minutes before the start of surgery. The dose may be repeated every 12 hours, but in most cases, not for longer than 24 hours. In surgeries with a high risk of infection (e.g., colorectal surgery) or when infection may have particularly serious consequences (e.g., open-heart surgery or joint prostheses), prophylactic use may continue for up to 72 hours after surgery.

Intravenous administration.

Sterile Medoceff powder may first be reconstituted using any compatible diluent (2.8 ml per g of cefoperazone) suitable for intravenous administration (Table 2). For easier reconstitution, it is recommended to use 5 ml of diluent per 1 g of Medoceff.

Table 2

Solutions recommended for reconstitution of cefoperazone sodium powder

After this, the entire volume of the obtained solution should be diluted with one of the standard intravenous infusion solvents (Table 3).

Table 3

Solvents for intravenous infusions

Intramuscular administration.

For the preparation of a solution intended for intramuscular administration, sterile or bacteriostatic water for injection may be used. In cases where administration of a solution with a concentration of 250 mg/ml or higher is anticipated, it is recommended to use lidocaine solution for reconstitution. Such a solution can be prepared using sterile water for injection and 2% lidocaine solution, with the final lidocaine concentration being 0.5%. When using lidocaine hydrochloride as a solvent, the safety information regarding lidocaine must be taken into account.

A two-step reconstitution method is recommended: first, add the required amount of sterile water for injection and shake until the Medocef powder is completely dissolved; then, add the required amount of 2% lidocaine solution and mix.

* An excess amount is provided, sufficient for obtaining and administering the declared volumes.

Intramuscular injection should be administered deeply into the gluteus maximus muscle or into the anterior thigh.

Storage of solutions.

Stability.

The parenteral solvents listed below and the approximate concentrations of Medoceff provide solution stability, provided the specified values and time intervals are observed. After expiration of the stated period, any unused solution must be discarded.

Stable at room temperature (15–25 °C), 24 hours

Reconstituted solutions of Medocef can be stored in glass or plastic syringes, glass or flexible plastic containers intended for parenteral solutions, for 5 days in a refrigerator (2-8 °C).

Reconstituted solutions of Medoceff can be stored in glass or plastic syringes, glass or flexible plastic containers intended for parenteral solutions, for 3 or 5 weeks in a freezer compartment (from -20 °C to -10 °C):

Reconstituted solutions of Medocefe can be 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.

Children.

Cefoperazone can be effectively used in infants. Extensive studies in premature infants and newborns have not been conducted. Therefore, before prescribing cefoperazone to premature infants and newborns, the potential benefits and possible risks of therapy with this drug should be carefully weighed.

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

Overdose.

Data on acute toxicity of sodium cefoperazone are limited. Expected manifestations of drug overdose are primarily an intensification of the drug's characteristic adverse reactions. It should be considered that high concentrations of β-lactam antibiotics in cerebrospinal fluid may cause neurological effects and seizures. Since cefoperazone is removed from the body during hemodialysis, this procedure may accelerate drug elimination in cases of overdose occurring in patients with impaired renal function.

Side effects

Nervous system disorders. Cefoperazone may significantly reduce the albumin reserve concentration and, when administered to newborns with jaundice, may increase the risk of bilirubin encephalopathy in neonates.

Blood and lymphatic system disorders. During treatment with the medicinal product, cases of mild neutrophil reduction have been reported. Very common: decreased hemoglobin levels, decreased hematocrit levels. Common: neutropenia, positive direct Coombs test, thrombocytopenia, eosinophilia. Rare: hypoprothrombinemia. Frequency not known: coagulopathy. Leukopenia, thrombocytopenia, anemia, bleeding, and prolonged prothrombin time have been reported.

Immune system disorders. Frequency not known: anaphylactoid reactions (anaphylactic shock), hypersensitivity reactions: maculopapular rashes, urticaria, eosinophilia, and drug fever. Such reactions to Medoceff treatment occur most frequently in patients with a history of allergic reactions, particularly to penicillins.

Vascular disorders. Common: phlebitis at the catheter insertion site. Rare: hemorrhage.

Gastrointestinal disorders. Common: diarrhea. Uncommon: vomiting. Frequency not known: pseudomembranous colitis.

Hepatobiliary disorders. Common: increased levels of ALT, AST, and alkaline phosphatase, jaundice.

Skin and subcutaneous tissue disorders. Common: pruritus, urticaria, maculopapular rashes. Frequency not known: toxic epidermal necrolysis, Stevens–Johnson syndrome, exfoliative dermatitis.

Renal and urinary system disorders. Frequency not known: hematuria.

General disorders and administration site conditions. Uncommon: irritation, pain at the injection site, fever.

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

Nervous system disorders: hyperesthesia of the oral mucosa, restlessness.

Allergic reactions: chills, bronchospasm, dyspnea, laryngospasm, erythema, rash.

Other: superinfection.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should 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 a temperature not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Incompatibilities.

Solutions of Medoceff and aminoglycosides should not be administered simultaneously due to physical incompatibility. If combination therapy with Medoceff and an aminoglycoside is intended, it can be performed by alternating intravenous infusions, provided that separate intravenous administration systems are used and the primary intravenous line is flushed with an appropriate solution between infusions. It is recommended to administer Medoceff before aminoglycosides.

Packaging. Vials containing 1 g of powder; 1, 10, or 100 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medocem Limited / Medochemie Limited.

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