Cebopim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEBOPI M (CEBOPIM)

Composition:

Active substance: cefepime in the form of cefepime dihydrochloride monohydrate (sterile, calculated as 100% anhydrous cefepime) – 500 mg, 1 g, 2 g;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder ranging from white to light yellow.

Pharmacotherapeutic group. Antibacterials for systemic use. Other beta-lactam antibiotics. Fourth-generation cephalosporins. ATC code J01D E01.

Pharmacological Properties

Pharmacodynamics

Cefepime acts by inhibiting bacterial cell wall enzyme synthesis. The drug has a broad spectrum of activity against both Gram-positive and Gram-negative bacteria, high resistance to hydrolysis by most beta-lactamases, low affinity for chromosomally mediated beta-lactamases, and rapidly penetrates Gram-negative bacterial cells.

Cefepime is active against the following microorganisms:

Gram-positive aerobes:

Staphylococcus aureus (including beta-lactamase-producing strains); Staphylococcus epidermidis (including beta-lactamase-producing strains); other staphylococcal strains, including S. hominis, S. saprophyticus; Streptococcus pyogenes (Group A streptococci); Streptococcus agalactiae (Group B streptococci); Streptococcus pneumoniae (including strains with intermediate penicillin resistance – MIC [minimum inhibitory concentration] from 0.1 to 1 mcg/mL); other beta-hemolytic streptococci (Groups C, G, F); S. bovis (Group D); Viridans group streptococci.

Most strains of enterococci, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are also resistant to most cephalosporin antibiotics, including cefepime.

Gram-negative aerobes:

Pseudomonas spp., including P. aeruginosa, P. putida, P. stutzeri; Escherichia coli; Klebsiella spp., including K. pneumoniae, K. oxytoca, K. ozaenae; Enterobacter spp., including E. cloacae, E. aerogenes, E. sakazakii; Proteus spp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (subsp. anitratus, lwoffi); Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; Haemophilus influenzae (including beta-lactamase-producing strains); Haemophilus parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including beta-lactamase-producing strains); Neisseria gonorrhoeae (including beta-lactamase-producing strains); Neisseria meningitidis; Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia spp. (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

Cefepime is inactive against some strains of Xanthomonas maltophilia (Pseudomonas maltophilia).

Anaerobes:

Bacteroides spp., including B. melaninogenicus and other oral microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp. (cefepime is inactive against Bacteroides fragilis and Clostridium difficile).

Pharmacokinetics

The elimination half-life of cefepime is approximately 2 hours. In healthy individuals, no drug accumulation has been observed.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Total clearance is about 120 mL/min. The drug is primarily excreted by the kidneys (average renal clearance is 110 mL/min). Approximately 85% of the administered dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, about 6.8% as N-methylpyrrolidine oxide, and about 2.5% as cefepime epimer. Plasma protein binding of cefepime is independent of drug concentration in serum and is less than 19%.

Cefepime is widely distributed in the body and achieves therapeutic concentrations in urine, bile, peritoneal fluid, bronchial mucosal secretions, sputum, prostate, appendix, and gallbladder.

Plasma concentrations of cefepime in healthy adult males after single intravenous/intramuscular administration are shown in the table below.

Mean plasma concentrations of cefepime (mcg/mL)

Cefepime dose	0.5 hour	1 hour	2 hours	4 hours	8 hours	12 hours
Intravenous
500 mg	38.2	21.6	11.6	5.0	1.4	0.2
1 g	78.7	44.5	24.3	10.5	2.4	0.6
2 g	163.1	85.8	44.8	19.2	3.9	1.1
Intramuscular
500 mg	8.2	12.5	12.0	6.9	1.9	0.7
1 g	14.8	25.9	26.3	16.0	4.5	1.4
2 g	36.1	49.9	51.3	31.5	8.7	2.3

In patients with impaired renal function, the elimination half-life of cefepime is prolonged. In patients with severe renal impairment undergoing dialysis, the elimination half-life is 13 hours with hemodialysis and 19 hours with peritoneal dialysis.

The pharmacokinetics of cefepime are not altered in patients with hepatic impairment or cystic fibrosis. Dose adjustment is not required for such patients.

Children

In children aged 2 months to 11 years, following a single intravenous injection, the total clearance and steady-state volume of distribution are 3.3 (± 1.0) mL/min/kg and 0.3 (± 0.1) L/kg, respectively.

Approximately 60.4 (± 30.4)% of the administered dose of cefepime is excreted unchanged in urine, and renal clearance is 2.0 (± 1.1) mL/min/kg. After intramuscular administration, the mean steady-state plasma concentration of cefepime reaches a peak of 68 mcg/mL at 0.75 hours. Eight hours after intramuscular administration, the plasma concentration of cefepime is 6 mcg/mL. The absolute bioavailability following intramuscular injection of cefepime averages 82%. Patient age and sex do not influence drug clearance.

Drug concentrations in cerebrospinal fluid (CSF) and plasma in children with bacterial meningitis

Time after administration (h)	Plasma concentration (μg/mL)*	CSF concentration (μg/mL)*	CSF/plasma concentration ratio*
0.5	67.7 ± 51.2	5.7 ± 0.14	0.12 ± 0.14
1	44.1 ± 7.8	4.3 ± 1.5	0.10 ± 0.04
2	23.9 ± 12.9	3.6 ± 2.0	0.17 ± 0.09
4	11.7 ± 15.7	4.2 ± 1.1	0.87 ± 0.56
8	4.9 ± 5.9	3.3 ± 2.8	1.02 ± 0.64

* Age from 3.1 months to 12 years with a standard deviation in age of ± 3 years.

Drug dosage 50 mg/kg body weight administered intravenously over 5–20 minutes every 8 hours. Plasma concentration and MIC were determined at the end of infusion on day 2 or 3 of treatment with the drug.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia, bronchitis;
• skin and subcutaneous tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• urinary tract infections, including pyelonephritis;
• gynecological infections;
• septicemia.

Empirical therapy in patients with febrile neutropenia.

Prophylaxis of postoperative complications in intra-abdominal surgery.

Children.

• Pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and subcutaneous tissue infections;
• septicemia;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

• Hypersensitivity to cefepime or L-arginine;
• hypersensitivity to cephalosporin antibiotics, penicillins, or other beta-lactam antibiotics.

Interaction with other medicinal products and other types of interactions.

Cefepime solution is compatible with the following parenteral solutions: 0.9% sodium chloride solution, 5% or 10% glucose solutions, 6 M sodium lactate injection solution, Ringer's lactate solution with 5% dextrose injection solution.

Due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics, concomitant administration of high doses of these agents with cefepime requires monitoring of renal function.

Concomitant use of cephalosporins with diuretics (e.g., furosemide) increases the nephrotoxicity of the former.

To avoid possible drug interactions with other agents, cefepime solution (like most other beta-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, and netilmicin sulfate. If Cebopim is prescribed together with any of these drugs, each antibiotic should be administered separately.

Concomitant treatment with bacteriostatic antibiotics may interfere with the action of beta-lactam antibiotics.

Effect on laboratory test results. Cefepime administration may cause false-positive glucose urine test results when using Benedict's reagent. It is recommended to use glucose tests based on enzymatic glucose oxidation reactions.

Special precautions.

Hypersensitivity

Before administering the medicinal product, it is necessary to determine whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactam antibiotics.

Cefepime should be administered with caution to patients with asthma or allergic diathesis. The patient's condition should be closely monitored during the first administration. If an allergic reaction occurs, treatment should be discontinued immediately.

Antibiotics should be prescribed with caution to all patients with any form of allergy, especially to medicinal products. If an allergic reaction occurs, the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require administration of adrenaline and other forms of therapy.

Patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation, reduced bone marrow activity due to malignant hematological disorders with severe progressive neutropenia) may not respond adequately to monotherapy, and therefore combination antimicrobial therapy is indicated.

Antibacterial activity of cefepime

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection, or its prophylactic use, will be beneficial; moreover, this increases the risk of emergence of bacteria resistant to this drug.

Prolonged use of cefepime (as with other antibiotics) may lead to the development of superinfection. Repeated assessment of the patient's condition is necessary. If superinfection develops, appropriate therapeutic measures should be initiated.

Renal impairment

Dosage adjustment of the drug is required in patients with impaired renal function (creatinine clearance < 50 mL/min) to compensate for reduced renal elimination rate. Since high antibiotic concentrations in serum may occur at standard doses in patients with renal impairment or other conditions that may impair renal function, the maintenance dose of cefepime should be reduced in such patients. When determining the next dose of the drug, the degree of renal impairment, severity of infection, and susceptibility of the causative microorganisms should be taken into account.

During post-marketing surveillance, the following serious adverse reactions have been reported: reversible encephalopathy (disturbance of consciousness, including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including epileptic status), and/or renal failure. Most cases occurred in patients with renal impairment who received doses of cefepime exceeding the recommended ones.

Symptoms of nephrotoxicity were mostly reversible and resolved after discontinuation of cefepime and/or hemodialysis.

Clostridium difficile-associated diarrhea

Antibiotic-associated diarrhea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported during treatment with nearly all antibiotics, including cefepime, with manifestations ranging from mild diarrhea to fatal colitis. Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after cefepime administration. If antibiotic-associated diarrhea or antibiotic-associated colitis is suspected or confirmed, antibacterial therapy, particularly cefepime, should be discontinued and appropriate therapeutic measures should be initiated immediately. Antiperistaltic agents are contraindicated in this situation.

Elderly patients

Cefepime is predominantly excreted by the kidneys, and the risk of toxic reactions to this drug may be higher in patients with renal impairment. Since elderly patients are more likely to have decreased renal function, dose selection should be cautious, and renal function should be monitored.

Serological testing

Cephalosporins may be absorbed onto the surface of erythrocytes and react with antibodies directed against the drugs, resulting in a positive Coombs test. Cases of positive Coombs test results in the absence of hemolysis have been reported in patients receiving cefepime twice daily.

False-positive results may occur in urine glucose testing. For this reason, during treatment with the drug, urine glucose should be determined using glucose oxidase methods.

Patients should have their prothrombin time monitored.

When lidocaine is used as a solvent, safety information regarding lidocaine should be taken into account.

It has been demonstrated that L-arginine alters glucose metabolism and simultaneously increases serum potassium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. Effects at lower doses are currently unknown.

Use during pregnancy or breastfeeding.

Animal studies have shown no effect on reproductive function and no harmful effects on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted; therefore, Cefepime may be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime passes into breast milk in very small amounts; therefore, breastfeeding should be discontinued during treatment with Cefepime.

Ability to affect reaction speed when driving or operating machinery.

The ability of the medicinal product to affect reaction speed when driving or operating machinery has not been studied. If dizziness, hallucinations, confusion, or other nervous system side effects that may affect reaction speed occur, patients should refrain from driving or operating machinery.

Administration and dosage.

Dosage and route of administration may vary depending on the sensitivity, location, and type of microorganisms, severity of infection, as well as the patient's age and functional status. Usually, adults should be administered 1 g of the drug intravenously/intramuscularly every 12 hours. The treatment course lasts 7–10 days. Severe infections may require prolonged treatment.

Dosage recommendations for the drug Cebopim in adults are presented in Table 1.

Table 1

Urinary tract infections (mild to moderate severity)	500 mg – 1 g intravenously or intramuscularly	every 12 hours
Other infections (mild to moderate severity)	1 g intravenously or intramuscularly	every 12 hours
Severe infections	2 g intravenously	every 12 hours
Very severe and life-threatening infections	2 g intravenously	every 8 hours

Patients aged 65 years and older with normal renal function do not require dose adjustment of the medicinal product.

Prophylaxis of potential infection during surgical procedures. 2 g of the drug should be administered intravenously by infusion over 30 minutes, 1 hour prior to the start of surgery. After completion of the infusion, an additional 500 mg of metronidazole should be administered intravenously. Metronidazole solution should not be administered simultaneously with the drug Cebopim. If both antibiotics are used concomitantly, each should be administered via separate infusion systems. If a single infusion system is used for both drugs, the system must be flushed before administering metronidazole.

During prolonged surgical procedures (exceeding 12 hours), a repeat dose of the same amount of Cebopim should be administered 12 hours after the first dose, followed by administration of metronidazole.

Children aged 1 to 2 months. Should be used only for life-threatening indications. Administer at a dose of 30 mg/kg body weight every 12 or 8 hours. Children with body weight under 40 kg receiving Cebopim therapy must be continuously monitored.

Children aged 2 months and older. The maximum dose for children should not exceed the recommended adult dose. The recommended dose for children with body weight under 40 kg is 50 mg/kg every 12 hours (for patients with febrile neutropenia and bacterial meningitis – every 8 hours). The duration of therapy is 7–10 days; severe infections may require longer treatment.

For children with body weight of 40 kg and above, Cebopim should be administered as in adults.

Renal function impairment. In patients with impaired renal function (creatinine clearance less than 30 mL/min), the dosing regimen must be adjusted. The initial dose of Cebopim is the same as for patients with normal renal function. Recommended maintenance doses of Cebopim are shown in Table 2.

Table 2

Creatinine clearance (ml/min)	Recommended maintenance doses
	Urinary tract infections (mild to moderate severity)	Other infections (mild to moderate severity)	Severe infections	Very severe and life-threatening infections
> 50	500 mg every 12 hours	1 g every 12 hours	2 g every 12 hours	2 g every 8 hours
	Standard dosing according to infection severity; dose adjustment not required
30–50	500 mg every 24 hours	1 g every 24 hours	2 g every 24 hours	2 g every 12 hours
11–29	500 mg every 24 hours	500 mg every 24 hours	1 g every 24 hours	2 g every 24 hours
≤ 10	250 mg every 24 hours	250 mg every 24 hours	500 mg every 24 hours	1 g every 24 hours
hemodialysis	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

Creatinine clearance is calculated using the following formula:

Men:

Women:

During hemodialysis, approximately 68% of the administered dose of the drug is eliminated from the body within 3 hours. A supplemental dose equivalent to the initial dose should be administered after each hemodialysis session. For continuous ambulatory peritoneal dialysis, the drug may be administered at normal recommended doses depending on the severity of infection, with a 48-hour interval between doses.

For children with impaired renal function, dosage reduction or prolonged dosing intervals are recommended as indicated in Table 2.

Calculation of creatinine clearance in children:

or

Administration of the drug.

Cefepime should be administered intravenously or deep intramuscularly into a large muscle mass (e.g., the upper outer quadrant of the gluteal muscle).

Intravenous administration. This route is preferred for patients with severe, life-threatening infections.

For intravenous administration, cefepime should be dissolved in 5 or 10 mL of sterile water for injection, 5% dextrose solution, or 0.9% sodium chloride solution, as specified in Table 3. The prepared solution should be administered slowly as an intravenous bolus over 3–5 minutes or by intravenous infusion using an intravenous administration set.

Intramuscular administration. Cefepime should be dissolved in sterile water for injection, 0.9% sodium chloride solution, 5% dextrose solution for injection, bacteriostatic water for injection containing parabens or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at the concentrations specified in Table 3.

When lidocaine is used as a solvent, a skin test for tolerance should be performed prior to administration.

As with all parenterally administered drugs, reconstituted cefepime solutions should be inspected visually for particulate matter prior to administration.

Table 3

	Volume of diluent (ml)	Approximate volume of reconstituted solution (ml)	Approximate concentration of cefepime (mg/ml)
Intravenous administration
500 mg/vial	5	5.7	90
1 g/vial	10	11.4	90
2 g/vial	10	12.8	160
Intramuscular administration
500 mg/vial	1.5	2.2	230
1 g/vial	3.0	4.4	230

Children.

The medicinal product can be used in children aged 1 month and older.

If lidocaine is used as a solvent, safety information regarding lidocaine should be taken into account.

Overdose.

Symptoms: In case of significant exceeding the recommended doses, adverse effects are intensified, especially in patients with impaired renal function. Symptoms of overdose include encephalopathy accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus, epileptiform seizures, and neuromuscular excitability.

Treatment. Administration of the medicinal product should be discontinued and symptomatic therapy initiated. Hemodialysis accelerates the elimination of cefepime from the body; peritoneal dialysis is poorly effective. Severe immediate-type allergic reactions require administration of adrenaline and other forms of intensive therapy.

Adverse reactions

Adverse reactions are rare.

Immune system: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema.

Skin and subcutaneous tissue: skin rashes, pruritus, urticaria.

Gastrointestinal system: nausea, vomiting, oral candidiasis, diarrhea, colitis, constipation, abdominal pain, dyspepsia, altered taste sensation.

Hepatobiliary system: hepatitis, cholestatic jaundice.

Nervous system: dizziness, headache, restlessness, insomnia, paresthesia, confusion/loss of consciousness, seizures/epileptiform attacks, myoclonus, encephalopathy, hallucinations, stupor, coma.

General disorders and administration site conditions: increased body temperature, sweating, chest/back pain, asthenia, injection site reactions including inflammation, phlebitis, pain.

Infections: candidiasis, vaginitis, genital pruritus, pseudomembranous colitis, other superinfections.

Respiratory system: respiratory disorders, cough, sore throat, dyspnea.

Cardiovascular system: tachycardia, vasodilation, chest pain.

Urinary system: renal failure.

Blood and lymphatic system: anemia, eosinophilia, transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia.

Laboratory findings: increased plasma levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin; prolonged prothrombin time or partial thromboplastin time (PTT); positive Coombs test without hemolysis; transient increase in blood urea nitrogen and/or serum creatinine; false-positive urine glucose test.

In addition to the above-mentioned adverse reactions, adverse effects typical for cephalosporin antibiotics are possible: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, liver function disorders, cholestasis, pancytopenia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://аіsf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

The reconstituted solution is stable for 24 hours at room temperature or 7 days when stored in a refrigerator (2–8 °C). From a microbiological standpoint, this medicinal product should be used immediately. If not used immediately, responsibility for storage duration and conditions during use lies with the user.

Incompatibilities. To avoid possible drug interactions, Cebopim (like most other beta-lactam antibiotics) should not be administered in the same syringe with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate. If Cebopim is prescribed together with any of the above-mentioned drugs, each antibiotic should be administered separately.

Do not mix with other medicinal products in the same container. Use only the diluents specified in the section "Dosage and administration".

Packaging. 500 mg powder for solution for injection in a vial. One vial per carton.

1 g powder for solution for injection in a vial. One vial per carton; one vial with diluent (water for injection) in 5 ml or 10 ml ampoule per carton with cardboard partition.

2 g powder for solution for injection in a vial. One vial per carton.

Prescription status. 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.