Cephelia

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

Composition:

Active substance: cefepime;

1 vial contains cefepime dihydrochloride monohydrate 1189.14 mg or 2378.28 mg, equivalent to cefepime 1000 mg or 2000 mg;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical properties: vial contains a powder from white to light yellow in color.

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

Pharmacological properties.

Pharmacodynamics.

Cefepime exerts its effect 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-lactam ase-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 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 resistant to most cephalosporin antibiotics, including cefepime.

Gram-negative aerobes:

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

Anaerobes:

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

Pharmacokinetics.

The elimination half-life 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 120 mL/min. Cefepime is primarily excreted by the kidneys (mean renal clearance is 110 mL/min). Approximately 85% of the administered dose is recovered in urine as unchanged cefepime, 1% as N-methylpyrrolidine, about 6.8% as N-methylpyrrolidine oxide, and about 2.5% as cefepime epimer. Protein binding of cefepime to plasma proteins 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 mucous 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 for hemodialysis and 19 hours for peritoneal dialysis.

The pharmacokinetics of cefepime are not altered in patients with hepatic impairment or cystic fibrosis. Dose adjustment is not required in 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 the renal clearance is 2.0 (±1.1) mL/min/kg. After intramuscular administration, the mean peak plasma concentration at steady state is 68 mcg/mL, achieved 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.

Concentrations of the drug in cerebrospinal fluid (CSF) and plasma in children with bacterial meningitis

Time after administration (h)	Concentration in blood plasma (μg/mL)*	Concentration in CSF (μg/mL)*	CSF/blood 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 drug administration.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms susceptible to the drug:

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

Empirical therapy in patients with febrile neutropenia.

Prophylaxis of postoperative complications in intra-abdominal surgery.

Children.

• Pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and soft tissue infections;
• sepsis;
• 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, high doses of these agents should be used concomitantly with cefepime under close 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 medicinal products, 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 Cefelia is prescribed together with these medicinal products, each antibacterial agent must be administered separately.

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

Effect on laboratory test results.

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

Special precautions for use.

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 used with caution in patients with asthma or allergic diathesis. The patient's condition must 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, administration of the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other forms of therapy.

In patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation, impaired bone marrow function due to malignant hematological disorders with severe progressive neutropenia), monotherapy may be insufficient, and combination antimicrobial therapy is indicated. Antibacterial activity of cefepime.

It is unlikely that administration of cefepime in the absence of proven or suspected bacterial infection or its prophylactic use will be beneficial, but it may increase the risk of emergence of bacteria resistant to this medicinal product. Prolonged use of cefepime (as with other antibiotics) may lead to development of superinfection. The patient's condition should be re-evaluated regularly. If superinfection develops, appropriate therapeutic measures should be initiated.

Renal impairment.

The dose of the medicinal product should be adjusted in patients with impaired renal function (creatinine clearance < 50 mL/min) to compensate for reduced renal elimination. Since high serum concentrations of the antibiotic may occur at standard doses in patients with renal impairment or other conditions that may impair renal function, the maintenance dose should be reduced when administering cefepime to such patients. The next dose of the drug should be determined based on the degree of renal impairment, severity of infection, and susceptibility of the causative microorganisms.

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. In most cases, symptoms of nephrotoxicity were 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 diarrhea associated with Clostridium difficile, have been reported with the use of nearly all antibiotics, including cefepime, and may range from mild diarrhea to fatal colitis. Therefore, this diagnosis must 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, including cefepime, should be discontinued and appropriate therapeutic measures should be initiated immediately. Antiperistaltic agents are contraindicated in this situation.

Elderly patients.

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

Serological testing.

Cephalosporins tend to adsorb onto the surface of erythrocytes and react with antibodies directed against drug preparations, resulting in a positive Coombs' test. A positive Coombs' test has been reported in patients receiving cefepime twice daily, in the absence of signs of hemolysis.

False-positive results may occur in urine glucose testing. For this reason, urine glucose should be determined by glucose oxidase methods during treatment with this medicinal product.

Prothrombin time should be monitored.

When lidocaine is used as a solvent, safety information regarding lidocaine should be taken into account. L-arginine has been shown to alter glucose metabolism and simultaneously increase 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 demonstrated 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, the medicinal product should 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.

Ability to influence reaction speed when driving or operating machinery.

Not studied. If dizziness, hallucinations, confusion, or other adverse effects on the nervous system that may affect reaction speed occur, patients should refrain from driving or operating machinery.

Method of administration and dosage.

Dosage and route of administration may vary depending on the sensitivity, location, and type of microorganisms involved, the severity of the infection, as well as the patient's age and physiological condition. The usual dose for adults is 1 g administered intravenously or intramuscularly every 12 hours. The treatment course lasts 7–10 days. Severe infections may require prolonged therapy. Dosage recommendations for Cefelia in adults are provided in Table 1.

Table 1

Uncomplicated and moderate urinary tract infections	500 mg - 1 g intravenously or intramuscularly	every 12 hours
Other uncomplicated and moderate infections	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

For patients aged 65 years and older with normal renal function, dose adjustment is not required. Prophylaxis of potential infection during surgical procedures. 2 g of the medicinal product should be administered intravenously by infusion over 30 minutes, 1 hour prior to the start of surgery. After completion of infusion, an additional 500 mg of metronidazole should be administered intravenously. Metronidazole solution should not be administered simultaneously with Cefelia. In case of concomitant use, each antibiotic should be administered via separate infusion systems. If one infusion system is used for both medicinal products, the system should be flushed before metronidazole infusion.

During prolonged surgical procedures (exceeding 12 hours), a repeat dose of Cefelia equivalent to the initial dose is recommended 12 hours after the first dose, followed by administration of metronidazole.

Children aged 1 to 2 months. Use only when life-saving indications are present. Administer at a dose of 30 mg/kg body weight every 12 or 8 hours. Children with body weight below 40 kg receiving Cefelia treatment should be continuously monitored.

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

Children with body weight of 40 kg and above should receive Cefelia as for adults.

Renal impairment. In patients with impaired renal function (creatinine clearance less than 30 mL/min), the dosing regimen should be adjusted. The initial dose of Cefelia is the same as for patients with normal renal function. Recommended maintenance doses of Cefelia 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 appropriate to severity of infection; 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

If only the serum creatinine concentration is known, creatinine clearance can be calculated using the formula below.

Men:

body weight (kg) × (140 − age)

creatinine clearance (mL/min) = ---------------------------------------------------.

72 × serum creatinine (mg/dL)

Women:

creatinine clearance (mL/min) = the above value × 0.85.

During hemodialysis, approximately 68% of the administered dose of the drug is removed from the body over 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 the normal recommended doses depending on the severity of infection, with a 48-hour interval between administrations of individual doses.

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

Calculation of creatinine clearance in children:

0.55 × height (cm)

creatinine clearance (mL/min/1.73 m²) = ---------------------------------

serum creatinine (mg/dL)

or

0.52 × height (cm)

creatinine clearance (mL/min/1.73 m²) = ------------------------------------------ - 3.6.

serum creatinine (mg/dL)

Administration of the drug.

Cefeliy should be administered intravenously or deeply 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, dissolve Cefeliy 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 resulting solution should be administered slowly by bolus injection over 3–5 minutes or by intravenous infusion.

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

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

As with all parenterally administered drugs, the prepared drug 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.

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

Overdose.

Symptoms: In case of a significant overdose, especially in patients with impaired renal function, adverse effects are intensified. 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 cefepime elimination 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.

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

Respiratory system, thoracic organs and mediastinum disorders: dyspnea, cough, sore throat, shortness of breath.

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

Hepatobiliary disorders: hepatitis, cholestatic jaundice.

Renal and urinary system disorders: renal failure.

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

Cardiovascular system disorders: tachycardia, vasodilation, chest pain.

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

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

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

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

Laboratory findings: increased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), 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 may occur: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhages, liver function disorders, cholestasis, pancytopenia.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from light at temperatures not exceeding 30 °C. Keep out of reach of children.

Incompatibilities.

To avoid potential drug interactions, Cefelia (like most other beta-lactam antibiotics) should not be mixed in the same syringe with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate. If Cefelia is prescribed together with any of the above-mentioned medicinal products, each antibacterial agent should be administered separately.

Do not mix with other medicinal products in the same container. Use only the solvents specified in the section "Method of administration and dosage."

Packaging.

1000 mg or 2000 mg of powder in a vial; 1 or 10 vials per cardboard box.

Prescription category. Prescription only.

Manufacturer.

LDP – LABORATORIOS TORLAN, S.A.

Manufacturer's address and location of operations.

Ctra. de Barcelona, 135-B, Cerdanyola del Vallès, Barcelona, 08290, Spain.