Roxipim

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROXIPIME (ROXIPIME)

Composition:

Active substance: cefepime;

1 vial of the medicinal product contains cefepime (as cefepime dihydrochloride monohydrate) 1.0 g;

Excipient: arginine;

1 ampoule of solvent contains water for injections 10 ml.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: the product is a powder from white to pale yellow in color; the solvent is a clear, colorless solution.

Pharmacotherapeutic group.

Antibacterials for systemic use. Beta-lactam antibiotics.

ATC code J01D E01.

Pharmacological Properties

Pharmacodynamics

The active substance of the medicinal product, cefepime, is a β-lactam cephalosporin antibiotic of the 4th generation with a broad spectrum of activity intended for parenteral administration. It exerts a bactericidal effect by inhibiting cell wall synthesis.

Cefepime is active against Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or 3rd-generation cephalosporin antibiotics.

Cefepime is highly stable against the action of most β-lactamases, has low affinity for chromosomally mediated β-lactamases, and rapidly penetrates Gram-negative bacteria.

Within bacterial cells, the molecular targets of cefepime are penicillin-binding proteins (PBPs). In studies with Escherichia coli and Enterobacter cloacae, cefepime showed the highest affinity for PBP3, PBP2, PBP1a, and PBP1b. The degree of cefepime binding to penicillin-binding protein PBP2 significantly exceeds the affinity of other parenteral cephalosporins, which may enhance the antibacterial activity of cefepime.

Moderate affinity of cefepime for PBP 1a and 1b also contributes to its level of bactericidal activity.

The ratio of MBC (minimum bactericidal concentration) to MIC (minimum inhibitory concentration) for cefepime is less than 2 for more than 80% of isolates of all susceptible Gram-positive and Gram-negative bacteria.

In vitro studies on isolates of Pseudomonas aeruginosa have demonstrated synergistic effects of cefepime with aminoglycosides.

The prevalence of resistance among individual bacterial strains may vary geographically and over time. Therefore, it is advisable to consider local microbial resistance data before initiating therapy.

Cefepime is active against the microorganisms listed below.

Gram-positive aerobes: Staphylococcus aureus and Staphylococcus epidermidis (including β-lactamase-producing strains); other staphylococcal strains, including Staphylococcus hominis, Staphylococcus saprophyticus; Streptococcus pyogenes (Group A streptococci); Streptococcus agalactiae (Group B streptococci); Streptococcus pneumoniae (including strains with intermediate resistance to penicillin – MIC from 0.1 to 1 μg/mL); other β-hemolytic streptococci (Groups C, G, F), Streptococcus bovis (Group D), Viridans group streptococci.

Most enterococcal strains, such as Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to most cephalosporin antibiotics, including cefepime.

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

Cefepime is inactive against many strains of Stenotrophomonas maltophilia (formerly known as Xanthomonas maltophilia or Pseudomonas maltophilia).

Anaerobes: Bacteroides spp.; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Prevotella melaninogenicus (formerly known as Bacteroides melaninogenicus); Veillonella spp.

Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics

Absorption.

Cefepime is completely absorbed after intramuscular administration.

Mean plasma concentrations of cefepime in healthy adult males at various time points after single intravenous (i.v.) and intramuscular (i.m.) administration at doses of 0.5 mg, 1 mg, and 2 mg are presented in Table 1.

Table 1

Cefepime dose	Cefepime plasma concentration (mcg/mL)
	0.5 hour	1 hour	2 hours	4 hours	8 hours	12 hours
Intravenous administration
0.5 g	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 administration
0.5 g	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

Distribution.

Therapeutic concentrations of cefepime in various tissues and fluids are presented in Table 2.

Table 2

Mean concentrations of cefepime in various body fluids (mcg/mL) and tissues (mcg/g) in healthy adult males
Body fluids and tissues	Dose (IV)	Mean sampling time (hours) after dosing	Mean concentration
Urine	0.5 g 1 g 2 g	0-4 0-4 0-4	292 926 3120
Bile	2 g	9.4	17.8
Peritoneal fluid	2 g	4.4	18.3
Bullae fluid	2 g	1.5	81.4
Bronchial mucosa	2 g	4.8	24.1
Sputum	2 g	4.0	7.4
Prostate	2 g	1.0	31.5
Appendix	2 g	5.7	5.2
Gallbladder	2 g	8.9	11.9

Metabolism.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Approximately 85% of the administered dose of cefepime is excreted unchanged in urine, less than 1% as N-methylpyrrolidine, 6.8% as N-oxide, and 2.5% as cefepime epimer. The extent of cefepime plasma protein binding averages 16.4% and is independent of its plasma concentration.

Excretion.

After doses ranging from 250 mg to 2 g, the elimination half-life (T_1/2) of cefepime averages approximately 2 hours. In healthy volunteers receiving cefepime 2 g intravenously every 8 hours for 9 days, no accumulation of the drug was observed. Mean total clearance is 120 mL/min. Cefepime is eliminated almost entirely by the kidneys, primarily via glomerular filtration (mean renal clearance is 110 mL/min).

Pharmacokinetics in special patient groups.

Patients with cystic fibrosis.

Clinically significant improvement was observed in patients with cystic fibrosis receiving cefepime for acute pulmonary exacerbations (n=24, mean age 15 years, age range 5–47 years). Antibiotic therapy may not achieve bacteriological eradication in these patients. No clinically significant changes in cefepime pharmacokinetics were observed in patients with cystic fibrosis.

Patients with renal impairment.

In patients with varying degrees of renal impairment, T_1/2 is prolonged, and a linear relationship exists between total clearance and creatinine clearance. Dosage adjustment of cefepime is required in patients with impaired renal function (see section "Dosage and administration"). The mean T_1/2 in patients with severe renal impairment requiring dialysis is 13 hours during hemodialysis and 19 hours during continuous ambulatory peritoneal dialysis.

Patients with hepatic impairment.

In patients with hepatic impairment receiving a single 1 g dose of cefepime, pharmacokinetics were not altered. Dose adjustment of cefepime is not necessary in this patient group.

Elderly patients.

After a single intravenous dose of 1 g cefepime in healthy volunteers aged 65 years and older, an increase in the area under the concentration-time curve (AUC) and a decrease in renal clearance were observed compared to younger volunteers. Dose adjustment of cefepime is recommended in elderly patients with impaired renal function (see section "Dosage and administration").

Children.

Pharmacokinetic studies of cefepime were conducted in children aged 2 months to 11 years after single or multiple doses administered every 8 or every 12 hours. After a single intravenous injection, mean total body clearance and steady-state volume of distribution averaged 3.3 mL/min/kg and 0.3 L/kg, respectively. Urinary excretion of unchanged cefepime accounted for 60.4% of the administered dose, and mean renal clearance was 2 mL/min/kg.

Following repeated intravenous administration, plasma cefepime concentrations at steady state were similar to those after a single dose, with only minimal accumulation.

Other pharmacokinetic parameters in infants and children did not differ significantly between single and multiple dosing, or between different dosing regimens (8 or 12 hours).

Age and gender had no significant effect on cefepime pharmacokinetics.

After intramuscular administration, mean peak plasma concentration at steady state was 68 µg/mL, reached within 0.75 hours.

Eight hours after intramuscular administration, mean plasma concentration of cefepime was 6 µg/mL. Absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Bioavailability of cefepime after intramuscular injection averaged 82%.

Cefepime concentrations (± standard deviation) in cerebrospinal fluid (CSF) and plasma, and CSF/plasma concentration ratios in infants and children are presented in Table 3*.

Table 3

Time after administration, hours	N	Concentration in blood plasma, mcg/mL	Concentration in CSF, mcg/mL	CSF/plasma concentration ratio
0.5	7	67.1 (51.2)	5.7 (7.3)	0.12 (0.14)
1	4	44.1 (7.8)	4.3 (1.5)	0.10 (0.04)
2	5	23.9 (12.9)	3.6 (2.0)	0.17 (0.09)
4	5	11.7 (15.7)	4.2 (1.1)	0.87 (0.56)
8	5	4.9 (5.9)	3.3 (2.8)	1.02 (0.64)

* Patient age ranged from 3.1 months to 12 years with a standard deviation of 2.6 (3.0) years. In patients with suspected central nervous system infections, the dose of cefepime was 50 mg/kg body weight administered intravenously over 5–20 minutes every 8 hours. Plasma and CSF concentrations were measured at the end of infusion on day 2 or 3 of cefepime administration.

Clinical characteristics.

Indications.

Adults.

Treatment of infections caused by microorganisms sensitive to cefepime:

• lower respiratory tract infections (including pneumonia and bronchitis);
• complicated and uncomplicated urinary tract infections (including pyelonephritis);
• skin and soft tissue infections;
• intra-abdominal infections (including peritonitis and biliary tract infections);
• gynecological infections;
• bacteremia caused or likely caused by any of the above-mentioned infections;
• febrile neutropenia*;
• prevention of surgical infections during intra-abdominal surgery.

Children.

Treatment of infections caused by microorganisms sensitive to cefepime:

• pneumonia;
• complicated and uncomplicated urinary tract infections (including pyelonephritis);
• skin and soft tissue infections;
• septicemia;
• febrile neutropenia*;
• bacterial meningitis.

* Cefepime may be used as monotherapy for empirical treatment of patients with febrile neutropenia. In patients at high risk of developing severe infections (e.g., recent bone marrow transplantation, arterial hypotension, hematologic malignancies, or severe or prolonged neutropenia), monotherapy may be insufficient. Such patients require combination antibacterial therapy (see section "Pharmacodynamics" in "Pharmacological properties").

Empirical therapy with cefepime may be initiated before susceptibility testing results are available, with subsequent adjustment of antibiotic choice and treatment regimen if necessary.

Cefepime may be used as monotherapy prior to pathogen identification, as it has a broad spectrum of antibacterial activity against both gram-positive and gram-negative microorganisms.

In patients at risk of mixed aerobic and anaerobic infections, especially if microorganisms resistant to cefepime may be involved (see section "Pharmacodynamics" in "Pharmacological properties"), concomitant therapy with an anti-anaerobic agent is recommended until pathogen identification. After pathogen identification and confirmation of susceptibility to cefepime, treatment should be adjusted according to test results.

Contraindications.

Hypersensitivity to cefepime and/or any excipients of the medicinal product, and/or to other cephalosporin-class antibiotics, β-lactam antibiotics (e.g., penicillins, carbapenems, monobactams).

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

Anticoagulants, thrombolytics, antiplatelet agents.

Concomitant use may increase the risk of bleeding.

Probenecid.

Concomitant use enhances and prolongs the effect of cefepime due to delayed elimination.

Alcohol-containing products/beverages.

Concomitant use may result in a disulfiram-like or antabuse-like reaction with nausea and vomiting.

Bacteriostatic antibacterial agents.

Concomitant use may reduce the efficacy of cefepime.

Laboratory tests.

Cefepime use may lead to false-positive results in urine glucose testing. Therefore, enzymatic tests using glucose oxidase are recommended for urine glucose determination.

Special precautions.

Risk of hypersensitivity reactions.

As with other β-lactam antibiotics, severe hypersensitivity reactions, including fatal outcomes, have been reported. Prior to initiating therapy, it is essential to determine whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins, other β-lactam antibiotics, or any other medicinal products.

The drug should be administered with caution to patients with a history of asthma or those predisposed to allergies. Patients should be closely monitored at the beginning of treatment.

If an allergic reaction occurs, the drug should be discontinued immediately and appropriate therapy initiated. Severe hypersensitivity reactions may require administration of epinephrine and other supportive measures.

Antibacterial activity of cefepime.

Prior to administration, appropriate tests should be performed to identify the causative microorganism(s) and determine susceptibility to cefepime (see section "Pharmacodynamics" in "Pharmacological properties").

Use in patients with renal impairment.

In patients with impaired renal function (creatinine clearance ≤ 50 mL/min) or other conditions that may affect renal function, the dose should be adjusted to compensate for reduced renal elimination. Since prolonged plasma concentrations of the antibiotic may occur when cefepime is administered at usual doses in patients with renal impairment or other conditions affecting renal function, the maintenance dose of cefepime should be reduced in such patients. The degree of renal impairment, severity of infection, and microbial susceptibility to cefepime should be considered when determining subsequent dosing (see sections "Pharmacokinetics" and "Dosage and administration").

During post-marketing surveillance of cefepime, severe, life-threatening, or fatal adverse reactions have been reported: encephalopathy (disturbances of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with renal impairment who received doses exceeding the recommended dose; less frequently, cases occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or hemodialysis. In some cases, fatal outcomes were reported.

Risk of Clostridium difficile -associated diarrhea (CDAD).

Diarrhea associated with Clostridium difficile (CDAD) has been reported with the use of nearly all antibiotics, including cefepime, with severity ranging from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. Careful monitoring for CDAD is necessary, as cases have been reported up to two months after antibiotic treatment. If CDAD is suspected or confirmed, antibiotics not active against Clostridium difficile should be discontinued.

Superinfection risk.

Prolonged use of cefepime may lead to superinfection. Appropriate measures should be taken if superinfection occurs.

Concomitant use with potentially nephrotoxic agents.

When cefepime is used concomitantly with potentially nephrotoxic agents such as aminoglycosides or potent diuretics, renal function should be closely monitored.

Elderly patients.

In clinical trials involving over 6400 adult patients (35% aged 65 years and older, 16% aged 75 years and older), the clinical efficacy and safety of cefepime at the usual recommended adult dose were comparable to those in younger adults with normal renal function, except in elderly and geriatric patients. A slight increase in T1/2 and reduction in renal clearance were observed compared to younger volunteers. Dose adjustment is recommended in patients with renal impairment (see section "Dosage and administration").

Since cefepime is primarily excreted by the kidneys, patients with impaired renal function are at increased risk of toxic reactions. In elderly patients, who are more likely to have decreased renal function, dose selection should be cautious, and renal function should be monitored (see subsection "Pharmacodynamics" in "Pharmacological properties" and section "Adverse reactions").

Severe adverse reactions have been observed in elderly patients with renal insufficiency receiving usual doses of cefepime, including reversible encephalopathy (disturbances of consciousness, including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including non-convulsive epileptic status), and/or renal failure (see section "Adverse reactions").

Effect on laboratory test results.

A positive Coombs' test result may occur during cefepime therapy, without hemolysis. As with other cephalosporins, false-positive results in glucosuria tests may occur when using copper reduction methods (e.g., Benedict's solution, Fehling's solution, or Clinistix tablets). Therefore, during cefepime therapy, enzymatic glucose oxidase tests are recommended for urine glucose testing.

Use during pregnancy or breastfeeding.

Pregnancy.

Adequate and well-controlled studies in pregnant women have not been conducted. Reproductive studies in mice, rats, and rabbits revealed no direct or indirect harmful effects on fetal development. However, sufficient preclinical data on the effects of cefepime on fertility, fetal development, parturition, and postnatal development are lacking. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding period.

Cefepime is excreted in breast milk in small amounts. The drug should be used with caution during breastfeeding and only if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility.

In rat studies, no adverse effects on fertility were observed. There are no data on the effect of cefepime on human fertility. The potential risk in humans is unknown.

Ability to affect reaction speed when driving or operating machinery.

Studies have not been conducted. However, adverse reactions such as disturbances of consciousness, dizziness, confusion, or hallucinations may occur during cefepime therapy, which could impair the ability to drive or operate machinery (see sections "Special precautions" and "Adverse reactions").

Method of Administration and Dosage

The medicinal product is intended for intravenous or intramuscular administration. The dosage of the medicinal product and route of administration depend on the severity of infection, renal function, and the patient's overall condition.

Method of Administration

Intravenous administration

The medicinal product should be administered intravenously to patients with severe or life-threatening infections, especially when there is a risk of developing septic shock.

For intravenous injection, dissolve the medicinal product powder in one of the following solvents (see Table "Preparation of solution for intramuscular and intravenous administration" below):

• Sterile water for injection
• 5% glucose solution for injection
• 0.9% sodium chloride solution for injection

The prepared solution should be administered intravenously slowly over 3–5 minutes.

For intravenous infusion, the prepared solution (preparation method as described above) should be added to a vial containing a compatible infusion solution and administered over at least 30 minutes. The prepared solution of the medicinal product at a concentration of 1–40 mg/mL is compatible with the following solutions:

• 0.9% sodium chloride solution for injection
• 5% or 10% glucose solution for injection
• 1/6 M sodium lactate solution for injection
• 5% glucose solution for injection and 0.9% sodium chloride solution for injection
• Ringer's lactate solution for injection and 5% glucose solution for injection

The prepared solution is stable for 24 hours at 15–25 °C or for 7 days at 2–8 °C.

Intramuscular administration

The medicinal product powder should be dissolved in one of the following solvents (solvent volumes, see Table "Preparation of solution for intramuscular and intravenous administration" below):

• Sterile water for injection
• 5% glucose solution for injection
• 0.9% sodium chloride solution for injection
• Bacteriostatic water for injection with parabens or benzyl alcohol
• 0.5% or 1.0% lidocaine hydrochloride solution for injection*

The prepared solution is stable for 24 hours at 15–25 °C or for 7 days at 2–8 °C.

The prepared solution of the medicinal product should be administered deep intramuscularly into a large muscle mass (e.g., the upper outer quadrant of the gluteus maximus). A dose of up to 1 g may be administered as a single injection. The maximum dose of 2 g should be administered as two injections at separate sites.

*Since intramuscular injections of the medicinal product are generally painless, in most cases there is no need to use lidocaine hydrochloride solution as a solvent.

Preparation of solution for intramuscular and intravenous administration

Table 4

Cefepime dose/vial	Volume of diluent added, ml	Approximate final volume, ml	Approximate cefepime concentration, mg/ml
Intravenous
0.5 g	5	5.6	90
1 g	10	11.4	90
2 g	10	12.8	160
Intramuscular
0.5 g	1.5	2.2	230
1 g	3.0	4.4	230

The medicinal product must not be mixed with other medicinal products in the same syringe or in the same infusion vial.

As with most β-lactam antibiotics, cefepime solution should not be added to solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate due to physical or chemical incompatibility. If concomitant administration with cefepime is indicated, each of these medicinal products should be administered separately.

Before administration, the prepared solution of the medicinal product must be inspected visually for particulate matter. The medicinal product should not be used if foreign particles are present.

As with other cephalosporins, the prepared solution of the medicinal product may have a yellowish-brown color, which does not affect its activity or quality.

Dosage regimen.

Adults and children with body weight > 40 kg with normal renal function.

The recommended dosage regimen for adults and children with body weight > 40 kg with normal renal function* is presented in Table 5.

Table 5

Type and severity of infection	Dose and route of administration	Interval between doses
Urinary tract infections of mild to moderate severity	0.5–1.0 g intravenously or intramuscularly	12 hours
Other infections of mild to moderate severity	1.0 g intravenously or intramuscularly	12 hours
Severe infections	2 g intravenously	12 hours
Very severe or life-threatening infections	2 g intravenously	8 hours

*The usual duration of therapy is 7–10 days; more severe infections may require longer treatment. For empirical treatment of febrile neutropenia, the usual duration of therapy is at least 7 days or until resolution of neutropenia.

Surgical infection prophylaxis in intra-abdominal procedures (adults).

2 g of the medicinal product should be administered intravenously as a 30-minute infusion, 60 minutes prior to the start of surgery. Immediately after completion of the infusion, 0.5 g of metronidazole should be administered intravenously. Due to pharmaceutical incompatibility between metronidazole and cefepime, they should not be mixed in the same infusion solution (see section "Incompatibilities"). The infusion system should be flushed with a compatible fluid before administration of metronidazole. During prolonged surgical procedures (exceeding 12 hours), the same dose of cefepime should be re-administered 12 hours after the first dose, followed by administration of metronidazole.

Patients with impaired renal function.

Dosage adjustment of the medicinal product is required in patients with impaired renal function to compensate for reduced renal elimination of cefepime. The recommended initial dose in adult patients with mild to moderate renal impairment should be the same as in patients with normal renal function.

Recommended maintenance doses for adult patients with impaired renal function

Table 6

Creatinine clearance (ml/min)	Recommended maintenance doses
> 50	Normal dose, no dose adjustment required
	2 g every 8 hours	2 g every 12 hours	1 g every 12 hours	0.5 g every 12 hours
30–50	2 g every 12 hours	2 g every 24 hours	1 g every 24 hours	0.5 g every 24 hours
11–29	2 g every 24 hours	1 g every 24 hours	0.5 g every 24 hours	0.5 g every 24 hours
≤ 10	1 g every 24 hours	0.5 g every 24 hours	0.25 g every 24 hours	0.25 g every 24 hours
Hemodialysis*	0.5 g every 24 hours	0.5 g every 24 hours	0.5 g every 24 hours	0.5 g every 24 hours

* According to pharmacokinetic studies in patients undergoing hemodialysis, the dose of the drug should be reduced.

For patients undergoing hemodialysis, the initial dose of the drug on the first day of therapy is 1 g; thereafter, the daily maintenance dose is 0.5 g for all infections except febrile neutropenia, for which the daily maintenance dose is 1 g. On the day of hemodialysis, the drug should be administered after completion of dialysis. The drug solution should be administered at the same time each day, whenever possible.

If only plasma creatinine concentration at steady state is known, creatinine clearance (CLcr) can be calculated using the Cockcroft-Gault formulas:

Men:

CLcr (mL/min) =

Women:

CLcr (mL/min) = CLcr (in men) × 0.85

Patients undergoing dialysis.

During 3-hour hemodialysis, approximately 68% of the administered dose of cefepime is removed from the body. During continuous ambulatory peritoneal dialysis, the drug may be administered at doses recommended for patients with normal renal function, e.g., 0.5 g, 1 g, or 2 g, depending on the severity of infection, with dosing intervals of

48 hours.

Patients with hepatic impairment.

Dose adjustment is not required.

Children aged 1 to 2 months.

Experience with cefepime in children under 2 months of age is limited. In children aged 1–2 months, cefepime may be used only for life-threatening indications at a dose of 30 mg/kg every 12 or 8 hours, depending on the severity of infection. The cefepime doses of 50 mg/kg for patients aged ≥2 months and 30 mg/kg for patients aged 1–2 months are comparable to the 2 g dose in adults. When administering the drug, patients in this age group must be under close monitoring.

Children with normal renal function aged ≥2 months.

Pneumonia, urinary tract infections, skin and soft tissue infections.

The usual recommended dose for children with body weight ≤40 kg is 50 mg/kg every 12 hours for 10 days. In more severe infections, the dosing interval may be reduced to every 8 hours.

Sepsis, bacterial meningitis, and empirical treatment of febrile neutropenia.

The usual recommended dose for children with body weight ≤40 kg is 50 mg/kg every 8 hours for 7–10 days.

For children with body weight >40 kg, the dosing regimen is similar to that in adults. The dose for children should not exceed the maximum recommended adult dose (2 g every 8 hours).

Experience with intramuscular administration of cefepime in children is limited.

Children with impaired renal function.

Since cefepime is primarily eliminated by the kidneys, the dose should be adjusted in children with impaired renal function by increasing the dosing intervals and/or reducing the dose according to the recommended maintenance doses for adult patients with impaired renal function.

Using the known plasma creatinine concentration, creatinine clearance is calculated using the following formulas:

CLcr (mL/min/1.73 m²) =

or

CLcr (mL/min/1.73 m²) =

Elderly patients.

In elderly patients, due to the higher likelihood of decreased renal function, the medicinal product should be used with caution and renal function should be monitored. Dose adjustment is recommended for patients with impaired renal function.

Children.

The medicinal product can be administered to children aged 1 month and older.

Overdose.

Symptoms.

Symptoms of overdose include encephalopathy (accompanied by impaired consciousness, hallucinations, stupor, coma), myoclonus, and seizures (see section «Adverse reactions»).

Treatment.

In case of overdose, symptomatic therapy should be administered. In the event of a significant overdose of cefepime, especially in patients with impaired renal function, hemodialysis should be performed. Peritoneal dialysis is ineffective. Accidental overdose has been observed with the use of high doses of cefepime in patients with impaired renal function (see sections «Contraindications» and «Administration and dosage»).

Adverse Reactions.

The following adverse reactions have been reported with other cephalosporins: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic neuropathy, aplastic anemia, hemolytic anemia, hemorrhage, and false-positive urine glucose test results.

In clinical studies of cefepime (n=5598), the most commonly reported adverse reactions were gastrointestinal disorders and hypersensitivity reactions.

Immune system disorders:

Common – rash; uncommon – pruritus, urticaria; very rare – anaphylaxis.

Nervous system disorders:

Uncommon – headache; rare – dizziness, paresthesia, taste disturbance; very rare – seizures.

Gastrointestinal disorders:

Common – diarrhea; uncommon – nausea, vomiting, oral candidiasis, colitis (including pseudomembranous colitis); rare – abdominal pain, constipation, candidiasis.

Other reactions:

Common – injection site reactions during intravenous infusion, including phlebitis, inflammation, and pain at the site of intramuscular injection; uncommon – fever, vaginitis, erythema;
rare – vasodilation, dyspnea, genital pruritus, chills, infusion site inflammation during intravenous infusion.

Post-marketing experience.

The adverse reactions listed below are classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data). Within each category, adverse reactions are listed in decreasing order of severity.

Infections and infestations:

Uncommon – oral candidiasis, vaginal infections; rare – candidiasis.

Blood and lymphatic system disorders:

Common – anemia, eosinophilia; uncommon – thrombocytopenia, leukopenia, neutropenia; frequency not known – aplastic anemia, hemolytic anemia, agranulocytosis.

Immune system disorders:

Rare – anaphylactic reactions, angioedema; frequency not known – anaphylactic shock.

Psychiatric disorders:

Frequency not known – confusion, hallucinations.

Nervous system disorders:

Uncommon – headache; rare – seizures, paresthesia, dysgeusia, dizziness; frequency not known – coma, stupor, encephalopathy, altered consciousness, myoclonus.

Vascular disorders:

Common – phlebitis at injection site; rare – vasodilation; frequency not known – hemorrhage.

Respiratory, thoracic and mediastinal disorders:

Rare – dyspnea.

Gastrointestinal disorders:

Common – diarrhea; uncommon – pseudomembranous colitis, colitis, nausea, vomiting; rare – abdominal pain, constipation; frequency not known – gastrointestinal disorders.

Skin and subcutaneous tissue disorders:

Common – rash; uncommon – erythema, urticaria, pruritus; frequency not known – toxic epidermal necrolysis*, Stevens-Johnson syndrome*, erythema multiforme*.

Renal and urinary disorders:

Frequency not known – renal function impairment, toxic nephropathy*.

Reproductive system and breast disorders:

Frequency not known – genital pruritus.

General disorders and administration site conditions:

Common – infusion site reactions, pain at injection site, inflammation at injection site; uncommon – fever, infusion site inflammation; rare – chills.

Investigations:

Very common – positive Coombs' test; common – increased alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), increased plasma bilirubin, prolonged prothrombin time, prolonged partial thromboplastin time; uncommon – increased plasma urea, increased plasma creatinine; frequency not known – false-positive plasma glucose test*.

*Adverse reactions typically associated with other cephalosporin agents.

Pediatric population.

The safety profile of cefepime in neonates and children is similar to that in adults. The most commonly reported adverse reaction in clinical studies was rash.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

Roxipim – 3 years.

Solvent – 5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, protected from light and out of reach of children.

The reconstituted solution is stable for 24 hours at 15–25 °C or for 7 days at 2–8 °C.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products in the same syringe or infusion vial. Only the solvents specified in the section "Dosage and administration" should be used.

As with most β-lactam antibiotics, cefepime solution should not be added to solutions of metronidazole, vancomycin, gentamicin, tobramycin, or netilmicin due to physical or chemical incompatibility. If concomitant therapy with cefepime is indicated, each of these medicinal products must be administered separately.

Packaging.

1 vial of powder with 1 ampoule of solvent (water for injection), 10 ml, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

PharmaVision San. ve Tic. A.S.

Manufacturer's address and location of operations.

Davutpasa Cad. No:145 Zeytinburnu Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.