Cefepime abril

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFEPIME ABRYL (CEFEPIME ABRYL)

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to cefepime 1000 mg;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder from white to pale yellow in color.

Pharmacotherapeutic group.

Antibacterials for systemic use. Other β-lactam antibiotics. Fourth-generation cephalosporins. Cefepime. ATC code J01D E01.

Pharmacological properties.

Pharmacodynamics.

Cefepime is a fourth-generation broad-spectrum β-lactam cephalosporin antibiotic intended for parenteral administration. It exerts a bactericidal effect. It is active against Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporin antibiotics such as ceftazidime. Cefepime is highly stable against the action of most β-lactamases and rapidly penetrates Gram-negative bacteria. The binding affinity of cefepime to penicillin-binding protein PBP 3 significantly exceeds that of other parenteral cephalosporins. Moderate affinity of cefepime to PBP 1a and 1b also contributes to its level of bactericidal activity. The MBC (minimum bactericidal concentration)/MIC (minimum inhibitory concentration) ratio for cefepime is less than 2 for more than 80% of isolates of all susceptible Gram-positive and Gram-negative bacteria.

Cefepime inhibits the synthesis of enzymes in the bacterial cell wall. The drug has low affinity for chromosomally encoded β-lactamases.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (including β-lactamase-producing strains) and Staphylococcus epidermidis (including β-lactamase-producing strains); other staphylococcal strains (including S. hominis, S. saprophyticus), Streptococcus pyogenes (group A); Streptococcus agalactiae (group B); Streptococcus pneumoniae (including strains with intermediate penicillin resistance — MIC from 0.1 to 1 μg/mL); other β-hemolytic streptococci (groups C, G, F); S. bovis (group D); Viridans group streptococci (most enterococcal strains, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are 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 (including subspecies anitratus, Iwoffi); Aeromonas hydrophila, Capnocytophaga spp.; Citrobacter spp. (including C. diversus, C. freundii), Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including β-lactamase-producing strains); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including β-lactamase-producing strains); Neisseria gonorrhoeae (including β-lactamase-producing strains); N. meningitidis; Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

Cefepime is inactive against many strains of Xanthomonas (Pseudomonas) maltophilia;

Anaerobes: Bacteroides spp., including B. melaninogenicus and other oral cavity microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp.

Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics.

Cefepime is completely absorbed after intramuscular administration.

Mean plasma concentrations of cefepime in healthy adult males at various time points after single intravenous and intramuscular administration are presented in Table 1.

Plasma concentrations of cefepime (μg/mL) following intravenous (i.v.) and intramuscular (i.m.) administration

Table 1

Therapeutic concentrations of cefepime are also achieved in urine, bile, peritoneal fluid, bronchial mucosal secretions, sputum, prostate, appendix, and gallbladder.

The average elimination half-life of cefepime is approximately 2 hours and is independent of dose within the range of 250 mg to 2 g. No drug accumulation was observed after intravenous administration of doses up to 2 g every 8 hours for 9 days.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to the N-methylpyrrolidine oxide. Cefepime is primarily eliminated via glomerular filtration (total cefepime clearance is approximately 120 mL/min, mean hepatic clearance is 110 mL/min). Approximately 80–85% of the administered dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the cefepime epimer. Plasma protein binding of cefepime is less than 19% and does not depend on drug concentration in serum.

Dose adjustment is not required in patients aged 65 years and older with normal renal function.

In patients with renal impairment, the elimination half-life of cefepime is prolonged, and a linear relationship is observed between total drug clearance and creatinine clearance. The elimination half-life in patients with severe renal dysfunction requiring hemodialysis is 13 hours, and 19 hours in those undergoing continuous ambulatory peritoneal dialysis. Dose adjustment should be individualized in patients with abnormal renal function.

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

Children. Pharmacokinetic studies of cefepime have been 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, the mean total body clearance and steady-state volume of distribution were 3.3 (1.0) mL/min/kg and 0.3 (0.1) L/kg, respectively. Renal excretion of unchanged cefepime was 60.4 (30.4)% of the administered dose, and mean renal clearance was 2 (1.1) mL/min/kg. Patient age and sex did not significantly influence total body clearance or volume of distribution when corrected for body weight. When cefepime was administered at a dose of 50 mg/kg every 12 hours, no drug accumulation was observed, whereas with dosing at 50 mg/kg every 8 hours, maximum plasma concentration, area under the curve, and elimination half-life increased by approximately 15% at steady state. Cefepime exposure in children after intravenous administration of 50 mg/kg is comparable to that in adults receiving a 2 g intravenous dose. After intravenous administration, the mean peak plasma concentration at steady state was 68 µg/mL, reached within 0.75 hours. Eight hours after intramuscular injection, the mean plasma concentration of cefepime was 6 µg/mL. The absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Due to the inability to identify the causative pathogen and determine its antibiotic susceptibility, or due to time constraints, cefepime may be used for empirical therapy, as it has a broad spectrum of antibacterial activity. In patients at risk of mixed aerobic-anaerobic infections, treatment with cefepime may be initiated before pathogen identification, either alone or in combination with an anti-anaerobic agent.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia and bronchitis;
• skin and soft tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• 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, as well as to cephalosporin antibiotics, penicillins, or other β-lactam antibiotics.

Interaction with other medicinal products and other types of interactions.

When administering high doses of aminoglycosides concomitantly with cefepime, renal function should be closely monitored due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with diuretics such as furosemide.

Cefepime at concentrations from 1 to 40 mg/mL is compatible with the following parenteral solutions: 0.9% sodium chloride injection; 5% and 10% dextrose injection; 6 M sodium lactate injection; 5% dextrose and 0.9% sodium chloride injection; Ringer's solution with lactate and 5% dextrose injection.

To avoid potential drug interactions with other medicinal products, solutions of Cefepime Abril (as with most other β-lactam antibiotics) should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. If co-administration of Cefepime Abril with any of these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results.

Cefepime administration may result in false-positive urine glucose tests when using Benedict's reagent. Enzymatic glucose oxidation tests are recommended for glucose determination.

Special precautions for use.

In patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation associated with reduced bone marrow activity due to severe progressive malignant hemolytic disease and severe neutropenia), monotherapy may be insufficient; therefore, combination antimicrobial therapy is indicated.

It is necessary to clarify whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any form of allergy, especially drug allergies. If an allergic reaction occurs, the drug should be discontinued immediately. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other therapeutic interventions.

Use with caution in patients with gastrointestinal disorders (particularly with a history of colitis).

Cases of pseudomembranous colitis have been reported during treatment with nearly all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition in patients who develop diarrhea during therapy. Research indicates that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is confirmed, appropriate therapeutic measures should be initiated. Mild to moderate cases may resolve after discontinuation of the drug. In cases of moderate or severe colitis, consideration should be given to administration of fluids and electrolytes, protein supplementation, and use of an antibacterial agent effective against Clostridium difficile.

In patients with impaired renal function (creatinine clearance ≤ 60 mL/min), the dose of cefepime must be adjusted to compensate for reduced renal elimination. Since prolonged serum concentrations of the antibiotic may occur when cefepime is administered at usual 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. The degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic should be taken into account when determining the subsequent dose of cefepime. During post-marketing surveillance of cefepime-containing products, severe adverse events, including life-threatening or fatal cases, have been reported: encephalopathy (disturbances of consciousness, including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with impaired renal function who received doses of cefepime exceeding the recommended dosage. Some 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.

Warning.

It is unlikely that administration of cefepime in the absence of proven or suspected bacterial infection, or for prophylactic use, will be beneficial; moreover, such use may increase the risk of developing bacteria resistant to this drug. Prolonged use of cefepime (as with other antibiotics) may lead to development of superinfection. The patient's condition should be re-evaluated periodically. If superinfection develops, appropriate measures should be taken.

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. High-risk patients include those with impaired liver or kidney function, those with poor nutrition, and those receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in high-risk patients, and vitamin K should be administered if necessary.

During cefepime therapy, positive results in the direct Coombs' test may occur. When performing hematological or transfusion procedures, including blood grouping by cross-matching, or when performing the Coombs' test in newborns whose mothers received cephalosporin antibiotics before delivery, it should be recognized that a positive Coombs' test may be due to the drug.

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. The effects at lower doses are still unknown.

Use during pregnancy or breastfeeding.

The drug 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 small amounts; therefore, breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

The effect of cefepime on reaction speed during driving or operating machinery has not been studied; however, it should be considered that adverse reactions affecting the nervous system may occur during treatment.

Dosage and Administration.

The usual dose for adults is 1000 mg administered intravenously or intramuscularly at 12-hour intervals. The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

However, dosage and route of administration vary depending on the susceptibility of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for adults are provided in Table 2.

Table 2

For prevention of infections during surgical procedures. Adults should receive 2 g of the drug intravenously over 30 minutes, 60 minutes before the start of surgery. After completion, an additional 500 mg of metronidazole should be administered intravenously. Metronidazole solution should not be administered simultaneously with cefepime. The infusion system must be flushed before administration of metronidazole.

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

Renal function impairment. Cefepime is eliminated by the kidneys via glomerular filtration; therefore, the dose must be adjusted in patients with impaired renal function (creatinine clearance less than 30 mL/min) (Table 3).

Recommended doses of cefepime for adult patients

Table 3

*On the day of dialysis, the injection must be administered after the dialysis session.

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

Men:

body weight (kg) × (140 − age)

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

72 × serum creatinine (mg/dL)

Women:

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

During hemodialysis, approximately 68% of the drug dose is removed from the body over 3 hours. After each dialysis session, a supplemental dose equal to the initial dose must be administered. For continuous ambulatory peritoneal dialysis, the drug can be used at the initial standard recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a dosing interval of 48 hours.

Children aged 1 to 2 months. The drug should be administered only for life-threatening indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the severity of infection. Children with body weight under 40 kg receiving cefepime therapy must be closely monitored.

Children aged 2 months and older. The maximum dose for children should not exceed the recommended adult dose. The usual recommended dose for children with body weight up to 40 kg in cases of complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and empirical treatment of febrile neutropenia is 50 mg/kg every 12 hours (every 8 hours for febrile neutropenia and bacterial meningitis). The usual duration of treatment is 7–10 days; severe infections may require longer treatment. Children with body weight of 40 kg or more should receive cefepime doses as recommended for adults.

For children with impaired renal function, dose reduction or extended dosing intervals are recommended.

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)

The drug can be administered by deep intramuscular injection (0.5 g and 1 g), slow intravenous injection, or infusion (over 3–5 to 30 minutes).

Intravenous administration. Cefepime should be dissolved in water for injection or any other compatible diluent at concentrations specified in Table 3. Solutions for intravenous administration may be given directly into the vein by slow (3–5 minutes) injection via an intravenous line or directly into a compatible infusion solution (to be administered over 30 minutes).

For intravenous administration, cefepime is compatible with the following diluents: water for injection, 0.9% sodium chloride injection (with or without 5% dextrose solution); 5% and 10% dextrose injection solutions; 1/6 M sodium lactate injection solution; lactated Ringer’s solution (with or without 5% dextrose solution).

Intramuscular administration. The drug can be dissolved in water for injection, 0.9% sodium chloride injection, 5% dextrose injection, bacteriostatic water for injection with parabens or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at concentrations specified in Table 4.

Table 4

The prepared solution should be stored for 24 hours at a temperature not exceeding 30 °C or for up to 7 days at 2–8 °C.

As with other parenterally administered medicinal products, the prepared solutions of the drug should be inspected for the absence of mechanical particles before administration.

To identify the causative microorganism(s) and determine susceptibility to cefepime, appropriate microbiological studies should be performed. However, the drug may be used as monotherapy prior to identification of the causative microorganism due to its broad spectrum of antibacterial activity against both gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic-anaerobic infection (including Bacteroides fragilis), treatment may be initiated in combination with an agent active against anaerobes, pending identification of the causative pathogen.

Children.

The drug may be administered to children aged 1 month and older.

Overdose.

Symptoms. In cases of 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 drug 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.

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

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

Cardiovascular system disorders: tachycardia, vasodilation.

Gastrointestinal disorders: nausea, vomiting, dyspepsia, oral candidiasis, taste disturbances, diarrhea, colitis (including pseudomembranous colitis), abdominal pain, constipation.

Nervous system disorders: headache, insomnia, restlessness, convulsions, dizziness, paresthesia, epileptiform seizures, encephalopathy (loss of consciousness, hallucinations, stupor, coma), myoclonus.

Hepatobiliary disorders: hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria.

Other: asthenia, increased sweating, fever, vaginitis, erythema, chest pain, back pain, peripheral edema, genital pruritus, candidiasis, renal failure.

Local reactions at the site of administration:

intravenous administration – phlebitis and inflammation;

intramuscular administration – pain, inflammation.

Laboratory findings: increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin; anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time, and positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine, transient leukopenia, neutropenia, agranulocytosis, transient thrombocytopenia.

Possible adverse reactions typical for cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, hepatic dysfunction, cholestasis, pancytopenia.

Reporting suspected adverse reactions

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

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Incompatibility.

The medicinal product must not be mixed in the same container with other medicinal products except for the solvents specified in the section "Administration and dosage".

Packaging.

1 vial of powder in a cardboard package.

Prescription status.

Prescription only.

Marketing authorization holder.

Abhil Formulations Pvt. Ltd.

Address of the marketing authorization holder.

17406-A, Minocha Colony, Bathinda-151001, India.

Manufacturer.

Sens Laboratories Pvt. Ltd.

Manufacturer's address and manufacturing site address.

VI/51B, Post Office No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.