Cefepime powder for the preparation of a solution for intravenous and intramuscular administration 1.0 g

pharmachologic effect

Antibacterial agent from the group of IV generation cephalosporins. It acts bactericidal, disrupting the synthesis of the cell wall of microorganisms. It has a wide spectrum of action against gram-positive and gram-negative bacteria, strains resistant to aminoglycosides and/or third generation cephalosporin antibiotics. Highly resistant to hydrolysis by most beta-lactamases and quickly penetrates gram-negative bacterial cells. Inside the bacterial cell, the molecular target is penicillin-binding proteins.

Active in vivo and in vitro against gram-positive aerobes: Staphylococcus aureus (only methicillin-sensitive strains), Streptococcus pneumoniae, Streptococcus pyogenes (group A), Streptococcus viridans group; gram-negative aerobes: Enterobacter spp., Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa.

In vitro active (but clinical significance unknown) against gram-positive aerobes: Staphylococcus epidermidis (only methicillin-sensitive strains), Staphylococcus saprophyticus, Streptococcus agalactiae (group B); gram-negative aerobes: Acinetobacter lwoffii, Citrobacter diversus, Citrobacter freundii, Enterobacter agglomerans, Haemophilus influenzae (including strains producing beta-lactamase), Hafnia alvei, Klebsiella oxytoca, Moraxella catarrhalis (including strains producing beta-lactamase), Morganella morganii, Proteus vulgaris , Providencia rettgeri, Providencia stuartii, Serratia marcescens.

Most strains of Enterococcus spp., including Enterococcus faecalis, methicillin-resistant staphylococci, Stenotrophomonas maltophilia (formerly known as Xanthomonas maltophilia and Pseudomonas maltophilia), Clostridium difficile are not sensitive to cefepime.

Pharmacological properties of the drug Cefepime

IV generation cephalosporin antibiotic with a broad spectrum of action for parenteral use. Acts bactericidal. 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 resistant to most β-lactamases; quickly penetrates into gram-negative bacteria. The degree of binding of cefepime to the penicillin-binding protein PBP 3 significantly exceeds the affinity of other cephalosporins for parenteral use. The moderate affinity of cefepime for PBP 1a and 1b also likely determines the degree of its bactericidal activity. The MBC (minimum bactericidal concentration)/MIC ratio for cefepime is less than 2 for more than 80% of isolates of all susceptible gram-positive and gram-negative microorganisms. Gram-positive aerobes are sensitive to cefepime: Staphylococcus aureus (including strains producing β-lactamase), Staphylococcus epidermidis (including strains producing β-lactamase), other strains of staphylococci, including S. hominis, S. 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 0.3 μg/ml), other β-hemolytic streptococci (groups C, G, F ), S. bovis (group D ), S. viridans (most strains of streptococci, such as 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. ozenae ), Enterobacter spp . (including E. cloacae, E. aerogenes, E. agglomerans, E. sakazakii ), Proteus spp. (including P. mirabilis, P. vulgaris ), Acinetobacter calcoaceticus (subsp. Anitratus, Iwofii), Aeromonas hydrophila, Capnocytophaga spp., Citrobacter spp . (including C. diversus, C. freundii ), Campylobacter jejuni, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including β-lactamase producing strains), Haemophilus parainfluenzae, Hafnia alvei, Legionella spp., Morganella morganii, Moraxella catarrhalis (including strains , producing β-lactamase), Neisseria gonorrhoeae (including strains producing β-lactamase), Neisseria 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 maltophilia (Pseudomonas maltophilia)); anaerobes: Bacteroides spp. (including B. melaninogenicus and other oral microorganisms belonging to Bacteroides ), Clostridum perfringens, Fusobacterium spp., Mobiluncus spp., Peptostreptococcus spp., Veillonella spp. (cefepime is inactive against Bacteroides fragilis and Clostridium difficile ). Cefepime is completely absorbed after intramuscular administration. Metabolized to form N-methylpyrrolidine, which is rapidly converted to the corresponding N-oxide. About 80% of cefepime is excreted unchanged in the urine, mainly due to glomerular filtration; less than 1% of the administered dose is found in urine as N-methylpyrrolidine, 6.8% as N-oxide and 2.5% as cefepime epimer. The binding of cefepime to serum proteins is less than 19% and does not depend on the concentration of the antibiotic in the blood. The half-life of cefepime averages 2 hours, the release of cefepime does not depend on the dose in the dose range from 250 mg to 2 g. In healthy volunteers who received doses of up to 2 g IV at intervals of 8 hours for 9 days, the drug accumulated in the body was not observed. The total clearance of the drug is 120 ml/min. The average renal clearance of cefepime is 110 ml/min. The pharmacokinetics of cefepime does not change significantly in patients with impaired liver function (no dose adjustment is required); in renal failure, the half-life of cefepime increases, and a linear relationship is observed between the total clearance of cefepime and creatinine clearance. The half-life of cefepime during hemodialysis is 13 hours, and during continuous ambulatory peritoneal dialysis it is 19 hours.

Pharmacokinetics

Bioavailability - 100%. The time to reach maximum concentration after intravenous and intramuscular administration at a dose of 0.5 g is 1 to 2 hours by the end of the infusion, respectively. The maximum concentration for intramuscular administration in doses of 0.5, 1 and 2 g is 14, 30 and 57 mcg/ml, respectively; when administered intravenously in doses of 0.25, 0.5, 1 and 2 g - 18, 39, 82 and 164 mcg/ml, respectively; time to achieve average therapeutic concentration in plasma - 12 hours; the average therapeutic concentration for intramuscular administration is 0.2 mcg/ml, for intravenous administration is 0.7 mcg/ml. High concentrations are determined in urine, bile, peritoneal fluid, blister exudate, bronchial mucous secretion, sputum, prostate gland, appendix and gall bladder. Volume of distribution - 0.25 l/kg, in children from 2 months to 16 years - 0.33 l/kg. Communication with plasma proteins - 20%. Metabolized in the liver and kidneys by 15%. The half-life is 2 hours, the total clearance is 120 ml/min, the renal clearance is 110 ml/min. It is excreted by the kidneys (through glomerular filtration unchanged - 85%), with breast milk. The half-life for hemodialysis is 13 hours, and for continuous peritoneal dialysis it is 19 hours.

Indications for use

Infectious and inflammatory diseases caused by microorganisms sensitive to cefepime: pneumonia (moderate and severe) caused by Streptococcus pneumoniae (including cases of association with concomitant bacteremia), Pseudomonas aeruginosa, Klebsiella pneumoniae or Enterobacter spp.

Febrile neutropenia (empirical therapy).

Complicated and uncomplicated urinary tract infections (including pyelonephritis) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis;

Uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (only methicillin-sensitive strains), Streptococcus pyogenes;

Complicated intra-abdominal infections (in combination with metronidazole) caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter spp.

Contraindications

Hypersensitivity to cefepime, components of the drug, other cephalosporins, penicillins, other beta-lactam antibiotics, children under 2 months (for intravenous administration), children under 12 years of age (for intramuscular administration), lactation period.

Carefully

Diseases of the gastrointestinal tract (including a history), especially colitis, regional enteritis or antibiotic-associated colitis, severe chronic renal failure.

Use during pregnancy and lactation

The use of the drug during pregnancy is possible only in cases where the potential benefit to the mother outweighs the risk to the fetus.

If it is necessary to prescribe the drug during lactation, breastfeeding should be suspended.

special instructions

If pseudomembranous colitis occurs with prolonged diarrhea, stop taking it and prescribe vancomycin (orally) or metronidazole.

Cross-hypersensitivity is possible in patients with allergic reactions to penicillins.

In case of combined severe renal and liver failure, the concentration of the drug in plasma should be regularly determined (dose adjustment is carried out depending on creatinine clearance).

With long-term treatment, regular monitoring of peripheral blood, indicators of the functional state of the liver and kidneys is necessary.

In case of mixed aerobic-anaerobic infection, before identifying the pathogens, a combination with drugs active against anaerobes is advisable.

Patients in whom meningeal dissemination occurs from a distant site of infection, meningitis is suspected, or the diagnosis of meningitis is confirmed, should be prescribed an alternative antibiotic with proven clinical effectiveness for this situation.

It is possible to detect a false-positive Coombs test, a false-positive test for glucose in urine.

Impact on the ability to drive vehicles and operate machinery

During the treatment period, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Special instructions for the use of Cefepime

Due to its broad spectrum of bactericidal action against gram-positive and gram-negative microorganisms, cefepime can be used as monotherapy until the pathogen is identified. In case of mixed aerobic/anaerobic infection (including if one of the pathogens is Bacteroides fragilis ), before identifying the pathogens, it is recommended to prescribe a drug that affects anaerobes simultaneously with cefepime. Cefepime should be used with caution in patients with allergic diseases. If allergic reactions occur, cefepime should be discontinued. With the development of immediate hypersensitivity reactions, the administration of epinephrine, corticosteroids and appropriate symptomatic therapy may be required. When using almost all broad-spectrum antibiotics, including cefepime, the development of pseudomembranous colitis is possible, which must be taken into account if a patient develops diarrhea while using an antibiotic. Mild forms of colitis usually require only discontinuation of cefepime; in more severe cases, special therapy may be required. With long-term treatment with cefepime, superinfection caused by insensitive microflora may develop; in such cases, adequate therapy is prescribed. During pregnancy, cefepime is prescribed only for absolute indications. Cefepime passes into breast milk in very small amounts, but caution must be exercised when prescribing it during breastfeeding. The effectiveness of cefepime in children under 13 years of age has not been established. No dose adjustment of cefepime is required in elderly patients.

Directions for use and doses

Intravenous infusion (over at least 30 minutes) or intramuscularly (only for complicated or uncomplicated mild to moderate urinary tract infections caused by Escherichia coli).

Pneumonia (moderate to severe) caused by Streptococcus pneumoniae (including cases of association with concomitant bacteremia), Pseudomonas aeruginosa, Klebsiella pneumoniae or Enterobacter spp.: 1 - 2 g intravenously every 12 hours for 10 days.

Febrile neutropenia (empirical therapy): 2 g IV every 8 hours for 7 days or until neutropenia resolves.

Complicated or uncomplicated urinary tract infections of mild to moderate severity caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis: intravenously or intramuscularly (only for infections caused by Escherichia coli) 0.5 - 1 g every 12 hours for 7 - 10 days.

Severe complicated or uncomplicated urinary tract infections (including pyelonephritis) caused by Escherichia coli or Klebsiella pneumoniae: 2 g intravenously every 12 hours for 10 days.

Moderate to severe skin and soft tissue infections caused by Staphylococcus aureus (methicillin-sensitive strains only), Streptococcus pyogenes: intravenously

2 g every 12 hours for 10 days.

Complicated intra-abdominal infections (in combination with metronidazole) caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter spp.: intravenously 2 g every 12 hours for 7 - 10 days.

In children from 2 months to 16 years and weighing up to 40 kg, the recommended dosage regimen for all indications (excluding febrile neutropenia) is 50 mg/kg every 12 hours intravenously; for febrile neutropenia - 50 mg/kg every 8 hours. Duration of treatment is the same as for adults.

In chronic renal failure, the dose is prescribed depending on the severity of the infection and creatinine clearance (CC): more than 60 ml/min - 0.5 - 1 - 2 g every 12 hours or 2 g every 8 hours, with creatinine clearance 30 - 60 ml/min - 0.5 - 1 - 2 g every 24 hours or 2 g every 12 hours, with CC 11 - 29 ml/min - 0.5-1-2 g every 24 hours, less than 11 ml/min - 0.25 - 0.5 - 1 g every 24 hours; continuous ambulatory peritoneal dialysis - 0.5 - 1 - 2 g every 48 hours. For hemodialysis patients, administer 1 g on day 1, then 0.5 g every 24 hours for all infections and 1 g every 24 hours for febrile neutropenia. On the day of hemodialysis, the drug is administered after the end of the hemodialysis session; It is advisable to administer cefepime at the same time every day. Data on the use of the drug in children with concomitant chronic renal failure are not available, however, given the similarity of pharmacokinetics in children and adults, the dosage regimen (reducing the dose or increasing the interval between doses) in children with chronic renal failure is similar to the dosage regimen in adults.

Preparation of injection solutions

To prepare a solution for intravenous administration, the drug (1.0 g) is dissolved in 10 ml of sterile water for injection, 5% dextrose solution or 0.9% sodium chloride solution. For intravenous infusion, the prepared solution is combined with other solutions for intravenous infusion (0.9% sodium chloride solution, 5% or 10% dextrose solution, Ringer's solution with lactate and 5% dextrose solution; maximum concentration 40 mg/ml) and administered for at least 30 minutes.

To prepare a solution for intramuscular administration, the drug (1.0 g) is dissolved in 2.4 ml of sterile water for injection, 0.9% sodium chloride solution, bacteriostatic water for injection with paraben or benzyl alcohol, 0.5% or 1% lidocaine hydrochloride solution.

Cefepime

Intravenous (IV), intramuscular (IM).

Doses and route of administration depend on the sensitivity of the pathogens, the severity of the infection, the state of renal function and the general condition of the patient.

Intravenous administration is recommended for patients with severe or life-threatening infections, especially those at risk of septic shock.

Adults and children weighing more than 40 kg, with normal kidney function:

- mild to moderate urinary tract infections - 0.5-1 g IV or IM every 12 hours;

- mild to moderate infections of other locations - 1 g IV or IM every 12 hours;

- severe infections - 2 g IV every 12 hours;

- very severe and life-threatening infections, including febrile neutropenia - 2 g IV every 8 hours.

The usual duration of treatment is 7-10 days; Severe infections may require longer treatment. When treating febrile neutropenia, the usual duration of treatment is 7 days or until the neutropenia resolves.

Prevention of infection during surgical operations: 60 minutes before the start of surgery, 2 g of the drug is administered intravenously over 30 minutes. Immediately after the end of the infusion, 0.5 g of metronidazole is administered intravenously. Due to pharmaceutical incompatibility, metronidazole and cefepime solutions should not be mixed in the same infusion solution bottle. The infusion system should be flushed before administering metronidazole. During long-term (more than 12 hours) surgical operations, 12 hours after the first dose, repeated administration of cefepime at the same dose is recommended, followed by administration of metronidazole.

Children from 2 months weighing up to 40 kg:

- urinary tract infections, skin and soft tissue infections, pneumonia - 50 mg/kg IV or IM 2 times a day for 10 days; in case of severe infections - every 8 hours;

- febrile neutropenia, septicemia, bacterial meningitis - 50 mg/kg every 8 hours for 7-10 days.

The dose for children should not exceed the maximum recommended dose for adults - 2 g IV every 8 hours. Experience with IM use of the drug in children is limited.

Patients with impaired renal function: in case of renal failure, dose adjustment of the drug is required depending on creatinine clearance. The dosage regimen depends on the degree of renal dysfunction and the severity of the infection.

For mild to moderate renal impairment, the initial dose of cefepime is no different from that in patients with normal renal function.

Based on the known concentration of creatinine in the blood serum, creatinine clearance is calculated using the formula:

For men:

Creatinine clearance (ml/min) = body weight (kg) x (140 - age in years) / [72 x serum creatinine (mg/100 ml)]

For women: use the same formula, the result is multiplied by 0.85.

Maintenance doses of cefepime depending on creatinine clearance

For continuous ambulatory peritoneal dialysis, the recommended maintenance doses are 0.5 g, 1 g or 2 g, depending on the severity of the infection, with an interval between doses of 48 hours.

Patients on hemodialysis - 1 g on the first day of treatment, then 0.5 g every 24 hours for all infections, with the exception of febrile neutropenia, where the dose is 1 g every 24 hours. On hemodialysis days, the drug should be administered at the end of the hemodialysis procedure. If possible, administration is carried out at the same time every day.

For children with impaired renal function, it is recommended to reduce the dose or increase the interval between doses, as indicated in the table above.

Based on the known concentration of creatinine in the blood serum, creatinine clearance is calculated using the formula:

Creatinine clearance (ml/min/1.73 m2) = 0.55 x height (cm)/serum creatinine (mg/100 ml)

or

Creatinine clearance (ml/min/1.73 m2) = [0.52 x height (cm)/serum creatinine (mg/100 ml)] - 3.6

Patients with impaired liver function : no dose adjustment is required.

Preparation and administration of drug solutions

Intravenous bolus administration: 2.0 g of the drug is dissolved in 10 ml of water for injection, 5% dextrose solution or 0.9% sodium chloride solution (the volume of the resulting solution is 12.8 ml, the approximate concentration of cefepime is 160 mg/ml). Administer slowly intravenously over 3-5 minutes directly into a vein or into an intravenous line if the patient is receiving infusion therapy with a compatible infusion solution.

Intravenous drip: the prepared solution (see above) is transferred into a bottle containing 50-100 ml of a compatible solution for infusion. Administered through an intravenous infusion system over at least 30 minutes. Solutions of the drug with a concentration of approximately 20-40 mg/ml are compatible with infusion solutions: 0.9% sodium chloride solution; 5% or 10% dextrose solution; 1/6 M sodium lactate solution, 5% dextrose and 0.9% sodium chloride solution; Lactated Ringer's solution.

Intramuscular administration: 2.0 g of the drug is dissolved in 6 ml of water for injection, 0.9% sodium chloride solution, bacteriostatic water for injection, 0.5% or 1% lidocaine solution (the volume of the resulting solution is 8.8 ml, the approximate concentration of cefepime 230 mg/ml). Inject 2 intramuscular injections of 4.4 ml of solution containing 1 g of cefepime into different parts of the body with a pronounced muscle layer (for example, in both buttocks). An aspiration test is recommended to avoid unwanted injection of solution into the blood vessel. Since the administration of the drug is usually painless, in most cases there is no need to use lidocaine solution as a solvent.

Solutions of the drug prepared using water for injection, 1% lidocaine solution, 5% dextrose solution, 0.9% sodium chloride solution, 0.9% sodium chloride solution and 5% dextrose solution can be stored for 24 hours in the refrigerator at temperature (2-8) °C or for 12 hours at room temperature (not higher than 25 °C), without significant loss of activity. During storage, the powder and the prepared solution may darken, which does not affect the activity and quality of the drug.

Side effect

Allergic reactions: skin rash (including erythematous rashes), itching, fever, anaphylactoid reactions, anaphylactic shock, false-positive Coombs test, eosinophilia, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Local reactions: with intravenous administration - phlebitis, with intramuscular administration - hyperemia and pain at the injection site.

From the nervous system: headache, dizziness, insomnia, paresthesia, anxiety, confusion, convulsions, encephalopathy.

From the genitourinary system: vaginitis.

From the urinary system: impaired renal function.

From the digestive system: diarrhea, nausea, vomiting, constipation, abdominal pain, dyspepsia, pseudomembranous colitis.

From the hematopoietic organs: anemia, thrombocytopenia, leukopenia, neutropenia, pancytopenia, hemolytic anemia, bleeding, increased prothrombin time or partial thromboplastin time.

From the respiratory system: cough.

From the cardiovascular system: tachycardia, shortness of breath, peripheral edema.

Laboratory indicators: decreased hematocrit, increased prothrombin time, increased urea concentration, hypercreatininemia, hypercalcemia, increased activity of “liver” transaminases and alkaline phosphatase, hyperbilirubinemia.

Other: sore throat, chest pain, change in taste, increased sweating, back pain, asthenia, development of superinfection, oropharyngeal candidiasis.

Overdose

Symptoms (more often occur in patients with chronic renal failure): convulsions, encephalopathy, neuromuscular agitation.

Treatment: hemodialysis and symptomatic therapy.

Side effects of the drug Cefepime

Cefepime is generally well tolerated and side effects are rare, with an average incidence of 0.1–1%. Possible skin rash (1.8%), itching, urticaria, fever, nausea, vomiting, stomatitis, diarrhea (1.1%), colitis (including pseudomembranous), headache, vaginitis, erythema; side effects observed with a frequency of 0.05–0.1% are abdominal pain, constipation, vasodilation, shortness of breath, dizziness, paresthesia, itching in the genital area, changes in taste, chills; serious reactions, including anaphylaxis and convulsions, are observed with a frequency of less than 0.05%; local reactions are possible at the site of intravenous administration of the drug (noted in 5.2% of cases) - phlebitis (2.9%) or tissue inflammatory reaction (0.1%); with intramuscular use of cefepime, infiltration, inflammatory reactions and pain at the injection site are observed in 2.6% of cases. Changes in laboratory parameters in most cases are rare (1–2%) and are temporary; possible increased levels of ALT (3.6%), AST (2.5%), alkaline phosphatase, total bilirubin, anemia, eosinophilia, increased prothrombin time (2.8%) and a positive Coombs test result without hemolysis (18.7%) . A temporary increase in blood urea nitrogen and/or serum creatinine and transient thrombocytopenia are observed in 0.5–1% of cases. Isolated cases of encephalopathy have been reported in patients with impaired renal function who received uncorrected doses of cefepime. When using cephalosporin antibiotics, the development of Stevens-Johnson syndrome, polymorphic erythema, toxic epidermal necrolysis, toxic nephropathy, hemolytic anemia, hemorrhagic complications and the determination of false positive results when conducting glucosuric tests is possible.

Interaction with other drugs

Pharmaceutically incompatible with other antimicrobial drugs and heparin.

Diuretics reduce the tubular secretion of cefepime and increase its concentration in the blood serum, lengthen the half-life, and increase nephrotoxicity (increases the risk of nephronecrosis).

Non-steroidal anti-inflammatory drugs, by slowing down the elimination of cephalosporins, increase the risk of bleeding.

Incompatible with metronidazole solution (before administering metronidazole solution to prevent infections during surgical interventions, the infusion system should be flushed of cefepime solution).

Increases nephro- and ototoxicity of aminoglycosides.