Cefepim, 1 g 1 pc +1 lidocaine 3.5 ml

Pharmacotherapeutic group:

Cephalosporin antibiotic

ATX code:

J01DE01

Pharmacological properties

Pharmacodynamics
Cefepim is a broad spectrum cephalosporin antibiotic. Cefepime inhibits the synthesis of the bacterial cell wall proteins and has a broad spectrum of bactericidal activity against various 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 hydrolysis by most beta-lactamases, it has low affinity for beta-lactamases and penetrates rapidly into Gram-negative bacteria cells. Cefepime has been shown to have a very high affinity for penicillin-binding protein (PBP) type 3, a high affinity for PBP type 2 and a moderate affinity for PBP types 1a and 1b. Cefepime has bactericidal activity against a wide range of bacteria. Cefepim is active against the following microorganisms:

Gram-positive aerobes:
Staphylococcus aureus (including beta-lactamase-producing strains);
Staphylococcus epidermidis (including beta-lactamase-producing strains);
other strains of Staphylococcus spp, including Staphylococcus hominis, Staphylococcus saprophyticus;
Streptococcus pyogenes (group A streptococci);
Streptococcus agalactiae (group B streptococci);
Streptococcus pneumoniae (including strains with medium resistance to penicillin – minimum suppressive concentration from 0.1 to 1 mcg/ml);
Other beta-haemolytic Streptococcus spp. (groups C, G, F), Streptococcus bovis (group D), Streptococcus spp. group viridans.
Note: Most strains of enterocococci, such as Enterococcus faecalis, and staphylococci resistant to methicillin are resistant to the action of most cephalosporin antibiotics, including cefepime.

Gram-negative aerobes:
Acinetobacter calcoaceticus (sub strains anitratus, Iwoffii);
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 beta-lactamase-producing strains);
Haemophilus parainfluenzae;
Hafnia alvei;
Klebsiella spp., including Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella ozaenae;
Legionella spp.
Morganella morganii;
Moraxella catarrhalis (Branhamella catarrhalis) (including strains producing beta-lactamases);
Neisseria gonorrhoeae (including strains producing beta-lactamase);
Neisseria meningitidis;
Pantoea agglomerans (previously 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, including Serratia marcescens, Serratia liquefaciens;
Shigella spp.;
Yersinia enterocolitica.
Note: cefepim is inactive against many strains of Stenotrophomonas maltophilia (previously known as Xanthomonas maltophilia and Pseudomonas maltophilia).

Anaerobes:
Bacteroides spp;
Clostridium perfringens;
Fusobacterium spp;
Mobiluncus spp;
Peptostreptococcus spp.
Prevotella melaninogenica (known as Bacteroides melaninogenicus);
Veillonella spp.
Note: cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics
Mean plasma concentrations of cefepime in healthy adult men at different times after a single intravenous injection for 30 minutes to 12 hours and the maximum concentration (Cmax) are shown in the table below.

The mean plasma concentrations of cefepime (µg/ml) after intravenous administration

After intramuscular administration, cefepime is fully absorbed.

The cmax and time to maximum concentration (Tmax) after a single intramuscular injection are shown in the table below.

The mean plasma concentrations of cefepime (µg/ml) after intramuscular administration

Therapeutic concentrations of cefepime are detectable in the following fluids and tissues: urine, bile, peritoneal, bullosa fluid, bronchial mucosa, sputum, prostate, appendix, and gallbladder. Binding of cefepime with serum proteins averages 16.4% and does not depend on the drug concentration in blood serum.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide.

Cefepim is excreted mainly by the kidneys, by glomerular filtration (renal clearance averages 110 ml/min). About 85% of the administered dose of unchanged cefepime, less than 1% of N-methylpyrrolidine, about 6.8% of N-methylpyrrolidine oxide and about 2.5% of cefepime epimer are found in the urine.

After administration of doses from 250 mg to 2 g the half-life of cefepime from the body is on average about 2 hours. Total clearance averages 120 ml/min. No cumulation of the drug was observed when administered intravenously to healthy volunteers at a dose of 2 g every 8 hours for 9 days.

Patients with impaired renal function
The elimination half-life in renal failure is prolonged, with a linear relationship between total clearance and creatinine clearance. In severe renal function disorders that require dialysis sessions, the half-life is on average 13 hours in hemodialysis and 19 hours in continuous peritoneal dialysis. Dose adjustment is required if renal function is impaired.

Patients with impaired hepatic function
Pharmacokinetics of cefepime in patients with impaired hepatic function does not change. No dose adjustment is required for these patients.

Patients older than 65 years
After a single intravenous infusion of 1 g of the drug in healthy volunteers older than 65 years, an increase in the area under the curve “concentration-time” (AUC) and decrease in renal clearance as compared to young volunteers were noted. Dose adjustment is required in elderly patients with impaired renal function.

In children
Pharmacokinetics of the drug was studied in children aged 2 months to 11 years after a single dose of 50 mg/kg body weight intravenously or intramuscularly and after repeated administration of the drug (every 8-12 hours, for at least 48 hours). After a single intravenous injection, total clearance and volume of distribution were 3.3 ml/min/kg and 0.3 l/kg, respectively. The elimination half-life averaged 1.7 h. Renal excretion of cefepime unchanged was 60.4% of the administered dose, and renal clearance averaged 2.0 ml/min/kg.

After multiple intravenous administration, equilibrium plasma cefepime concentrations and other pharmacokinetic parameters did not differ from those after single administration. Patients’ age and sex had no significant effect on total clearance and volume of distribution adjusted for body weight. After intramuscular administration the maximum plasma concentration of cefepime in equilibrium averaged 68 µg/ml and was reached on average within 0.75 h. Eight hours after intramuscular administration plasma concentrations of cefepime averaged 6 µg/ml. Absolute bioavailability of cefepime after intramuscular injection averaged 82%.

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

** patient age: 3.1 months to 12 years, mean age: 3 years. The drug dose was 50 mg/kg body weight when administered intravenously for 5 to 20 minutes every 8 hours. Plasma and CSF concentrations were determined at the end of administration on day 2 or 3 of drug treatment.

Indications

Infectious and inflammatory diseases caused by cefepime-sensitive microorganisms in adults:

– Lower respiratory tract infections, including pneumonia and bronchitis;
– Urinary tract infections, both complicated, including pyelonephritis, and uncomplicated;
– Skin and soft tissue infections;
– Abdominal infections, including peritonitis and biliary tract infections;
– Gynecological infections;
– Septicemia;
– Febrile neutropenia.

Prevention of possible infections during abdominal surgical operations.

Infectious and inflammatory diseases caused by cefepim-sensitive microorganisms in children:

– Pneumonia;
– Urinary tract infections, both complicated, including pyelonephritis, and uncomplicated;

Active ingredient

Composition

How to take, the dosage

Cefepime can be administered intravenously (IV) or intramuscularly (IM). Doses and route of administration depend on the sensitivity of the pathogens, severity of infection, renal function and general condition of the patient. Intravenous route of administration is recommended for patients with severe or life-threatening infections, especially if there is a threat of septic shock. Intramuscularly a dose up to 1 g (volume <3.1 ml) can be administered as a single injection. The maximum dose (2 g/6.2 ml) should be administered as two injections at different sites.

In children, the dose should not exceed the maximum recommended dose for adults (2 g v/v every 8 hours). There is limited experience with intramuscular administration of cefepime in children.

Adults and children with a body weight greater than 40 kg with normal renal function

Urinary tract infections, mild to moderate severity

0.5 g-1 g w/v or w/v/m

Every 12 hours

Other infections, mild to moderate severity

1 g w/v or w/v/m

Every 12 hours

Another infections of mild to moderate severity/tr>

Severe infections

2 g w/v

Every 12 hours

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Very severe and life-threatening infections

2 g w/v

Every 8 hours

The usual duration of treatment is 7-10 days; severe infections may require longer treatment.

In the case of treatment of febrile neutropenia, the usual duration of treatment is 7 days or until neutropenia disappears.

Prevention of possible infections during surgical procedures
60 minutes before surgery, 2 g of the drug is given intravenously as an infusion for 30 minutes. Immediately after the end of the infusion, 500 mg of metronidazole is administered intravenously. Because of the incompatibility of metronidazole and cefepime, they should not be administered simultaneously or mixed. The infusion system should be flushed prior to metronidazole administration (see “Intravenous administration”). Metronidazole solution should be prepared according to the instructions for use of metronidazole. During prolonged (more than 12 hours) surgical procedures, 12 hours after the first dose, a second injection in the same dose of Cefepim is recommended, followed by administration of metronidazole.

Children from 2 months with body weight up to 40 kg
The usual recommended dose for urinary tract infections, skin and soft tissue infections, pneumonia is 50 mg/kg every 12 hours for 10 days. In case of severe infections, every 8 hours. Patients with febrile neutropenia, septicemia, bacterial meningitis should be administered 50 mg/kg every 8 hours for 7-10 days.

Patients with impaired renal function require dosage adjustment of cefepime to compensate for decreased urinary excretion rate. The dosing regimen should be prescribed depending on the degree of renal impairment, the severity of the infection and the sensitivity of microorganisms. In patients with mild to moderate renal impairment the initial dose of the drug should be the same as in patients with normal renal function.

The recommended maintenance doses of cefepime are shown in the table. Creatinine clearance for men can be calculated based on serum creatinine concentration using the following formula:

The creatinine clearance for women can be calculated by multiplying the value obtained by 0.85.

Hemodialysis removes approximately 68% of the administered dose from the body in 3 hours.

In continuous ambulatory peritoneal dialysis, the drug can be used in the initial recommended doses of 0.5 g, 1 g, or 2 g depending on the severity of the infection with an interval of 48 hours between doses.

Children with impaired renal function
In children with impaired renal function, a reduced dose or increased interval between injections is recommended as indicated in the table above. Creatinine clearance is calculated using the following formulas:

Patients with impaired liver function
No dose adjustment is required for patients with impaired liver function.

Intravenous administration
Recommended for patients with severe or life-threatening infections, especially when septic shock is threatened.

Preparing the solution for intravenous administration
The drug is dissolved in 5, 10 or 20 ml of sterile water for injection, 5% dextrose solution and 0.9% sodium chloride solution for injection as indicated in the table below and is injected for 3-5 minutes either directly into a vein or into an IV system through which a compatible IV solution is delivered to the patient.

Preparing the intravenous infusion solution
The prepared solution (see above) is transferred to an infusion vessel with other compatible intravenous infusion solutions (see below) and injected for at least 30 minutes.

Intramuscular administration: a dose up to 1 g (volume < 3.1 ml) may be administered as a single injection. The maximum dose (2 g/6.2 ml) should be administered as two injections at different sites.

Preparation of solution for intramuscular injection
The drug is dissolved in sterile water for injection, 5% dextrose solution or 0.9% sodium chloride solution for injection, bacteriostatic water for injection with parabens or benzyl alcohol, 0.5% or 1% lidocaine solution as indicated in the table below.

The prepared solutions of the drug for intramuscular and intravenous administration are stable for 24 hours at room temperature or 7 days when stored in the refrigerator (2-8°C).

As with all solutions for parenteral use, prepared solutions of the drug should be checked for the absence of visible mechanical inclusions before administration. If not, the prepared solution should not be used.

The powder and prepared solution may darken during storage without affecting the activity and quality of the drug.

Interaction

The drug solution is pharmaceutically incompatible with metronidazole, vancomycin, gentamicin, tobramycin sulfate, netilmicin sulfate solutions, therefore they should not be mixed. However, when cefepime and the above drugs are administered at the same time, each can be administered separately.

The data on the compatibility of cefepime and other drug solutions and their stability are shown in the table below.

Special Instructions

In the presence of factors that may cause renal dysfunction, the dose of cefepime should be adjusted to compensate for the reduced urinary excretion rate. Dosing regimen depends on the degree of renal failure, severity of infection and sensitivity of microorganisms. In mild to moderate renal impairment the initial dose of the drug is the same as in normal renal function. The risk of toxic reactions especially increases in elderly patients with impaired renal function.

The following serious adverse reactions, including life-threatening or fatal, have been reported during post-registration monitoring: encephalopathy (impaired consciousness including confusion, hallucinations, stupor and coma), myoclonus, seizures and non-convulsive status epilepticus.

The majority of cases have been reported in patients with renal impairment who have not had dose adjustments. However, in some cases neurotoxicity has been noted in patients who have received dose adjustment depending on the degree of renal impairment. In most cases, symptoms of neurotoxicity were reversible and disappeared after withdrawal of the drug and/or after hemodialysis. If neurotoxicity is associated with the use of cefepime, consideration should be given to discontinuing cefepime therapy or adjusting the dose in patients with renal impairment. Before starting treatment, it should be established whether the patient has a history of allergic reactions to cefepime, other cephalosporin antibiotics, penicillins and other beta-lactam antibiotics, as well as other forms of allergy. Cases of severe hypersensitivity reactions, sometimes fatal, have been reported with all types of beta-lactam antibiotics.

The antibiotics of the cephalosporin group may cause false-positive reactions for glucose in urine in tests based on the reduction of copper ions (with Benedict or Feling solutions or with Clinitest tablets), but not in enzyme tests (with glucose oxidase). Therefore it is recommended to use enzyme tests with glucose oxidase to determine glucose in the urine.

In case of allergic reactions, treatment with the drug should be stopped and appropriate measures should be taken. If a severe allergic reaction develops (e.g., anaphylactic reaction) immediately during administration of the drug, epinephrine and other supportive therapy may be required.

When prescribing empirical treatment, data on acquired resistance of the causative microorganisms must be taken into account.

The resistance of microorganisms can change over time and geographic location. Appropriate tests should be performed to identify the causative microorganism and determine sensitivity to cefepime. Cefepime may be used as monotherapy even before identification of the causative organism because it has a broad spectrum of antibacterial activity against Gram-positive and Gram-negative microorganisms. At the risk of mixed aerobic/anaerobic infection (especially when insensitive to cefepime microorganisms may be present) treatment with cefepime in combination with a drug acting on anaerobes may be started before identification of the pathogen.

After identification of the pathogen and determination of antibiotic sensitivity, treatment should be carried out in accordance with the test results.

As with other antibiotics, treatment with Cefepim may lead to colonization of insensitive microflora. If superinfections develop during treatment, appropriate measures should be taken.

In studies in rats, no effect on fertility has been noted. There are no data on the effect on fertility in humans when using cefepime.

Clostridium difficile-associated diarrhea
Almost all broad-spectrum antibiotics can cause Clostridium difficile-associated diarrhea (CDAD – Clostridium difficile-associated diarrhea) that may be either mild or severe, up to and including death.

If diarrhea occurs during treatment with the drug, the diagnosis of CDAD should be confirmed. The patient should be closely monitored for the development of CDAD, since cases of CDAD have been reported more than two months after discontinuation of antibiotics. If CDAD is suspected or confirmed, antibiotics other than those prescribed to suppress Clostridium difficile should be discontinued. Drugs that inhibit intestinal peristalsis should not be used.

The drug effect on the ability to concentrate has not been studied, but taking into account the possibility of side effects of the central nervous system, the drug treatment should not be used for driving vehicles and other potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Contraindications

Hypersensitivity to cefepime or L-arginine or to antibiotics of the cephalosporine group, penicillins or other beta-lactam antibiotics.

Children under 2 months of age.

A history of gastrointestinal diseases (especially colitis), renal insufficiency (creatinine clearance less than 60 ml/min).

Side effects

The most frequently reported side effects are gastrointestinal and allergic reactions. Side effects by organs and systems are listed below according to their frequency: very common (≥10%); common (≥1% and <10%); infrequent (≥0.1% and <1%); rare (≥0.01% and <0.1%); frequency unknown (no data on the frequency of this side effect).

Allergic reactions
Often – skin rash;
Infrequent – erythema, urticaria, pruritus;
Rarely – anaphylactic reactions;
Frequency unknown – anaphylactic shock, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, angioedema.

Infections
Infrequent – oral mucosal candidiasis, vaginal infections;
Rarely – candidiasis.

Central nervous system
Infrequent – headache;
Rarely – seizures, paresthesias, dysgesia, dizziness;
Frequency unknown (post-registration experience): Encephalopathy (impaired consciousness, including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and non-convulsive epileptic status.

While most cases occurred in patients with renal impairment who received cefepime at doses higher than recommended, in some cases neurotoxicity was noted in patients who received dose adjustments depending on the degree of renal impairment.

Uses of the urinary system
Frequency unknown – renal failure, toxic nephropathy.

Gastrointestinal system
Often – diarrhea;
Infrequent – nausea, vomiting, colitis (including pseudomembranous colitis);
Rarely – abdominal pain, constipation;
Frequently unknown – digestive disorders.

Respiratory system
Rarely – shortness of breath.

Cardiovascular system
Rarely – vasodilation;
Frequency unknown – bleeding.

General reactions and reactions at the injection site
Often – phlebitis at the injection site, pain at the injection site;
Infrequently – fever and inflammation at the injection site;
Rarely – chills.

Laboratory measures
Often – increase of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (ALP), total bilirubin, anemia, eosinophilia, increase of prothrombin time or partial thromboplastin time;
Infrequent – increase of blood urea nitrogen, serum creatinine, thrombocytopenia, leukopenia and neutropenia;
Frequency unknown – aplastic anemia, hemolytic anemia, agranulocytosis.

Other
Rarely – genital itching, change in taste, vaginitis, erythema, false positive Coombs test without hemolysis.

Overdose

Pregnancy use

Adequate and controlled clinical studies in pregnant women have not been conducted. In pregnancy, the drug should be used only if the estimated benefit to the mother exceeds the potential risk to the fetus.

Cefepim is detected in breast milk at very low concentrations.

The drug should be used during breastfeeding only if the expected benefit to the mother exceeds the potential risk to the baby.