Cefepime - instructions for use, dose, side effects, contraindications

active substance: Cefepime dihydrochloride monohydrate 1.19 g / 2.38 g, equivalent to cefepime base 1.0 g / 2.0 g. adjuvant: L-Arginine 0.780 g / 1.56 g.

Description:Crystalline powder white or white with a yellowish hue.

Pharmacotherapeutic group:Antibiotic-cephalosporin

ATX: & nbsp

J.01.D.E.01 Cefepim

Pharmacodynamics:

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

Cefepime has a bactericidal effect against a wide range of bacteria. The drug is active against the following microorganisms: gram-positive aerobes: Staphylococcus aureus (including strains, producing beta-lactamase), Staphylococcus epidermidis (including strains producing beta-lactamase), other strains Staphylococcus spp., including Staphylococcus saprophyticus, Staphylococcus hominis; Streptococcus pyogenes; Streptococcus agalactiae; Streptococcus pneumoniae (including strains with an average resistance to penicillin - a minimum suppressive concentration of 0.1 to 1 μg / ml); other beta-hemolytic Streptococcus spp. (groups C,F,G), Streptococcus bovis (Group D), Streptococcus spp. groups viridans.

Most strains of enterococci and staphylococcus aureus resistant to methicillin are resistant to cefepime.

gram-negative aerobes: Acinetobacter calcoaceticus (sub-stems anitratus, lwoffii), Aeromonas hydrofphila, 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 strains producing beta-lactamase), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp., including Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella ozaenae, Legionella spp., Morganella morganii, Moraxella catarrhalis (including strains producing beta-lactamase), Neisseria gonorrhoeae (including strains producing beta-lactamase), Neisseria meningitides, 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 stutzer, Salmonella spp., Shigella spp., Serratia spp., including Serratia marcescens, Serratia liquefaciens, Yersinia enterocolitica.

Most strains Stenotrophomonas maltophilia (before the well-known as Xanthomonas maltophilia and Pseudomonas maltophilia).
anaerobes: Bacteroides spp., Clostridium perfringens, Fusobacterium spp., Mobilincus spp., Peptostreptococcus spp., Prevotella melaninogenicus (famous as Bacteroides melaninogenicus), Veilonella spp.
Cefepim inactive at respect Bacteroides fragilis, Clostridium difficile.

Pharmacokinetics:

Bioavailability 100%. The average therapeutic concentration for in / m administration is 0.2 μg / ml, with an IV dose of 0.7 μg / ml.

Therapeutic concentrations are determined in urine, bile, peritoneal fluid, blister exudate, bronchial mucus secretion, sputum, prostate gland, appendix and gallbladder.

Cefepime is metabolized in Nmethylpyrrolidine, which rapidly converts into an oxide Nmethylpyrrolidine. Cefepim is displayed mainly kidney, by glomerular filtration (renal clearance is on average 110 ml / min). In urine, approximately 85% of the administered dose of unchanged cefepime is found, less than 1% N-methylpyrrolidine, about 6.8% oxide Nmethylpyrrolidine and about 2.5% of cefepime epimer. The binding of cefepime to plasma proteins is on average 16.4% and does not depend on the concentration of the drug in the blood serum.

The half-life of cefepime from the body is on average about 2 hours. With intravenous administration of 2 g of the drug with an interval of 8 hours for 9 days, cumulation of the drug was not observed.

Patients over 65 years of age and patients with impaired renal function

After a single intravenous injection of 1 g of the drug to healthy volunteers over 65 years of age, there was an increase in the pharmacokinetic index AUC (area under the "concentration-time" curve) and a decrease in renal clearance in comparison with young volunteers. Therefore, when renal dysfunction in older patients requires adjustment of the dose.

In patients with varying degrees of renal failure, the elimination half-life of the body increases in a linear relationship between total clearance and creatinine clearance. In case of severe violations of kidney function requiring dialysis sessions, the half-life period averages 13 hours for hemodialysis and 19 hours for peritoneal dialysis. Patients with impaired renal function require a dose adjustment.

Patients with impaired liver function

The pharmacokinetics of cefepime in patients with impaired liver function does not change.A dose adjustment for such patients is not required.

Children from 2 months to 11 years of age

The pharmacokinetics of cefepime 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 several doses of the drug every 8 hours or every 12 hours but not less than 48 hours. After a single intravenous injection, the total clearance and volume of distribution were 3.3 ml / min / kg and 0.3 l / kg, respectively.

The half-life of the body is on average 1.7 hours.

The excretion of cefepime in an unchanged form by the kidneys was 60.4% of administered dose, and renal clearance of an average of 2.0 ml / min / kg. After multiple intravenous plasma cefepime concentration blood in an equilibrium state and other pharmacokinetic parameters are not differed from the parameters after a single injection. Age and gender patients did not significantly affect the overall clearance and volume distribution taking into account the correction for the body weight of each.

After intramuscular injection, the maximum concentration of cefepime in plasma in the equilibrium state averaged 68 μg / ml for median 0.75 hours. 8 hours after intramuscular administration cefepime concentrations in the blood plasma averaged 6 μg / ml. Absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Indications:

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

- infections of the lower respiratory tract, including pneumonia, exacerbation of chronic bronchitis;

- urinary tract infections, both complicated (including pyelonephritis), and uncomplicated;

- infections of the skin and soft tissues;

- intra-abdominal infections (including peritonitis and bile duct infections);

- gynecological infections;

- septicemia;

- febrile neutropenia.

Prevention of infections in the conduct of cavitary surgery.

Infectious and inflammatory diseases caused by microorganisms sensitive to cefepime, in children:

- pneumonia;

- urinary tract infections, both complicated (including pyelonephritis), and uncomplicated;

- infections of the skin and soft tissues;

- septicemia;

- febrile neutropenia;

- bacterial meningitis.

Contraindications:

Hypersensitivity to cefepime or L-arginine, as well as antibiotics of the cephalosporin group, penicillins or other beta-lactam antibiotics, children under 2 months.

Carefully:

Diseases of the gastrointestinal tract in history (especially colitis), renal failure (creatinine clearance less than 50 ml / min).

Pregnancy and lactation:

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

Cefepime is found in breast milk in very low concentrations.

During the period of breastfeeding, the drug should be used only if the intended benefit to the mother exceeds the potential risk to the child.

Dosing and Administration:

Intravenously (intravenously) or intramuscularly (in / m). The dose and route of administration depend on the sensitivity of the pathogens, the severity of the infection, the state of kidney function, and the general condition of the patient.

Intravenous The introduction is recommended for patients with severe or life-threatening infections, especially when there is a risk of septic shock.

Preparation of a solution for intravenous administration

The drug is dissolved in 10 ml of sterile water for injection, 5% solution dextrose and 0.9% solution of sodium chloride for injection, as indicated in following table, and administered within 3-5 minutes either directly into the vein, or into the system for intravenous administration, through which a compatible solution for intravenous administration enters the patient's body.

Preparation of a solution for intravenous infusion

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

Drug solutions with a concentration of 1-40 mg / ml are compatible with the following parenteral solutions: 0.9% solution of sodium chloride for injection; 5% or 10% dextrose solution for injection; 1/6 M sodium lactate for injection, 5% dextrose solution and 0.9% sodium chloride for injection; Ringer's lactate solution.

Intramuscular administration: the dose 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 locations.

Preparation of solution for intramuscular injection

The drug is dissolved in sterile water for injection, 5% dextrose solution or 0.9% solution of sodium chloride for injection, bacteriostatic water for injection with parabens or benzyl alcohol, 0.5% or 1% lidocaine solution (1 g in 3.0 ml ).

Dosing regimens of cefepime depending on the disease, body weight and age of the patient

The dose for children should not exceed the maximum recommended for adults (2 g IV, every 8 hours). The experience of intramuscular administration of the drug to children is limited.

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

Urinary tract infections, mild and moderate:	500 mg - 1 g IV or IM	every 12 hours
Other infections, mild and moderate:	1 g IV or IM	every 12 hours
Severe infections:	2 g IV	every 12 hours
Very serious and life-threatening infections:	2 g IV	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 infections during surgical operations

60 minutes prior to the beginning of the surgical operation, 2 g of the drug are administered intravenously in the form of infusion, for 30 minutes. Immediately after the end of the infusion, the patient is administered 500 mg of metronidazole intravenously. A solution of metronidazole is prepared according to the instructions for its use. Due to the pharmaceutical incompatibility of metronidazole and cefepime, they should not be mixed in a single vessel. Infusion system before the introduction of metronidazole should be washed. During prolonged (more than 12 hours) surgical operations 12 hours after the first dose, repeated administration of cefepime in the same dose is recommended with the subsequent administration of metronidazole.

Children from 2 months with a body weight of up to 40 kg

For urinary tract infections, skin and soft tissue infections, pneumonia, the recommended dose 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

Patients with impaired renal function require an adjustment of the dosage of cefepime to compensate for the reduced rate of excretion of the drug withurine. The dosage regimen depends on the degree of impaired renal function, the severity of infection and the sensitivity of microorganisms. With weak or moderate disturbances of kidney function, the initial dose of the drug is the same as with normal kidney function.

Recommended maintenance doses of cefepime depending on the creatinine clearance are presented in the table below.

The creatinine clearance for men is calculated from the serum creatinine concentration using the following formula:

Creatinine clearance (ml / min) = body weight (kg) x (140 - age) / 72 x serum creatinine (mg / dL)

The creatinine clearance for women is calculated by the same formula, using a factor of 0.85.

Clearance creatinine (ml / min)	Recommended maintenance doses
>60	(usual dose, dose adjustment is not required)
>60	2 grams every 8 hours	2 grams every 12 hours	1 g every 12 hours	500 mg every 12 hours
30-60	2 grams every 12 hours	2 grams every 24 hours	1 g every 24 hours	500 mg every 24 hours
11-29	2 grams every 24 hours	1 g every 24 hours	500 mg every 24 hours	500 mg every 24 hours
< 10	1 g every 24 hours	500 mg every 24 hours	250 mg every 24 hours	250 mg every 24 hours
Patients on hemodialysis *	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

* For patients on hemodialysis, a dose reduction is recommended:

1g on the first day of treatment and then 500 mg per day for all infections, with the exception of febrile neutropenia, where the dose is 1 g per day. In the days of dialysis, the drug should be administered after the end of dialysis. If possible, the drug should be administered at the same time every day.

With hemodialysis within 3 hours, approximately 68% of the administered dose is removed from the body.

With continuous ambulatory peritoneal dialysis, the drug can be used in the initial recommended doses of 500 mg, 1 g and 2 g, depending on the severity of the infection, with intervals between administrations - 48 hours.

Children with impaired renal function

Children with impaired renal function are recommended to reduce the dose or increase the interval between administrations, as indicated in the table above.

Creatinine clearance is calculated by the following formulas:

Creatinine clearance (ml / min / 1.73²) = 0.55 x height (cm) / serum creatinine (mg / dl)

Creatinine clearance (ml / min / 1.73²) = 0.52 x height (cm) / serum creatinine (mg / dl) - 3.6

Patients with impaired hepatic function

Dose adjustments for patients with impaired liver function are not required.

Side effects:

The most common side effects are from the gastrointestinal tract and allergic reactions.The following are side effects of organs and systems according to their frequency: very frequent (≥10%); frequent (≥1% and <10%); infrequent (≥0.1 and <1%); rare (≥0.01% and <0.1%); the frequency is unknown (there is no data on the incidence of this side effect).

Infections: infrequently - candidiasis of the oral mucosa, vaginal infections; rarely - candidiasis

Allergic reactions: often - rashes on the skin; infrequently - erythema, urticaria, itching; rarely anaphylactic reactions; frequency unknown - anaphylactic shock, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome

From the central nervous system: infrequently - a headache; rarely - cramps, paresthesia, dysgesia, dizziness; frequency unknown - confusion, short-term loss of consciousness, hallucinations, coma, stupor, encephalopathy, myoclonic cramps

From the side of the vessels: rarely - vasodilation; frequency unknown - bleeding

On the part of the respiratory system: rarely shortness of breath

From the gastrointestinal tract: often - diarrhea, infrequently - nausea, vomiting, colitis (including pseudomembranous colitis); rarely - abdominal pain, constipation; frequency is unknown - digestive disorders

From the urinary system: frequency unknown - renal failure, toxic nephropathy

General reactions at the site of administration: often - phlebitis at the injection site, pain at the injection site, infrequently - fever and inflammation at the injection site; rarely - chills

Other: rarely - genital itching, taste change, vaginitis, erythema, false-positive Coombs test without hemolysis

Changes in laboratory indicators: often - increased activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, anemia, eosinophilia, increased prothrombin time or partial thromboplastin time and, rarely, increased blood urea nitrogen, serum creatinine, thrombocytopenia, leukopenia and neutropenia; frequency unknown - aplastic anemia, hemolytic anemia, agranulocytosis.

Post-registration experience: frequency unknown - encephalopathy (impaired consciousness, including confusion, hallucinations, stupor and coma), myoclonus, convulsions and anonzodorozhny status epilepticus. Despite the fact that most cases were noted in patients with renal failure who received cefepime in doses higher than recommended, in some cases, neurotoxicity was noted in patients undergoing dose adjustment, depending on the degree of renal insufficiency.

Overdose:

Symptoms: encephalopathy (confusion, hallucinations, stupor, coma), myoclonic cramps, increased neuromuscular excitability.

In cases of significant excess of recommended doses, especially in patients with impaired renal function, hemodialysis is indicated.

Interaction:

Cefepime is not pharmaceutically compatible with other antimicrobial drugs.

Pharmaceutically incompatible with solutions of metronidazole, vancomycin, gentamicin, tobramycin, netilmicin. It is not compatible with the solution of metronidazole: before the administration of the solution of metronidazole for the prevention of infections during surgical interventions, the infusion system should be rinsed from the cefepime solution. To avoid possible drug interactions with other drugs, cefepime solutions (like most other beta-lactam antibiotics) should not be administered concomitantly with solutions of vancomycin, gentamicin, tobramycin, netilmicin.When using cefepime with the listed products, each antibiotic should be administered separately.

Diuretics, aminoglycosides, polymyxin B reduce the tubular secretion of cefepime and increase its concentration in the blood plasma, lengthen T_1/2, increase nephrotoxicity (increased risk of nephronecrosis). Cefepim increases the ototoxicity of aminoglycosides.

Nonsteroidal anti-inflammatory drugs, slowing the excretion of cephalosporins, increase the risk of bleeding. When used simultaneously with bactericidal antibiotics (aminoglycosides), synergism is manifested, with bacteriostatic (macrolides, chloramphenicol, tetracyclines) - antagonism.

Special instructions:

In the presence of factors that can cause a violation of kidney function, correction of the dose of cefepime is required in order to compensate for the reduced rate of excretion of the drug with urine. The dosage regimen depends on the degree of renal failure, the severity of infection and the sensitivity of microorganisms. With weak or moderate disturbances of kidney function, the initial dose of the drug is the same as with normal kidney function.The risk of developing toxic reactions is especially increased in elderly patients with impaired renal function.

As with other representatives of this class, cases of encephalopathy in patients (usually reversible) (confusion, hallucinations, stupor), myoclonic seizures, (including unsafe epileptic status), and / or renal failure were noted in the practice of cefepime. Most cases were observed in patients with impaired renal function, who were given doses higher than those recommended. Usually, the symptoms of neurotoxicity disappeared after the interruption of treatment and / or after hemodialysis, but sometimes they ended in a fatal outcome. In patients with impaired renal function or in the presence of other factors that may lead to a delay in the excretion of cefepime, its dose should be adjusted.

Before using the drug Cefepim It should be determined whether the patient had a history of allergic reactions to cefepime, other cephalosporin antibiotics, penicillins and other beta-lactam antibiotics. When developing an allergic reaction, discontinue drug treatment and take appropriate measures.When developing a severe allergic reaction (for example, anaphylactic reaction) directly during the administration of the drug Cefepim may require the use of epinephrine and other maintenance therapy.

When appointing empirical treatment, it is necessary to take into account data on the acquired resistance of microorganisms-pathogens.

The stability of microorganisms can change over time, and also depends on the geographical location. To identify the microorganism-pathogen and determine sensitivity to cefepime, appropriate tests should be carried out. But, Cefepim can be used in monotherapy even before the identification of the microorganism-pathogen, since it has a broad spectrum of antibacterial action against gram-positive and gram-negative microorganisms. Likewise, with the risk of mixed aerobic / anaerobic infection (especially when microorganisms insensitive to cefepime may be present), treatment with the drug Cefepim in combination with a drug acting on anaerobes, can begin before identification of the pathogen.

After identifying the pathogen and determining the sensitivity to antibiotics, treatment should be carried out in accordance with the test results.

Clostridium difficile associated diarrhea

With almost all broad-spectrum antibiotics, the occurrence of diarrhea associated with Clostridium difficile (CDAD - Clostridium difficile-associated diarrhea), which can occur both in the form of light forms, and in the form of heavy fatalities.

If diarrhea occurs during treatment with the drug, it is necessary to confirm the diagnosis CDAD. Care should be taken to monitor the patient for development CDAD, Since antibiotics were used for more than two months, cases of its occurrence were recorded. If suspected or confirmed CDAD, should stop the use of antibiotics inactive in relation to Clostridium difficile.

The use of drugs that inhibit the intestinal peristalsis is contraindicated.

As with other antibiotics, drug treatment Cefepim can lead to colonization of insensitive microflora. With the development of superinfections during treatment, appropriate measures must be taken.

Effect on the ability to drive transp. cf. and fur:

During treatment with cefepime, you should refrain from driving vehicles and performing work that requires an increased speed of psychomotor reactions.

Form release / dosage:

Powder for the preparation of solution for intravenous and intramuscular injection 1.0 g and 2.0 g.

Packaging:

1.0 g, 2.0 g of active ingredient per bottle with a capacity of 20 ml of colorless transparent glass type III, sealed with a plug of chlorobutyl rubber, crimped with an aluminum cap with a safety plastic cap.

1 The bottle together with the instruction for use is placed in a cardboard box.

For hospitals: 50 bottles together with an equal number of instructions for use are placed in a cardboard box.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

2 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004079

Date of registration:16.01.2017

Expiration Date:16.01.2022

The owner of the registration certificate:Karnataka Antibiotics & Pharmaceuticals LimitedKarnataka Antibiotics & Pharmaceuticals Limited India

Manufacturer: & nbsp

KARNATAKA ANTIBIOTICS & PHARMACEUTICALS, Limited India

Representation: & nbspRusyurofarm, Open CompanyRusyurofarm, Open Company

Information update date: & nbsp30.01.2017

Illustrated instructions

Instructions

Cefepim (Cefepime)