Meropenem-DECO - instructions for use, doses, side effects, contraindications

Meropenem is an antibiotic from the carbapenem group for parenteral administration. Virtually does not degrade in the renal tubules dehydropeptidase-1 (does not need a combination with cilastatin - a specific dehydropeptidase-1 inhibitor). Has a bactericidal effect by suppressing the synthesis of the bacterial cell wall. The high bactericidal activity of meropenem against a wide range of aerobic and anaerobic bacteria is due to the high capacity of meropenem to penetrate the bacterial cell wall,a high level of stability to most beta-lactamases and a significant affinity for various penicillin-binding proteins (PSBs). The minimum bactericidal concentrations (MBCs) are usually the same as the minimum inhibitory concentrations (MICs). For 76% of the tested bacterial species, the ratio of MBC / MIC was 2 or less. Tests in vitro show that meropenem acts synergistically with various antibiotics. In the tests in vitro and in vivo shown, that meropenem has a post-antibiotic effect.

Microorganisms may possess one or more of the listed mechanisms of resistance to meropenem: a violation of the permeability of the cell wall of Gram-negative bacteria due to a violation of the synthesis of porins; reduce the affinity for target penicillin-binding proteins; activation of efflux mechanisms; production of beta-lactamases, under the action of which hydrolysis of carbapenems takes place.

The only recommended criteria sensitivity to meropenem based on the pharmacokinetics of the drug and on the correlation of clinical and microbiological data - the diameter of the zone and MIC, determined for the relevant pathogens.

Category of the pathogen	Diameter of the zone, mm
Sensitive	≥14
Intermediate	12-13
Resistant	≤11

The following table shows the threshold values of MIC of meropenem in the European Union (EU) for bacterial pathogens in clinical settings.

Pathogenic microorganisms	Sensitivity, mg / l	Resistance, mg / l
Enterohacteriaceae	≤2	>8
Pseudomonas	≤2	>8
Acinetohacter	≤2	>8
Streptococcus groups A, B, C, G	≤2	>2
Streptococcus pneumoniae¹	≤2	>2
Other streptococci	2	2
Enterococcus⁵	-	-
Staphylococcus²	depends on the presence of sensitivity to methicillin
Haemophilus influenzae¹ Moraxella catarrhalis	≤2	>2
Neisseria meningitidis^{2, 3}	≤0,25	>0,25
Gram-positive anaerobes	≤2	>8
Gram-negative anaerobes	≤2	>8
Nonspecific thresholds⁴	≤2	>8

¹ - threshold of sensitivity for Streptococcus pneumoniae and Haemophilus influenza when meningitis - 0.25 mg / l.

² - strains for which the MIC above sensitivity threshold, rare or not detected at the moment. If such a strain is detected, the MIC test is performed again, upon confirmation of the result, the strain is sent to a reference laboratory, and the strain is considered resistant until a confirmed clinical effect is obtained with respect to it.

³ - values to be used only with meningitis.

⁴ - for all other pathogens, according to pharmacokinetic and pharmacodynamic data, without taking into account the specific distribution of MICs of specific pathogenic microorganisms.

⁵ - The sensitivity test is not recommended, since this agent is not the optimal target for meropenem.

Meropenem is active against the following clinically relevant microorganisms:

Gram-positive aerobes:

Enterococcus faecalis¹; Staphylococcus aureus (methicillin-sensitive)² ; clan Staphylococcus (methicillin-sensitive), including Staphylococcus epidermidlis; Streptococcus agalactiae group B; Group Streptococcus milleri (S. anginosus, S. constellatus, S. intermedins); Streptococcus pneumonia; Streptococcus pyogenes group A.

gram-negative aerobes:

Citrobacter freundii; Citrobacter koseri; Enterobacter aerogenes; Enterobacter cloacae; Escherichia coli; Haemophilus influenza; Klebsiella oxytoca; Klebsiella pneumonia; Morganella morganii; Neisseria meningitides; Proteus mirabilis; Proteus vulgaris; Serratia marcescens.

Gram-positive anaerobes:

Clostridium perfringens; Peptoniphilus asaccharolyticus; pod Peptostreptococcus (including P. micros, P. anaerobius, P. magnus).

Gram-negative anaerobes:

Bacteroides caccae; Bacteroides fragilis; Prevotella bivia; Prevotella disiens.

Pathogenic microorganisms, for which the problem of acquired resistance:

Gram-positive aerobes:

Enterococcus faecium¹

gram-negative aerobes:

pod Acinetobacter; Burkholderia cepacia; Pseudomonas aeruginosa.

Pathogenic microorganisms possessing natural resistance:

gram-negative aerobes:

Stenotrophomonas maltophilia; Legionella spp.

other pathogens:

Chlamidophila pneumoniae; Chlamidophila psittaci; Coxiella burnetii; Mycoplasma pneumoniae.

¹ - pathogens with intermediate sensitivity.

²- all methicillin-resistant staphylococci are resistant to meropenem.

Pharmacokinetics:

With intravenous injection of 0.5 and 1 g for 30 minutes, the maximum plasma concentrations are about 23 μg / ml and 49 μg / ml, respectively.Absolute pharmacokinetic proportional dependence on the administered dose for maximum concentration and area under the pharmacokinetic curve "concentration-time" (AUC) no. When the dose is increased from 0.25 g to 2 g, the plasma clearance decreases from 287 to 205 ml / min.

With an intravenous bolus injection of 0.5 g for 5 min, the maximum plasma concentration is about 52 μg / ml, 1 g is about 112 μg / ml. Just 6 hours after intravenous administration of 0.5 g, the concentration of meropenem in the blood plasma is reduced to 1 μg / ml and lower.

The connection with plasma proteins is about 2%.

The extended (up to 3 hours) infusion of carbapenems (including meropenem) can lead to optimization of their pharmacokinetic and pharmacodynamic parameters. With a standard 30-minute infusion of healthy volunteers, two doses of 0.5 g and 2 g every 8 hours, the value of% T> MIC (the ratio between the time period when the drug concentration exceeds the minimum inhibitory concentration for sensitive microorganisms (MIC), and the dosing interval; MIC taken a value of 4 μg / ml) was 30% and 58%, respectively. When the same doses were administered by the 3-hour infusion every 8 hours, the% T> MIC index increased to 43% and 73%, respectively for 0.5 g and 2 g.The mean plasma concentration in healthy volunteers after intravenous bolus administration of 1 g of meropenem for 10 min exceeded the MIC of 4 μg / ml for 42% of the dosing interval, compared to 59% for a 3 hour infusion of the same dose of the drug.

It penetrates well into most tissues and body fluids, including spinal fluid of patients with bacterial meningitis, reaching concentrations exceeding those required for suppression of the majority of bacteria (bactericidal concentrations are created 0.5-1.5 hours after the start of infusion). In small amounts penetrates into breast milk.

Exposed to a slight metabolism in the liver with the formation of a single inactive metabolite. Half-life is about 1 hour, in children under 2 years it is about 1.5-2.3 hours. In the dose range of 10-40 mg / kg in adults and children, a linear dependence of pharmacokinetic parameters is observed. Do not cumulate.

It is excreted by the kidneys - 70% unchanged for 12 hours. The concentration of meropenem in the urine, exceeding 10 μg / ml, is maintained for 5 hours after the administration of 0.5 g of the drug.

Renal insufficiency

In patients with renal insufficiency, the clearance of meropenem correlates with creatinine clearance, therefore a dose adjustment and interval between administrations is necessary.

Have elderly patients a decrease in the clearance of meropenem correlates with a decrease in creatinine clearance associated with age.

Meropenem is excreted in hemodialysis with a clearance of about 4 times the clearance of meropenem in patients with anuria.

Liver failure

Diseases of the liver have no effect on the pharmacokinetics of meropenem.

Indications:

Infectious-inflammatory diseases (monotherapy or in combination with other antimicrobial drugs) caused by one or more meropenem-sensitive pathogens:

- infections of the lower respiratory tract (pneumonia, including hospital);

- intra-abdominal infections (complicated appendicitis, peritonitis);

- urinary tract infection (pyelonephritis, pyelitis);

- infections of the skin and soft tissues (erysipelas, impetigo, secondarily infected dermatoses);

- infection of the pelvic organs (endometritis, pelvioperitonitis);

- bacterial meningitis;

- septicemia;

- empirical treatment (in the form of monotherapy or in combination with antiviral or antifungal drugs) with suspected infection in adult patients with febrile episodes with neutropenia.

The effectiveness of the drug has been proven both in monotherapy mode and in combination with other antimicrobial agents in the treatment of polymicrobial infections.

Contraindications:

Hypersensitivity to meropenem and other components of the drug, pronounced hypersensitivity (anaphylactic reactions, severe skin reactions) to any antibacterial agent having a beta-lactam structure (ie to penicillins or cephalosporins), children under 3 months.

Carefully:

When used simultaneously with potentially nephrotoxic drugs, patients with gastrointestinal complaints (diarrhea), especially those suffering from colitis.

Pregnancy and lactation:

The use of the drug during pregnancy is possible only on strict indications after a careful evaluation by the attending physician of the ratio of benefit to the mother and the risk to the fetus.

If it is necessary to prescribe the drug, breastfeeding should be discontinued.

Dosing and Administration:

Meropenem is administered as an intravenous bolus injection, or intravenously infusion. The dose and duration of therapy should be determined depending on the type, severity of the infection and the condition of the patient.

Adults

- In the treatment of pneumonia, urinary tract infections, infectious and inflammatory diseases of the pelvic organs (including endometritis), infections of the skin and soft tissues - intravenously, 0.5 g every 8 hours;

- in the treatment of hospital pneumonia, peritonitis, with a suspected bacterial infection in patients with symptoms of neutropenia, septicemia - intravenously, 1 g every 8 hours;

- In the treatment of meningitis - 2 g intravenously infusion every 8 hours. The safety of taking a dose of 2 g in the form of a bolus injection has not been sufficiently studied.

In case of impaired renal function

In patients with a creatinine clearance less than 51 ml / min, the dose should be adjusted as follows:

Creatinine clearance, ml / min	Dose (based on a unit dose of 500 mg, 1 g, 2 g)	Frequency of introduction
26-50	one dose unit	every 12 hours
10-25	0.5 unit dose	every 12 hours
less than 10	0.5 unit dose	every 24 hours

Meropenem is excreted in hemodialysis and hemofiltration. To restore the effective plasma concentration, it is necessary to administer a single dose of meropenem recommended for the corresponding pathology upon completion of the hemodialysis procedure.

Currently, there is no evidence of experience with the use of meropenem in patients on peritoneal dialysis.

When a violation of liver function

In patients with impaired hepatic function, there is no need for dose adjustment.

Elderly patients

In elderly patients with normal renal function or creatinine clearance greater than 50 ml / min, dose adjustment is not required.

Children

- for children aged 3 months to 12 years (with a body weight of less than 50 kg), the recommended dose for intravenous administration is 10-20 mg / kg every 8 hours;

- for children weighing more than 50 kg, doses for adults should be used;

- With meningitis, the recommended dose for intravenous infusion is 40 mg / kg every 8 hours.

The safety of administering a dose of 40 mg / kg in the form of a bolus injection has not been adequately studied.

Experience with the use of meropenem in children with impaired renal and hepatic function is absent.

Rules for the preparation of solutions for intravenous administration

Meropenem for intravenous administration is given as an intravenous bolus injection for at least 5 minutes, or as an intravenous infusion for 15-30 minutes. The possibility of using meropenem in the regime of extended (up to 3 hours) infusion is based on pharmacokinetic and pharmacodynamic parameters (see section "Pharmacokinetics.") To date, data on the clinical efficacy and safety of the extended infusion regimen are limited.

To prepare a solution for intravenous bolus injections the drug should be dissolved with water for injection (5 ml per 250 mg), while the concentration of meropenem in the solution should be 50 mg / ml. The resulting solution remains stable for 3 hours at a temperature of up to 25 ° C and for 16 hours when stored in a refrigerator (2-8 ° C).

To prepare a solution for intravenous infusion Use compatible infusion liquids: 0.9% sodium chloride solution or 5% dextrose solution. 0.5 g or 1 g of the drug is dissolved in 10 ml of water for injection. The resulting solution is transferred to a vial with a compatible infusion fluid, and the concentration of meropenem in the solution should be from 1 to 20 mg / ml. The solution of the preparation, prepared using 0.9% sodium chloride solution, remains stable for 3 hours at a temperature of up to 25 ° C and for 24 hours when stored in a refrigerator (2-8 ° C). A solution prepared using a 5% dextrose solution should be used immediately.

The drug solution should not be frozen.

The prepared solution is recommended to be administered immediately after preparation (from the microbiological point of view), if the conditions for the preparation of the solution do not exclude the possibility of microbiological contamination.

Side effects:

Generally, meropenem is characterized by good tolerability. In rare cases, side effects led to the abolition of therapy. Serious adverse reactions are rare.

The incidence of adverse reactions listed below was determined according to the following gradation: very often (> 1/10), often (> 1/100, ≤1/10), infrequently (> 1/1000, ≤1/100), rarely (> 1/10000, ≤1/1000), very rarely ≤1/10000).

From the digestive system:

often: nausea, vomiting, diarrhea; increased activity of "liver" transaminases, alkaline phosphatase, lactate dehydrogenase and serum bilirubin concentration

infrequently: constipation **, cholestatic hepatitis **

rarely: pseudomembranous colitis

From the urinary system:

infrequently: increasing the concentration of creatinine in the blood, increasing the concentration of urea in the blood

From the skin:

infrequently: rash, hives, itching,

rarely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

From the side immune system:

rarely: angioedema, manifestations of anaphylaxis

From the nervous system:

infrequently: head pain, paresthesia, fainting**, hallucinations **, depression**, anxiety **, increased excitability **, insomnia **

rarely: convulsions

From the cardiovascular system:

infrequently: heart failure **, cardiac arrest **, tachycardia **, bradycardia **, myocardial infarction **, decreased or increased blood pressure **, pulmonary embolism **

From the respiratory system:

infrequently: dyspnoea **

From the hemopoietic organs *:

often: thrombocytosis

infrequently: eosinophilia, thrombocytopenia

rarely: leukopenia, neutropenia, agranulocytosis

rarely: hemolytic anemia

Other:

often: local reactions - inflammation, thrombophlebitis, pain at the injection site

rarely: vaginal candidiasis, candidiasis of the oral mucosa

* There have been reports of cases of positive direct or indirect Coombs test, as well as cases of partial thromboplastin time reduction.

* Causal relationship with the use of the drug is not established. Side effects were observed in a study involving 2904 immunocompetent adult patients treated with meropenem (500 mg or 1000 mg every 8 hours) due to infections not affecting the central nervous system.In 36 patients, therapy was discontinued due to adverse events. In 5 cases, the relationship of death to ongoing therapy is not excluded. Against the backdrop of the severe condition of patients, numerous diseases and multiple concomitant therapy with other medications, it was not possible to conclude that the side effect was related to drug therapy.

Overdose:

Treatment: symptomatic. Hemodialysis is effective.

Interaction:

Probenecid inhibits renal excretion of meropenem, causing an increase in its half-life and increasing the concentration of meropenem in the blood plasma. Joint administration of probenecid with meropenem is not recommended.

The combined administration of carbapenems (including meropenem) and valproic acid preparations led to a decrease in the concentration of valproic acid in blood plasma by 60-100% after two days of therapy. In connection with the rapid and significant reduction in the concentration of valproic acid, joint administration of meropenem and valproic acid preparations is not recommended.

The use of meropenem during the administration of other drugs was not accompanied by the development of unfavorable pharmacological interactions.Studies to study the interaction of meropenem with other drugs (with the exception of probenecid) were not conducted.

There have been reported cases of increased anticoagulant effect when combined with indirect anticoagulants (eg, warfarin). During joint administration of antibiotic and indirect anticoagulant and for some time after its termination, frequent monitoring of the international normalized relationship (INR) is recommended.

Special instructions:

Patients with a history of hypersensitivity to carbapenems, penicillins or others. beta-lactam antibiotics, can exercise hypersensitivity to meropenem.

Application of the drug meropenem in patients with liver disease should be carried out under careful monitoring of the activity of "liver" transaminases and bilirubin concentrations.

In the process of treatment, the development of resistance of pathogens is possible, and therefore prolonged treatment is carried out under the constant control of the spread of resistant strains.

In patients with diseases of the gastrointestinal tract, especially colitis, it is necessary to consider the possibility of developing pseudomembranous colitis (toxin produced Clostridium difficile, is one of the main causes of colitis associated with antibiotics), the first symptom of which can be the development of diarrhea on the background of treatment. With the development of pseudomembranous colitis should cancel the drug. Contraindicated use of drugs that inhibit intestinal peristalsis.

When using meropenem in monotherapy in patients with an identified or suspected lower respiratory tract infection of severe course caused by Pseudomonas aeruginosa, it is recommended that a test be carried out regularly to determine the sensitivity of the pathogen to meropenem.

Against the background of carbapenems, including meropenem, infrequent reports of seizures occurred. Care should be taken when using the drug in patients with a reduced threshold of convulsive readiness.

The use of the drug for infections caused by methicillin-resistant staphylococcus is not recommended.

The experience of using the drug in pediatrics in patients with neutropenia, with primary or secondary immunodeficiency is not.

There are clinical and laboratory signs of cross-allergic reactions between other carbapenems and beta-lactam antibiotics, penicillins and cephalosporins.There are rare reports of cases of hypersensitivity reactions (including fatal outcome) with the use of meropenem, as well as other beta-lactam antibiotics (see the "Side effect" section). Before starting therapy with meropenem, the patient should be thoroughly examined, paying special attention to the hypersensitivity reactions to beta-lactam antibiotics in the anamnesis (see the section "Contraindications"). If there was an allergic reaction to meropenem, it is necessary to stop the introduction of the drug and take appropriate measures.

The prevalence of acquired antibiotic resistance of various pathogens can vary depending on the region and over time. It is desirable to have up-to-date information on the resistance of common pathogens in a particular region, especially when treating severe infections. If the prevalence is such that the effectiveness of the drug in relation to at least Some infections become dubious, you should consult an expert.

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

Given the possibility of developing side effects from the central nervous system,patients need to be careful in managing vehicles and other mechanisms that require increased attention and speed of psychomotor reactions.

Form release / dosage:

Powder for solution for intravenous injection, 1.0 g.

Packaging:

By 1.0 g of active substance (meropenem) in glass vials of 20 or 30 ml capacity hermetically sealed with rubber stoppers, crimped with aluminum or combined caps.

1 bottle with instruction for use is placed in an individual pack of cardboard.

5 bottles with instructions for use in an amount of 5 pieces are placed in a box of cardboard.

10 bottles with instructions for use in the amount of 10 pieces are placed in a box of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:4 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001718

Date of registration:02.07.2012 / 09.09.2014

Expiration Date:02.07.2017

The owner of the registration certificate:Company DEKO, LLC Company DEKO, LLC Russia

Manufacturer: & nbsp

Company DEKO, LLC Russia

Representation: & nbspCompany DEKO, LLCCompany DEKO, LLC

Information update date: & nbsp04.09.2016

Illustrated instructions

Instructions

Meropenem-DECO (Meropenem-DEKO)