Meropenem-LEXVM - instructions for use, dose, side effects, contraindications

Antibiotic for parenteral use from the group of Karabapenems, has a bactericidal action (suppresses the synthesis of the bacterial cell wall), easily penetrates the bacterial cell wall, is resistant to the action of most beta-lactamases.

Unlike imipenem, it practically does not break down in the renal tubules with dehydropeptidase-1 (it does not need to be combined with cilastatin, a specific inhibitor of dehydropeptidase-1) and, accordingly, no nephrotoxic degradation products are formed,has a high affinity for proteins that bind penicillin.

Bactericidal and bacteriostatic concentrations practically do not differ.

Meropenem interacts with receptors-specific penicillin-binding proteins on the surface of the cytoplasmic membrane, inhibits the synthesis of the peptidoglycan layer of the bacterial cell wall, which eventually causes their death.

Microorganisms may possess one or more of the listed mechanisms of resistance to meropenem: violation permeability of the cell wall of gram-negative bacteria due to impaired porin synthesis; decreased affinity for the 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 for sensitivity to meropenem are based on the pharmacokinetics of meropenem and on the correlation of clinical and microbiological data - the diameter of the zone and the minimum inhibitory concentration (MIC) determined for the respective pathogens.

Categories of the pathogen	Diameter of the zone (mm)
Sensitive	≥14
Intermediate	from 12 to 13
Resistant	≤11

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

Pathogens	Sensitivity	Resistance
	(mg / L)	(mg / L)
Enterobacteriaceae	≤2	>8
Pseudomonas	≤2	>8
Acinetobacter	≤2	>8
Streptococcus groups A, B, C, G	≤2	>2
Streptococcus pneumoniae¹	≤2	>2
Other streptococci	2	2
Enterococcus⁵	-	-
Staphylococcus²	Depends on the availability of sensitivity to
	methicillin
Haemophilus influenzae¹, Moraxella catarrhalis	≤2	>2
Neisseria meningitides^2,3	≤0,25	>0,25
Gram-positive anaerobes	≤2	>8
Gram-negative anaerobes	≤2	>8
Nonspecific thresholds⁴	≤2	>8

1 - Sensitivity threshold for Streptococcus pneumoniae and Haemophilus influenzae when meningitis - 0.25 mg / l.

2 - Strains for which MICs are above the sensitivity threshold are rare or not currently detectable. If such a strain is detected, the MIC test is repeated, when the result is confirmed, 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 used only for meningitis.

4 - For all other pathogens, according to pharmacokinetic and

pharmacodynamic data, without taking into account the specific distribution of MIC specific pathogens.

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

The sensitivity to meropenem should be determined using standard methods. Interpretation of results should be carried out in accordance with local guidelines.

Microorganisms sensitive to meropenem: gram-positive aerobes: Enterococcus faecalis¹, Staphylococcus aureus (methicillin-sensitive)², Staphylococcus spp. (methicillin-sensitive), including Staphylococcus epidermidis, Streptococcus agalactiae (group B), Streptococcus milleri (S. anginosus, S. constellatus and S. intermedius). Streptococcus pneumonia, Streptococcus pyogenes (Group A); gram-negative aerobes: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens; Gram-positive anaerobes: Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus spp. (including P. micros, P. anaerobius, P. magnus); Gram-negative anaerobes: Bacteroides caccae, Bacteroides fragilis, Prevotella bivia, Prevotella disiens. Microorganisms for which the problem of acquired resistance is actual: gram-positive aerobes: Enterococcus faecium¹; gram-negative aerobes: Acinetobacter spp., Burkholderia cepacia. Pseudomonas aeruginosa. Microorganisms possessing natural resistance: gram-negative aerobes: Stenotrophomonas maltophilia, Legionella spp .; other microorganisms: Chlamydophila pneumonia, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumonia.

1 - pathogens with intermediate sensitivity;

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

The effectiveness of the drug against the pathogens listed below is confirmed by clinical experience and guidelines for antibiotic therapy.

Pharmacokinetics:

When intravenous (iv) 250 mg for 30 minutes the maximum concentration of active substance in the blood plasma (Cmach) reaches 11 μg / ml, for a dose of 500 mg - 23 μg / ml, for a dose of 1.0 g - 49 μg / ml (absolute pharmacokinetic proportional to the administered dose for Cmax and the area under the curve "active substance concentration-time" (AUC) no). When the dose is increased from 0.25 g to 2.0 g the plasma clearance decreases from 287 to 205 ml / min.

With iv bolus administration for 5 minutes, 500 mg of C max is 52 μg / ml, for a dose of 1.0 g, 112 μg / ml.

Six hours after intravenous administration of 0.5 g, the concentration of meropenem in the blood plasma is reduced to 1 μg / ml and below.

Binding to plasma proteins is approximately 2%.

It penetrates well into most tissues and body fluids, including cerebrospinal fluid (CSF) in 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 (T1 / 2) - 1 hour, in children under 2 years - 1.5-2.3 hours. In the dose range of 10-40 mg / kg in children, a linear dependence of the pharmacokinetic parameters (for Cmax and T1 / 2). 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 500 mg.

Renal insufficiency

In patients with renal insufficiency, the clearance of meropenem correlates with creatinine clearance (CC). Such patients need dose adjustment. In elderly patients, a decrease in meropenem clearance correlates with a decrease in QC associated with age. Meropenem is derived in hemodialysis with a clearance of about 4 times the clearance of meropenem in patients with anuria.

Liver failure

In patients with liver disease, pharmacokinetics do not change.

Indications:

Meropenem is indicated for treatment in children older than 3 months and adults of the following infectious-inflammatory diseases caused by microorganisms sensitive to meropenem:

- Lower respiratory tract infections (including pneumonia, including hospital ones);

- urinary tract infections (incl.pyelonephritis, pyelitis);

- skin and soft tissue infections (including erysipelas, impetigo, secondarily infected dermatoses);

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

- septicemia;

- infections of the pelvic organs (including endometritis);

- bacterial meningitis;

- suspected bacterial infection in adults with febrile neutropenia (empiric therapy as monotherapy or in combination with antiviral or antifungal agents).

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:

Increased sensitivity to meropenem, other ingredients and other carbapenems, severe hypersensitivity (anaphylactic reaction, severe skin reaction) to other beta-lactam antibiotics (ie, to penicillins or cephalosporins, children's age (up to 3 months).

Carefully:

- With simultaneous use with nephrotoxic drugs, use with caution;

- patients with gastrointestinal disorders, especially suffering from colitis, be used with caution.

Pregnancy and lactation:

The use of the drug during pregnancy is possible only in cases where the intended benefit to the mother exceeds the potential risk to the fetus. In each case, the drug should be administered under strict medical supervision. If you need to use the drug during lactation, you should decide whether to stop breastfeeding.

Dosing and Administration:

Intravenously bolus for at least 5 minutes, or intravenously infuzionno within 15-30 minutes.

List of solvents: water for injection, 0.9% solution of sodium chloride, 5% dextrose solution.

Meropenem should not be mixed or added to other medications.

Intravenous bolus: to prepare a solution for intravenous bolus injections, the drug should be dissolved with water for injection (5 ml per 250 mg), with a solution concentration of 50 mg / ml. The solution is administered for at least 5 minutes.

Intravenous infusion: to prepare a solution for intravenous infusion the drug should be dissolved with 0.9% sodium chloride solution, or 5% dextrose solution, with the concentration of the solution should be from 1 to 20 mg / ml.A solution prepared using a 5% dextrose solution should be used immediately.

Do not freeze the prepared mortar. The prepared solution is recommended to be administered immediately after preparation (from the microbiological point of view), if the conditions of preparation do not exclude the possibility of microbiological contamination. The solution is introduced for 15-30 minutes.

The dose and duration of therapy are determined depending on the type and severity of the infection, and the patient's condition. The following doses are recommended:

Adults:

For pneumonia, urinary tract infections, pelvic infections, skin and soft tissue infections - intravenously, 500 mg every 8 hours;

With hospital pneumonia, peritonitis, septicemia, suspected bacterial infection in patients with neutropenia - intravenously, 1000 mg 3 times a day (every 8 hours);

For bacterial meningitis, 2000 mg every 8 hours.

The safety of administering a dose of 2000 mg in the form of a bolus injection has not been sufficiently studied.

If the renal function is impaired, the dose is adjusted depending on the creatinine clearance:

Clearance creatinine (ml / min)	Single dose: the proportion of the recommended single dose, corresponding pathology (500 mg, or 1000 mg, or 2000 mg)	Periodicity introduction of
26-50	100%	In 12 hours
10-25	50%	In 12 hours
<10	50%	After 24 hours

Meropenem is excreted in hemodialysis. To restore the effective plasma concentration, a single dose of meropenem recommended for the corresponding pathology should be administered after the hemodialysis procedure is completed.

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

If there is a violation of the liver, there is no need to adjust the doses. In elderly patients with normal renal function or creatinine clearance greater than 50 ml / min, dose adjustment is not required.

Children:

at the age of 3 months to 12 years (with a body weight of less than 50 kg), a single dose for intravenous administration is 10-20 mg / kg 3 times a day (every 8 hours), depending on the type and severity of the infection, the sensitivity of the pathogen and the condition the patient;

with meningitis - 40 mg / kg every 8 hours (maximum single dose of 2.0 g); the safety of administering a dose of 40 mg / kg as a bolus injection has not been sufficiently studied;

Children weighing more than 50 kg are given doses for adults.

Experience with children with impaired renal function is absent.

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 frequency of adverse reactions is given in the table in the form of 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).

Organs and Systems	Side effects
Hematology system *	Often: thrombocytosis Infrequently: eosinophilia, thrombocytopenia Rarely: leukopenia, neutropenia, agranulocytosis Rarely: hemolytic anemia
Nervous system	Infrequently: headache, paresthesia, syncope , hallucinations , depression , anxiety , increased excitability , insomnia Rarely: seizures
Gastrointestinal tract	Often: nausea, vomiting, diarrhea, increased activity of hepatic transaminases, alkaline phosphatase, lactate dehydrogenase and bilirubin concentration in serum Infrequently: constipation , cholestatic hepatitis Rarely: pseudomembranous colitis
Skin and subcutaneous tissue	Infrequently: rash, hives, itching Rarely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
The immune system	Rarely: angioedema, manifestations of anaphylaxis
The cardiovascular system	Infrequently: heart failure , cardiac arrest , tachycardia , bradycardia , myocardial infarction , decreased or increased blood pressure , thromboembolism of the pulmonary artery branches **
Kidneys and urinary tract	Infrequently: increasing the concentration of creatinine in the blood, increasing the concentration of urea in the blood
Respiratory tract	Infrequently: dyspnoea **
Other	Often: local reactions - inflammation, thrombophlebitis, pain at the injection site Rarely: vaginal candidiasis, candidiasis of the oral mucosa

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

** Causal relationship with taking the drug meropenem not installed. Side effects were observed in a study involving 2904 immunocompetent adult patients who received drug therapy 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 meropenem.

Overdose:

Possible accidental overdose during treatment, especially in patients with impaired renal function.

Treatment in case of an overdose should be symptomatic. Normally, there is rapid elimination of the drug through the kidneys. In patients with impaired renal function, hemodialysis effectively removes meropenem and its metabolite.

Interaction:

Special studies of the interaction of meropenem with other drugs, except for probenecid, were not conducted.

Probenecid

Probenecid competes with meropenem for active tubular secretion, and thus inhibits the excretion of meropenem by the kidneys, causing an increase in the half-life of T_1/2 and the concentration of meropenem in the blood plasma. Joint administration of probenecid with meropenem is not recommended.

Binding of other drugs with proteins

The potential impact of meropenem on the binding of other drugs with proteins or on their metabolism has not been studied. However, its binding to proteins is so insignificant that interaction with other substances in this mechanism is unlikely.

Valproic acid

With the simultaneous use of valproic acid and carbapenems, the concentration in the blood was reduced from 60% to 100% after 2 days of therapy. Due to the rapid and significant decrease in the concentration of valproic acid, simultaneous use of valproic acid and meropenem should be avoided.

Oral anticoagulants

With the simultaneous use of antibiotics and indirect anticoagulants, including warfarin, the anticoagulant effect of the latter may be intensified. In patients receiving antibacterial drugs, the anticoagulant effect of concomitantly taken oral anticoagulants, including warfarin. The risk of developing this effect varies depending on the type of infection, age and general condition of the patient, so the impact of antibiotics on increasing the international standardized ratio (INR) is difficult to assess.With the simultaneous use of antibiotics and indirect anticoagulants, frequent monitoring of INRs is recommended during and immediately after discontinuation of treatment with these drugs.

Special instructions:

Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may exhibit hypersensitivity to meropenem. Before the beginning of treatment meropenem it is necessary to familiarize in detail with reactions of a hypersensitivity to beta-lactam antibiotics, available in the anamnesis. If there is an allergic reaction to meropenem it is necessary to stop the administration of the drug and take appropriate measures, considering that when using beta-lactam antibiotics severe hypersensitivity reactions have been described, sometimes with a fatal outcome.

When monotherapy of an established or suspected lower respiratory infection of severe course caused by Pseudomonas aeruginosa, a regular determination of the sensitivity of the pathogen is recommended.

When using meropenem, the development of pseudomembranous colitis (toxin produced Clostridium difficile, is one of the main causes of colitis associated with antibiotics), which can vary in severity from mild to life-threatening forms. It is important to remember the possibility of developing pseudomembranous colitis when diarrhea occurs on the background of treatment. With the development of pseudomembranous colitis should cancel the drug. Contraindicated use of drugs that inhibit intestinal peristalsis.

As with other antibiotics, excessive growth of insensitive microorganisms is possible, and therefore constant monitoring of the patient is necessary.

The use of meropenem in infections caused by methicillin-resistant strains is not recommended Staphylococcus spp.

Against the background of the use of carbopenems, including meropenem, infrequently reported the occurrence of seizures. Care should be taken when using the drug in patients with a reduced threshold of convulsive readiness (see section "Side effects").

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.In case the resistance is such that the efficacy of the drug against at least some infections becomes questionable, an expert should be consulted. In the treatment of patients with renal insufficiency, a reduction in the dose of the drug is required (see the section "Dosing and Administration").

In the treatment of meropenem, liver function must be carefully monitored in connection with the risk of hepatotoxicity of this drug (impaired liver function with cholestasis and cytolysis) (see section "Side effects"). Patients with liver disease should carefully monitor its function when using the drug. In this case, dose adjustment is not required (see section "Method of administration and dose").

During treatment with Meropenem, a positive direct or indirect Coombs reaction may be observed (see section "Side effects").

Experience with the use of meropenem in children with neutropenia, with primary or secondary immunodeficiency is absent.

Meropenem contains sodium, which should be considered when treating patients on a diet with a controlled sodium content (500 mg meropenem contains approximately 2.0 mEq sodium, 1000 mg - 4.0 mEq).

It is not recommended joint use of meropenem and valproic acid because of a possible decrease in valproic acid in the blood serum. In some patients, a concentration below the therapeutic level can be achieved (see section "Interaction with other drugs").

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

There were no studies of the effect of the drug meropenem on the ability to drive vehicles, mechanisms. Nevertheless, it should be taken into account that when taking the drug meropenem there may be headache, paresthesia and seizures.

Form release / dosage:

Powder for solution for intravenous injection, 1.0 g.

Packaging:

1 g of active substance in a transparent glass bottle I of hydrolytic class, sealed with a rubber stopper, crimped aluminum cap or aluminum cap with a plastic cap "flip-off."

For 1 or 10 vials, together with the instructions for use are placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000023

Date of registration:03.11.2010 / 14.12.2017

Expiration Date:Unlimited

The owner of the registration certificate:PROTEK-SVM, LLC PROTEK-SVM, LLC Russia

Manufacturer: & nbsp

SANJIVANI PARANTERAL, Limited India

Information update date: & nbsp01.05.2018

Illustrated instructions

Instructions

Meropenem-LEXMM® (Meropenem-LEKSVM)