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

	0.5 g	1.0 g
Active substance:
Meropenem Trihydrate *	0.5704 g	1,1409 g
in terms of meropenem	0.5000 g	1,000,000 g
Excipient:
Sodium carbonate	0.1312 g	0.2624 g

* Represents a sterile mixture of meropenem trihydrate with sodium carbonate anhydrous in a ratio of 81.3% and 18.7%, respectively.

Description:A fine-grained white or white powder with a yellowish hue.

Pharmacotherapeutic group:Antibiotic carbapenem

ATX: & nbsp

J.01.D.H.02 Meropenem

J.01.D.H Carbapenems

Pharmacodynamics:

Meropenem is an antibiotic of the carbapenem class. is intended for parenteral administration, relatively resistant to dehydropeptidase-1 (DHP-1), does not require additional administration of DHP-1 inhibitor. Meropenem has a bactericidal effect due to the effect on 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 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 MBC / MIC ratio 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; decrease in affinity for the target PSB; 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 the drug and on the correlationClinical and microbiological data - zone diameter and MIC determined for the relevant pathogens.

Category 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 (mg / l)	Resistance (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
Enterococcus³	-	-
Staphylococcus³	Depends on the availability of sensitivity to methicillin
Haemophilus influenzae¹, Moraxella catarrhalis	≤ 2	> 2
Neisseria meningitidis²_'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 influenzae 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 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 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 MIC specific pathogens.

⁵- The sensitivity test is not recommended, since this agent is not the 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.

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

Pathogens sensitive to meropenem:

Gram-positive aerobes: Enterococcus faecalis¹, Staphylococcus aureus (methicillin-sensitive)², genus Staphylococcus (methicillin-sensitive) including Staphylococcus epidermidis, Streptococcus agalactiae groups AT, Group Streptococcus milleri (S. anginosus, S. constellatus, S. intermedins), Streptococcus pneumoniae, 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, clan Peptostreptococcus (including P. micros, P. anaerobius, P. magnus).

Gram-negative anaerobes: Bacteroides caccae, Bacteroides fragilis, Prevotella bivia, Prevotella disiens.

Pathogens for which the problem of acquired resistance is relevant:

Gram-positive aerobes: Enterococcus faecium¹.

Gram-negative aerobes: genus Acinetobacter, Burkholderia cepacia, Pseudomonas aeruginosa.

Pathogens with natural resistance:

Gram-negative aerobes: Stenotrophomonas maltophilia, Legionella spp.

Other pathogens: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.

¹ - pathogens with intermediate sensitivity.

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

Pharmacokinetics:

Intravenous administration of meropenem for healthy volunteers for 30 minutes results in a maximum plasma concentration of approximately 11 μg / ml for a dose of 250 mg, 23 μg / ml for a dose of 500 mg and 49 μg / ml for a dose of 1 g.

However, with respect to the maximum concentration (C_mOh) and the area under the pharmacokinetic curve "concentration-time" (AUC) there is no absolute pharmacokinetic proportional dependence on the administered dose. There was a decrease in plasma clearance from 287 to 205 ml / min for doses from 250 to 2 g.

Intravenous bolus injection of meropenem to healthy volunteers for 5 minutes results in a maximum plasma concentration of approximately 52 μg / ml for a dose of 500 mg and 112 μg / ml for a dose of 1 g.

After 6 hours after intravenous administration of 500 mg, the concentration of meropenem in the blood plasma is reduced to 1 μg / ml and lower.

Extended (up to 3 hours) infusion of carbapenems can lead to optimization of their pharmacokinetic and pharmacodynamic parameters.

With a standard 30-minute infusion, in healthy volunteers, two doses of 500 and 2000 mg every 8 hours, the value of% T> MIC (the ratio between the period of time when the drug concentration exceeds MIC and the dosing interval: MIC = 4 μg / ml) was 30% and 58%. When volunteers were given the same doses by a 3-hour infusion every 8 hours, the% T> MIC index increased to 43 and 73%, respectively, for 500 and 2000 mg. The average plasma concentration in healthy volunteers after intravenous bolus administration for 1000 mg exceeded the MIC of 4 μg / ml for 42% of the dosing interval, compared to 59% for a 3-hour infusion of 1000 mg. Meropenem well penetrates into most tissues and body fluids, including the cerebrospinal fluid of patients with bacterial meningitis, reaching concentrations exceeding those required for the suppression of most bacteria.

With repeated administration of meropenem with an interval of 8 hours, patients with normal renal function do not observe cumulation of the drug.In patients with normal renal function, the elimination half-life is approximately 1 hour. Binding to plasma proteins is approximately 2%.

About 70% of the intravenous dose of meropenem is excreted by the kidneys unchanged for 12 hours, after which insignificant renal excretion is determined. Concentrations of meropenem in urine, exceeding 10 mcg / ml. are maintained within 5 hours after the administration of a dose of 500 mg. With regimens of 500 mg every 8 hours or 1 g every 6 hours, there was no cumulation of meropenem in blood plasma and in urine in volunteers with normal liver function.

The only metabolite of meropenem is microbiologically inactive.

Studies in children have shown that the pharmacokinetics of meropenem in children and adults are similar. The half-life of meropenem in children under 2 years is approximately 1.5-2.3 hours, a linear dependence is observed in the dose range of 10-40 mg kg.

Renal insufficiency

Studies of pharmacokinetics in patients with renal insufficiency showed that the clearance of meropenem correlates with creatinine clearance. Such patients need dose adjustment.

A study of pharmacokinetics in elderly people revealed a decrease in the clearance of meropenem, which correlated with the age-related decrease in creatinine clearance.

Meropenem is excreted in hemodialysis with clearance, approximately 4 times higher than the clearance of meropenem in patients with anuria.

Liver failure

Studies of pharmacokinetics in patients with liver disease have shown that these pathological changes do not affect the pharmacokinetics of meropenem.

Indications:

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

- pneumonia, including nosocomial pneumonia;

- urinary tract infection;

- infection of the abdominal cavity;

- Infectious-inflammatory diseases of the pelvic organs, such as endometritis;

- infection of the skin and its structures;

- meningitis;

- septicemia.

Empirical therapy of adult patients with a presumed infection with febrile neutropenia symptoms in monotherapy or in combination with antiviral or antimicrobial agents.

The efficacy of meropenem has been demonstrated both in monotherapy mode and in combination with other antimicrobial agents in the treatment of polymicrobial infections.

Contraindications:

Hypersensitivity to meropenem, other components of the drug or other drugs of the carbapenem group.

Severe hypersensitivity (anaphylactic reactions, severe skin reactions) to any antibacterial agent having a beta-lactam structure (ie penicillins or cephalosporins).

Children up to 3 months.

Carefully:

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

Pregnancy and lactation:

Pregnancy

The safety of the use of meropenem in women during pregnancy has not been studied. Studies in animals have not shown any adverse effects on the developing fetus.

Meropenem should not be used during pregnancy, except when the potential benefit to the mother from its use exceeds the possible risk to the fetus. In each case, the drug should be administered under strict medical supervision.

Breastfeeding period

Data were obtained on the isolation of meropenem with breast milk. Meropenem should not be used during breastfeeding, except in cases where the potential advantage for the mother from the use of the drug exceeds the possible risk to the child. Having evaluated the advantage for the mother, a decision should be made to stop breastfeeding or to cancel the drug.

Dosing and Administration:

Adults

The dose and duration of therapy should be determined depending on the type and severity of the infection and the condition of the patient.

The following daily doses are recommended:

- 500 mg intravenously every 8 hours in the treatment of pneumonia, urinary tract infections, gynecological infections such as endometritis, skin infections and skin structures;

- 1 g intravenously every 8 hours in the treatment of nosocomial pneumonia, peritonitis, suspected bacterial infection in patients with symptoms of neutropenia, and septicemia.

In the treatment of meningitis, the recommended dose is 2 g every 8 hours.

In the treatment of certain infections, in particular, caused by less sensitive pathogens (such as Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp.), or for very serious infections, the recommended dose is up to 2 g every 8 hours.

The safety of administering a dose of 2 g as a bolus injection has not been sufficiently studied.

Dose the adult patients with impaired renal function

In patients with creatinine clearance less than 51 mL / min, the dose should be reduced as follows:

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

Meropenem is excreted in hemodialysis and hemofiltration. If long-term treatment with meropenem is required, it is recommended that the drug (depending on the type and severity of the infection) be administered at the end of the hemodialysis procedure in order to restore the effective concentration in the blood plasma.

At present, there is no evidence of experience with the use of meropenem for administration to patients on peritoneal dialysis.

Dosing in adult patients with impaired hepatic function

In patients with hepatic insufficiency, there is no need for dose adjustment (see section "Special instructions").

Elderly patients

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

Children

For children aged 3 months to 12 years, the recommended dose for intravenous administration is 10-20 mg / kg every 8 hours, depending on the type and severity of the infection,sensitivity of the pathogenic microorganism and the patient's condition.

Children weighing more than 50 kg should use doses for adults.

With meningitis, the recommended dose is 40 mg / kg every 8 hours.

In the treatment of certain infections, in particular, caused by less sensitive pathogens (such as Enterobacteriaceae, Pseudomonas aeruginosa, Acineiobacter spp.), or for very serious infections, the recommended dose is up to 40 mg / kg every 8 hours.

The safety of administering a dose of 40 mg / kg as a bolus injection has not been sufficiently studied.

There is no experience of using meropenem in children with impaired liver and kidney function.

Method of administration

Meropenem for intravenous administration can be administered as an intravenous bolus injection for at least 5 minutes, or as an intravenous infusion for 15-30 minutes; appropriate infusion liquids should be used for dilution.

The possibility of using meropenem in the regime of prolonged infusion (up to 3 hours) is based on pharmacokinetic and pharmacodynamic parameters (see the section "Pharmacokinetics"). To date, clinical data and safety data supporting this regimen are limited.

To prepare a solution for intravenous bolus injections meropenem should be dissolved with sterile water for injection (5 ml per 250 mg of meropenem), with a solution concentration of 50 mg / ml.

To prepare a solution for intravenous infusion meropenem should be dissolved 0.9% solution of sodium chloride for infusion or 5% solution of dextrose (glucose) for infusion, with the concentration of the solution should be from 1 to 20 mg / ml.

When diluting meropenem should follow the standard mode of asepsis. Prepared solution is recommended to enter immediately after preparation.

All vials are for single use only.

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 side effects is given below in the form of the following gradation: very often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1000 and <1/100), rarely (≥ 1 / 10000 and <1/1000), very rarely (<1/10000).

Violations from the blood and lymphatic system: often - thrombocytosis; infrequently - eosinophilia. thrombocytopenia; rarely - leukopenia, neutropenia, agranulocytosis; very rarely - hemolytic anemia.

Impaired nervous system: infrequently - headache, paresthesia, fainting *, hallucinations *, depression *, anxiety *, increased excitability *, insomnia *; rarely convulsions.

Disorders from the gastrointestinal tract: often - nausea, vomiting, diarrhea, increased activity of "liver" transaminases, alkaline phosphatase, lactate dehydrogenase and serum bilirubin concentration; infrequently - constipation *, cholestatic hepatitis *; very rarely - pseudomembranous colitis.

Disturbances from the skin and subcutaneous tissues: infrequently - a rash, hives, itchy skin; very rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Immune system disorders: very rarely - angioedema, manifestations of anaphylaxis.

Disorders from the cardiovascular system: infrequent heart attack *, cardiac arrest *, tachycardia *, bradycardia *, myocardial infarction *, decreased or increased blood pressure (BP) *, thromboembolism of the pulmonary arteries *.

Disorders from the kidneys and urinary tract: infrequently - increase concentration of creatinine in the blood, increased urea concentration in the blood.

Disturbances from the respiratory system: infrequently - dyspnea *.

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 meropenem is not established.

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:

Probenecid competes with meropenem for active tubular secretion, inhibiting renal excretion and causing an increase in the half-life and concentration of meropenem in plasma. Since the efficacy and duration of action of meropenem administered without probenecid is adequate, joint administration of probenecid with meropenem is not recommended.

The possible effect of meropenem on the degree of association of other drugs with plasma proteins or metabolism has not been studied. The association of meropenem with plasma proteins is low (about 2%), so interaction with other drugs based on the mechanism of displacement from plasma protein binding is not expected.

The combined administration of carbapenems and valproic acid preparations led to a decrease in the concentration of valproic acid in blood plasma by 60-100% after 2 days of therapy. Due to the rapid and significant decrease 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.

Repeatedly reported cases of increased anticoagulant effect in the joint administration of indirect anticoagulants (eg, warfarin) and antibacterial drugs. The risk of increased anticoagulant effect may depend on the nature of the infection,age and general condition of the patient, therefore it is difficult to assess the effect of the antibacterial drug on the increase in the international normalized ratio (INR). During joint administration of an antibacterial drug and an indirect anticoagulant, and for some time after its termination, frequent monitoring of INR is recommended.

Special instructions:

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. Before starting therapy with meropenem, the patient should be thoroughly questioned, paying special attention to the history of hypersensitivity reactions to beta-lactam antibiotics. Meropenem should be used with caution in patients with a history of hypersensitivity reactions to beta-lactam antibiotics (ie, to penicillins and cephalosporins). If there was an allergic reaction to meropenem, it is necessary to stop the introduction of the drug and take appropriate measures.

Treatment of patients with liver diseases should be carried out under careful monitoring of the activity of "liver" transaminases and bilirubin concentrations.

In the course of treatment, the development of resistance of pathogens is possible, and therefore prolonged treatment is carried out under the constant control of the distribution of resistant strains. The prevalence of acquired antibiotic resistance of various pathogens may 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.

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

In persons with diseases of the gastrointestinal tract, especially colitis, it is necessary to take into account 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.

In monotherapy of a known or suspected lower respiratory tract infection of severe course caused by Pseudomonas aeruginosa, it is recommended to conduct a regular test to determine the sensitivity of the pathogen to meropenem.

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

Against the background of carbapenems. 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.

Experience with the drug in children with neutropenia, with primary or secondary immunodeficiency absent.

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

There have been no studies of the effect of meropenem on the ability to drive a car and other equipment.

Given the possibility of developing headache, paresthesia and seizures, patients should be careful when driving vehicles and working with mechanisms that require increased attention.

Form release / dosage:

Powder for solution for intravenous administration, 0.5 g and 1.0 g.

Packaging:

0.5 g of meropenem in bottles of colorless neutral glass 1 hydrolytic class with a capacity of 10 ml or 20 ml and 1.0 g of meropenem in bottles of colorless neutral glass I hydrolytic class with a capacity of 30 ml.

The bottle is sealed with a rubber stopper and crimped with an aluminum cap with a plastic lid.

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

Storage conditions:

Store in a 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 expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004174

Date of registration:03.03.2017

Expiration Date:03.03.2022

The owner of the registration certificate:RAFARMA, CJSC RAFARMA, CJSC Russia

Manufacturer: & nbsp

RAFARMA, JSC Russia

Information update date: & nbsp04.04.2017

Illustrated instructions

Instructions

Meropenem (Meropenem)