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

Composition:	500 mg	1000 mg
Active substance
Meropenem Trihydrate	570 mg	1140 mg
(in terms of meropenem)	500 mg	1000 mg
Excipient Sodium carbonate anhydrous	131 mg	262 mg

Description:White or pale yellow powder.

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, intended for parenteral use, relatively resistant to human 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 following mechanisms resistance to meropenem: impaired permeability of the cell wall Gram-negative bacteria due to impaired 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 correlation of clinical and microbiological data - the diameter of the zone and MIC, determined for the respective pathogens.

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

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

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
Enterococcus⁵	-	-
Staphylococcus²	Depends on the availability 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 Sensitivity threshold for Streptococcus pneumoniae and Haemophilus influenzae at meningitis - 0.25 mg / l.

²Strains for which the 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.

³Values used only for meningitis.

⁴For all other pathogens, according to pharmacokinetic and pharmacodynamic data, without taking into account the specifics of MIC distribution of specific pathogens.

⁵The 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.

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 faecalis^]

Staphylococcus aureus (methicillin-sensitive)²

Genus Staphylococcus (methicillin-sensitive), including Staphylococcus epidermidis Streptococcus agalactiae group B

Group Streptococcus milleri (S. angiosus, S. constellatus, S. intermedius)

Streptococcus pneumoniae

Streptococcus pyogenes groups 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

Genus Peptostreptococcus (including R. micros, R. anaerobius, R. magnus)

Gram-negative anaerobes:

Youteraboutides sassai

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 during 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 (Cmax) 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 mg to 2 g. Intravenous bolus injection of meropenem to healthy volunteers for 5 min leads to 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% T> MIC (the ratio between the time period when the concentration of meropenem exceeds MIC and the dosing interval, MIC = 4 μg / ml) was 30% and 58%, respectively. 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 mean plasma concentration in healthy volunteers after intravenous bolus administration for 1000 min 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 penetrates well 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 of meropenem cumulation are not observed. 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 μg / ml are maintained for 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.

The 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 a clearance of about 4 times 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 symptoms of febrile neutropenia in monotherapy or in combination with antiviral or antifungal 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, to ancillary substances or other drugs of the carbapenem group in history, severe hypersensitivity (anaphylactic reactions, severe skin reactions) to other beta-lactam antibiotics (i.e.to penicillins or cephalosporins), children's age (under 3 months).

Carefully:

Simultaneous use with potentially nephrotoxic drugs.

Patients with gastrointestinal complaints (diarrhea), especially those suffering from colitis.

Pregnancy and lactation:

Pregnancy

The safety of the drug 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. Evaluating the advantage for the mother, you should decide whether 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 for 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 with very severe 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 for 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)	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 prolonged drug treatment is required Meropenem, it is recommended that the drug (depending on the type and severity of the infection) be administered at the end of the hemodialysis procedure 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 renal 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, the sensitivity of the pathogen and the patient's condition.

Children with a body weight of more than 50 kg should use doses for adults.

With meningitis, the recommended dose is 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.

Possibility of using the drug Meropenem in the regime of prolonged infusion (up to 3 hours) is based on pharmacokinetic and pharmacodynamic parameters (see Fig. section "Pharmacological properties" subsection "Pharmacokinetics"). To date, clinical data and safety data supporting this regimen are limited.

To prepare a solution for intravenous bolus injections, the drug Meropenem should be dissolved with sterile water for injection (5 ml per 250 mg of meropenem), with a solution concentration of 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, the drug 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. The resulting 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), if 0.9% sodium chloride solution was used for its preparation. A solution prepared using 5% glucose solution should be used immediately.

Solution of the drug Meropenem 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 is given in accordance with the WHO classification: 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, including individual messages; the frequency is unknown - it is impossible to set the frequency according to the available data.

Disorders from the gastrointestinal tract: often - nausea, vomiting, diarrhea; infrequently - constipation *, cholestatic hepatitis *; rarely - candidiasis of the oral mucosa; very rarely - pseudomembranous colitis.

Disorders from the kidneys and urinary tract: infrequent - renal dysfunction (hypercreatininaemia, increased urea concentration in the plasma).

Immune system disorders: infrequently - itching of the skin, skin rash, hives; very rarely - multiforme exudative erythema, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis, angioedema, anaphylactic shock.

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

Laboratory and instrumental data: often - thrombocytosis, hyperbilirubinemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (APF), lactate dehydrogenase (LDH); infrequently - eosinophilia, thrombocytopenia; rarely - leukopenia, neutropenia, agranulocytosis; very rarely - hemolytic anemia; frequency unknown - false positive or indirect Coombs test, decrease in partial thromboplastin time.

Heart Disease: infrequently - heart failure *, cardiac arrest *, tachycardia *, bradycardia *, myocardial infarction *.

Vascular disorders: infrequently - a decrease or increase in blood pressure *, thromboembolism of the pulmonary artery *.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath *.

Violations of the genitals and breast: rarely vaginal candidiasis.

General disorders and disorders at the site of administration: often - inflammation, thrombophlebitis, pain at the injection site.

* 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 the blood 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%); therefore, 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 enhancing the anticoagulant effect may depend on the nature of the infection, the age and general condition of the patient, so it is difficult to assess the effect of the antibacterial drug on increasing 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 carbapenems and beta-lactam antibiotics, penicillins and cephalosporins. Patients with a history of hypersensitivity to carbapenems, penicillins, cephalosporins, or other beta-lactam antibiotics may exhibit hypersensitivity to meropenem. Before starting treatment, you should carefully question the patient for any history of allergic reactions. If there is an allergic reaction to meropenem, it is necessary to stop the administration of meropenem and take appropriate measures.

The combined use of meropenem and valproic acid preparations is not recommended because of a possible decrease in the concentration of valproic acid in the blood plasma. In some patients, concentrations below therapeutic may be achieved.

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, there may be a 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 be canceled meropenem. Patients with developed pseudomembranous colitis are contraindicated in the use of drugs that inhibit intestinal peristalsis.

Treatment of patients with liver disease should be conducted 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 use of meropenem in infections caused by methicillin-resistant strains is not recommended Staphylococcus spp.

Against the background of the use of carbapenems, including meropenem, there were reports of seizures. Caution should be exercised when using meropenem in patients with a reduced threshold of convulsive readiness.

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 effectiveness of meropenem in respect of at least some infections becomes doubtful, an expert should be consulted.

Experience with the use of meropenem in pediatric practice in patients with neutropenia or with primary or secondary immunodeficiency is not present.

Effect on the ability to drive transp. cf. and fur:The study of the effect of meropenem on the ability to drive a car and other equipment was not conducted. 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 the preparation of a solution for intravenous administration of 500 mg, 1000 mg.

Packaging:

By 500 mg of meropenem in a bottle with a capacity of 10 ml or 20 ml of transparent glass 1-2 hydrolytic class,1000 mg of meropenem per bottle with a capacity of 30 ml of transparent glass 1-2 hydrolytic class.

1, 5 or 10 bottles with instructions for use are placed in a pack of cardboard.

50 bottles with an equal number of instructions for use are placed in a cardboard box for the hospital.

Storage conditions:

In the dark 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 the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004172

Date of registration:03.03.2017

Expiration Date:03.03.2022

The owner of the registration certificate:VELFARM, LLC VELFARM, LLC Republic of San Marino

Manufacturer: & nbsp

SYNTHESIS, OJSC Russia

Information update date: & nbsp30.03.2017

Illustrated instructions

Instructions

Meropenem (Meropenem)