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

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. It acts bactericidal (inhibits 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 proteins,which bind penicillin (BSP). The minimum bactericidal concentration (MBC) and the minimum inhibitory concentration (MIC) are virtually indistinguishable. Tests in vitro show the synergistic effect of meropenem with various antibiotics. Tests in vitro and in vivo show the post-antibiotic effect of meropenem.

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 MICs, determined for the respective pathogens.

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

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 (excluding vancomycin-resistant strains), Staphylococcus aureus (methicillin-sensitive)²; Staphylococcus spp. (methicillin-sensitive), including Staphylococcus epidermidis; Streptococcus agalactiae (group B), group Streptococcus milleri (S. anginosus, S. contellatus, S. intermedius), Streptococcus pneumoniae; Streptococcus pyogenes (Group A).

Gram-negative aerobes: Citrobacter freudii, 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.

Pathogens for which the problem of acquired resistance is relevant

Gram-positive aerobes: Enterococcus faecium ^1,3

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

Pathogens with natural resistance:

Gram-negative aerobes: Stenotrophomonas maltophilia, Legionella spp.

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

¹pathogens with intermediate sensitivity;

²all methicillin-resistant staphylococci are resistant to meropenem;

³ The level of resistance is ≥50% in one or more EU countries

Pharmacokinetics:

When intravenously administered 250 mg for 30 minutes, the maximum concentration (C_max) is about 11 μg / ml, for a dose of 500 mg about 23 μg / ml, for a dose of 1000 mg about 49 μg / ml. Absolute pharmacokinetic proportionality to the administered dose for C_max and AUC (area under the pharmacokinetic curve "concentration-time"). With an increase in the dose from 250 mg to 2000 mg, the plasma clearance decreases from 287 to 205 ml / min. With intravenous bolus administration for 5 min 500 mg C_max about 52 μg / ml, 1000 mg about 112 μg / ml.The maximum plasma concentrations for intravenous administration of 1000 mg of the drug for 2 min, 3 min and 5 min were 110, 91 and 94 μg / ml, respectively.

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

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 concentration of the drug exceeds MIC and the dosing interval, MIC = 4 μg / ml) was 30% and 58%. When volunteers are given the same doses by the 3-hour method infusion every 8 hours, the index% T> MIC increased to 43 and 73%, respectively, for 500 and 2000 mg. Average plasma concentration in healthy volunteers after intravenous bolus administration for 10 minn 1000 mg exceeded the MIC 4 μg / ml for 42% of the dosing interval versus 59% for a 3-hour infusion of 1000 mg. Meropenem well penetrates into most tissues and body fluids, including cerebrospinal fluid in patients with bacterial meningitis, reaching concentrations,sufficient to provide bactericidal action against 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 an insignificant renal excretion is determined. The concentration of meropenem in the urine, exceeding 10 μg / ml, is maintained for 5 hours after administration of 500 mg. With regimens of 500 mg every 8 hours or 1000 mg every 6 hours, no cumulation of meropenem in blood plasma and urine in volunteers with normal liver function was observed.

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

In patients with renal insufficiency, the clearance of meropenem correlates with creatinine clearance (CC). Such patients require dose adjustment. Meropenem is derived with a hemodiazile with a clearance of about 4 times the clearance of meropenem in patients with anuria.

In elderly patients, a decrease in meropenem clearance correlates with a decrease in QC associated with age.

Liver failure

In patients with liver disease, the pharmacokinetics of meropenem does not change.

Indications:

Infectious-inflammatory diseases caused by one or more microorganisms sensitive to the preparation:

- pneumonia, including nosocomial pneumonia;

- urinary tract infection;

- infection of the abdominal cavity;

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

- septicemia;

- infection of the skin and its structures;

- meningitis.

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 or other drugs of the carbapenem group in the anamnesis.

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

Children up to 3 months.

Carefully:

- Simultaneous use with potentially nephrotoxic drugs;

- patients with gastrointestinal complaints (diarrhea), especially with colitis.

Pregnancy and lactation:

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. The drug should not be used during pregnancy, except when the potential advantage for the mother from its use exceeds the possible risk to the fetus.

In each case, the drug should be administered under strict medical supervision. Meropenem is determined in the breast milk of animals in very low concentrations. The drug should not be used during breastfeeding, except when the potential advantage of its use justifies the possible risk to the child.Evaluating the advantage for the mother should decide whether to stop breastfeeding or to cancel the drug.

Dosing and Administration:

Adults

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

The following daily doses are recommended:

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

1 g intravenously every 8 hours for treatment nosocomial pneumonia, peritonitis, suspicion of bacterial infection in patients with symptoms of neutropenia, as well as septicemia.

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

The safety of taking a dose of 2 g in the form of a bolus injection has not been sufficiently studied.

Dose in adult patients with impaired renal function

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

Clearance creatinine (.ml / min)	The 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
<10	0.5 unit dose	every 24 hours

Meropenem is excreted in hemodialysis and hemofiltration. If required prolonged drug treatment Meropenem, it is recommended that the drug (depending on the type and severity of the infection) is introduced but the completion of the hemodialysis procedure in order to restore the effective concentration in the blood plasma.

Currently, there is no data on the experience of the drug Meropenem for administration to patients on peritoneal dialysis.

Dosing in adult patients with impaired hepatic function

Patients with hepatic insufficiency do not need a 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 weighing more than 50 kg should use doses for adults.

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

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

There is no experience of using the drug 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 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. 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 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:

The incidence of side effects is classified according to the recommendations of the World Health Organization: characterized as: very often (≥1 / 10); often (≥1 / 100 and <1/10); infrequently (≥1 / 1000 and <1/100); rarely (≥1 / 10,000 and <1/1000); very rarely (<1/10 000).

Hemopoietic system*: often - thrombocytosis; infrequently - eosinophilia, thrombocytopenia; rarely - Lakopenia, neutropenia, agranulocytosis; rarely hemolytic anemia.

From the nervous system: infrequently - headache, paresthesia, syncope **, hallucinations **, depression **, anxiety **, increased excitability **, insomnia **; rarely convulsions.

From the digestive system: often - nausea, vomiting, diarrhea, increased activity of "liver" transaminases, alkaline phosphatase, lactate dehydrogenase and bilirubin concentration in the blood plasma; infrequently - constipation **, cholestatic hepatitis **; rarely - pseudomembranous colitis.

From the skin and subcutaneous tissue: infrequently - skin rash, skin itching, hives; rarely - multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the immune system: very rarely - angioedema, manifestation of anaphylaxis.

From the side of the cardiovascular system: infrequently - heart failure **, ** heart failure, tachycardia, ** ** bradycardia, decreased or increased blood pressure **, ** myocardial infarction, thromboembolism ** branches of the pulmonary artery.

Kidneys and urinary tract: infrequently - an increase in the concentration of creatinine in the blood plasma, an increase in the concentration of urea in the blood plasma.

Respiratory tract: infrequently - dyspnoea**.

Other: often - local reactions - inflammation, thrombophlebitis, pain at the injection site; rarely - vaginal candidiasis and candidiasis of the oral mucosa.

* There were reported cases of positive direct or indirect Coombs test, as well as cases of partial thromboplastin time reduction.

** Causal relationship with the use of meropenem is not established.

Overdose:

In case of an overdose, which is possible mainly in the treatment of patients with impaired renal function, symptomatic treatment is performed. Normally, there is rapid elimination of the drug through the kidneys. In patients with impaired renal function, hemodialysis effectively removes the drug and its metabolite.

Interaction:

Probenecid competes with meropenem for active tubular secretion and, thus, inhibits renal excretion of meropenem, causing an increase in its half-life and plasma concentration. Because the efficacy and duration of action of meropenem without probenecid are adequate, co-administration of probenecid with meropenem ns is recommended. The possible effect of meropenem on metabolism and binding to proteins of other drugs is not was studied. But, uchseeking low binding meropenplasma protein (about 2%), it can be assumed that interaction with other drugs, based on the mechanism of displacement from the connection with plasma proteins, should not be. Meropenem can reduce the concentration of valproic acid in blood plasma. In some patients, concentrations below therapeutic may be achieved. 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, it does not recommendjoint use of meropenand preparations of valproic acid. 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 assess the effect of the antibacterial drug on enlargement of international normalized ratio (INR) is difficult.During joint administration of an antibacterial drug and an indirect anticoagulant, and for some time after its termination, frequent monitoring of INR is recommended.

Specific data on possible drug interactions (for exclusion of probenecid). The use of the drug during the administration of other drugs was not accompanied by the development of unfavorable pharmacological interactions.

Special instructions:

Experience in the use of the drug in pediatric practice in patients with neutropenia or with primary or secondary immunodeficiency is not present. As with the use of other antibacterial drugs in the use of meropenem in monotherapy in patients in critical condition with an identified lower respiratory tract infection caused by Pseudomonas aeruginosa or if it is suspected, it is recommended that the sensitivity test be regularly determined.

In rare cases, with the use of meropenem, as with almost all antibacterial drugs, pseudomembranous colitis develops (the toxin produced Clostridium difficile, is one of the main causes of colitis associated with antibacterial drugs), the first symptom of which can be the development of diarrhea.The severity of the manifestation of pseudomembranous colitis can vary from mild to life-threatening forms. In this case, consideration should be given to discontinuing therapy with meropenem and specific treatment Clostridium difficile. The use of drugs that inhibit intestinal peristalsis is contraindicated.

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

The use of meropenem in patients with liver disease should be carried out under close monitoring of the activity of "liver" transaminases and bilirubin concentrations.

In the course of treatment, excessive growth of insensitive microorganisms is possible, in connection with which it is necessary to constantly monitor the patient.

In the process of treatment, the development of resistance of pathogens is possible, in connection with this, long-term treatment is carried out under the constant control of the spread of resistant strains. The prevalence of acquired antibiotic resistance of different 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. With carbapenem therapy, including meropenem, cases of seizures were described. More often they were observed in patients with disorders of the central nervous system (for example, craniocerebral trauma and convulsions in the anamnesis), bacterial meningitis and in patients with impaired renal function. Patients with cramps in the history should strictly follow the recommended dosage regimens.In patients with epilepsy, anticonvulsant therapy is administered throughout the treatment with meropenem. In patients with tremors, myoclonus, epileptic seizures, it is necessary to assess the neurological status, and to prescribe anticonvulsant therapy (in the absence of it), as well as assess the need for either reducing the dose of the drug or canceling it.

It is not recommended to use joint use of meropenem and valproic acid preparations (see section "Interaction with other medicinal products").

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

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

During the treatment period, care must be taken when driving vehicles and engaging in potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions. When there are undesirable phenomena from the nervous system, for example, convulsions, one should refrain from performing these activities.

Form release / dosage:

Powder for solution for intravenous administration, 0.5 g, 1 g.

Packaging:

Primary packaging of medicinal product

0.5 g or 1 g in terms of meropenem anhydrous in a bottle of colorless clear glass with a capacity of 10 ml (0.5 g) or 20 ml (1 g), corked with rubber a cork, crimped with an aluminum cap with a plastic protective cover.

Secondary packaging of medicinal product

1 or 10 vials together with instructions for use in a cardboard box with the control of the first opening (with a ticker).

When the product is packaged with a solvent (at OJSC Pharmaseptez, Russia):

Primary packaging of medicinal product

0.5 g or 1 g in terms of meropenem anhydrous in a bottle of colorless clear glass with a capacity of 10 ml (0.5 g) and 20 ml (1 g), corked with a rubber stopper, crimped with an aluminum cap with a plastic protective cover.

10 ml of solvent in ampoules polyethylene from low density polyethylene or from polyethylene for infusion and injection preparations. Directly on the ampoule, mark the printer.

Secondary packaging of medicinal product

1 bottle with a drug and 1 ampoule (for a dosage of 0.5 g) or 2 ampoules (for a dosage of 1 g) with a solvent Water for Injection,solvent for the preparation of dosage forms for injection (No. RU LP-001844 dated 19.09.2012), 10 ml each, along with instructions for use in a pack of cardboard with an internal cardboard partition, for consumer packaging subgroups chrome or chrome-ersatz. The packets are placed in a group package.

Storage conditions:

Store in a dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

In the case of packaging the preparation complete with a solvent:

Store in a 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 the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-007540/09

Date of registration:28.09.2009 / 11.01.2016

Expiration Date:Unlimited

The owner of the registration certificate:S.P.Inkomed Pvt.LtdS.P.Inkomed Pvt.Ltd India

Manufacturer: & nbsp

S.P.INCOMED, Pvt.Ltd. India

FARMASINTEZ, JSC (Irkutsk) Russia

Representation: & nbspSP.INKOMED LLCSP.INKOMED LLC

Information update date: & nbsp01.05.2018

Illustrated instructions

Instructions

Meropenem (Meropenem)