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

1 bottle contains:	for a dosage of 500 mg	for a dosage of 1000 mg
active substance: meropenem trihydrate	570 mg	1140 mg
in terms of meropenem anhydrous	500 mg	1000 mg
Excipients: sodium carbonate	112.4mg	224.8 mg

Description:Crystalline powder from white to white with a yellowish hue of color.

Pharmacotherapeutic group:Antibiotic - carbapenem

ATX: & nbsp

J.01.D.H.02 Meropenem

J.01.D.H Carbapenems

Pharmacodynamics:

Antibiotic class of carbapenems for parenteral use. Resistant to dehydropeptidase-1 (DHP-1), does not require additional administration of DHP-1 inhibitor. It acts bactericidal (inhibits the synthesis of the bacterial cell wall), easily penetrates the bacterial cell wall, is resistant to the action of most beta-lactamases, and has a high affinity for proteins that bind penicillin.The minimum bactericidal concentration (MBC) and the minimum inhibitory concentration (MIC) are virtually indistinguishable. Among the known beta-lactam antibiotics has the highest activity against most aerobic and anaerobic gram-positive and gram-negative microorganisms. It interacts with receptors-specific penicillin-binding proteins on the surface of the cytoplasmic membrane, inhibits the synthesis of the peptidoglycan layer of the cell wall (due to structural similarity), suppresses transpeptidase, promotes the release of autolytic enzymes of the cell wall, which eventually causes its damage and death of bacteria.

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 recommended criteria for sensitivity to meropenem are based on the correlation of clinical and microbiological data (MIC for the respective pathogens and the diameter of the zone).

	Method of evaluation
Category causative agent	Diameter of the zone (mm)	MIC (mg / L)
Sensitive	≥14	≤4
Intermediate	12-13	8
Resistant	≤11	≥16

Meropenem is active in vitro against the following microorganisms:

Gram-positive aerobes: Bacillus spp., Corynebacterium diphtheriae, Enterococcus faecalis (except vancomycin-resistant strains), Enterococcus liquifaciens, Enterococcus avium, Listeria monocytogenes, Lactobacillus spp., Nocardia asteroides, Staphylococcus aureus (penicillinase-sparing and penicillinase-producing), Staphylococcus epidermidis, etc. coagulose negative staphylococci, Staphylococcus saprophyticus, Staphylococcus capitis, Staphylococcus eohnii, Staphylococcus xylosus, Staphylococcus wameri, Staphylococcus hominis, Staphylococcus simulans, Staphylococcus intermedius, Staphylococcus sciuri, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus pneumoniae (only penicillin-susceptible strains), Streptococcus pyogenes, Streptococcus viridians , Streptococcus equi, Streptococcus bovis, Streptococcus mitis, S treptococcus mitior, Streptococcus milleri, Streptococcus sanguis, Streptococcus salivarius, Streptococcus morbillorum, Streptococcus group G and F, Rhodococcus equi.

Gram-negative aerobes:

Achromobacter xylosoxidans, Acinetobacter anitratus, Acinetobacter lwoffii, Acinetobacter baumannii, Aeromonas hydrophila, Aeromonas sorbria, Aeromonas caviae, Alcaligenes faecalis, Bordetella bronchiseptica, Brucella melitensis, Campylobacter coli, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Citrobacter koseri, Citrobacter amalonaticus, Enterobacter aerogenes , Enterobacter (Pantoea) agglomerans, Enterobacter cloacae, Enterobacter sakazakii, Escherichia coli, Escherichia hermannii, Gardnerella vaginalis, Haemophilus influenzae (ampicillin-resistant, penitsillinazoprodutsiruyuschie strains), Haemophilus parainfluenzae, Haemophilus ducreyi, Hafiiia alvei, Helicobacter pylori, Neisseria gonorrhoeae (including penitsillinazoneprodutsiruyuschie, penitsillinustoychivye and streptomycin-resistant strains), Klebsiella pneumoniae, Klebsiella aerogenes, Kleb siella ozaenae, Klebsiella oxytoca, Moraxella (Branhamella) catarrhalis, Morganella morganii, Neisseria gonorrhoeae (including penitsillinazoneprodutsiruyuschie, penitsillinustoychivye and spektinomitsinustoychivye strains), Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Proteus penneri, Providencia rettgeri, Providencia stuartii, Providencia alcalifaciens , Plesiomonas shigelloides, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas alcaligenes, Burkholderia (Pseudomonas) cepacia, Pseudomonas fluorescens, Pseudomonas stutzeri, Pseudomonas pseudomallei, Pseudomonas acidovorans, Salmonella spp., Serratia marcescens, Serratia liquefaciens, Serratia rubidaea, Shigella sonnoi, Shigella flexneri, Shigella boydii, Shigella dysenteriae, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica.

Anaerobic bacteria:

Actinomyces odontolyticus, Actinomyces meyeri, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides-Prevotella-Porphyromonas spp., Bacteroides coagulans, Bacteroides capsillosis, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides gracilis, Bacteroides levii, Bacteroides ovatus, Bacteroides pneumosintes, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides variabilis, Bacteroides vulgatus, Bifidobacterium spp.,Bilophila wadsworthia, Clostridium bifermentans, Clostridium butyricum, Clostridium cadaveris, Clostridium clostridiiformis, Clostridium difficile, Clostridium innocuum, Clostridium perfringens, Clostridium ramosum, Clostridium sporogenes, Clostridium sordellii, Clostridium subterminale, Clostridium tertium, Eubacterium lentum, Eubacterium aerofaciens, Fusobacterium mortiferum, Fusobacterium necrophorum , Fusobacterium nucleatum, Fusobacterium varium, Mobiluncus curtisii, Mobiluncus mulieris, Peptostreptococcus anaerobius, Peptostreptococcus micros, Peptostreptococcus saccharolyticus, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus prevotii, Peptococcus saccharolyticus, Prevotella bivia, Prevotella buccalis, Prevotella buccae, Prevotella corporis, Prevotella disiens, Prevotella denticola, Prevotella intermedia, Prevotella melaninogenica, Prevotella oralis, Prevotella oris, Prevotella rumenicola, Prevotella splanchnicus, Porphyromonas asaccharolytica, P ropionibacterium acnes, Propionibacterium avidum, Propionibacterium granulosum. Stenotrophomonas maltophilia, Enterococcus faecium and methicillin-resistant staphylococci showed resistance to meropenem in vitro.

Pharmacokinetics:

When administered intravenously for 30 minutes, 250 mg C max (maximum concentration) is 11 μg / ml, for a dose of 500 mg - 23 μg / ml, for a dose of 1000 mg -49 μg / ml. Absolute pharmacokinetic proportional dependence on the administered dose for Cmax and AUC (area under the pharmacokinetic curve) is not present. With an increase in the dose from 250 mg to 2000 mg, the plasma clearance decreases from 287 to 205 ml / min. With an intravenous bolus injection for 5 minutes, 500 mg of C max is 52 μg / ml, 1000 mg is 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. Connection with plasma proteins - 2%.

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

With the administration of 500 mg every 8 hours and 1000 mg every 6 hours, patients with normal renal function of cumulation of meropenem in urine and blood plasma are not observed.

Extended (up to 3 hours) infusion of carbapenems can lead to optimization of their pharmacokinetic and pharmacodynamic parameters. In a standard 30-minute infusion, in healthy volunteers, two doses of 500 mg and 2000 mg every 8 hours, the value of% T> MIC (minimum inhibitory concentration) (the ratio between the time period when the drug concentration 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 mg and 2000 mg, respectively. 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.

In patients with normal renal function, the half-life period (T_1/2) is about 1 hour.

Meropenem penetrates well into most tissues and body fluids, including cerebrospinal fluid in patients with bacterial meningitis, reaching concentrations sufficient to ensure bactericidal action against most bacteria.

In small amounts penetrates into breast milk.

Meropenem undergoes a slight metabolism in the liver with the formation of a single inactive metabolite. 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 administration of 500 mg.

In patients with renal insufficiency, the clearance of meropenem correlates with creatinine clearance (CC). Such patients require a dose adjustment. In elderly patients, a decrease in meropenem clearance correlates with a decrease in QC associated with age. T_1/2) - 1.5 hours. It is excreted in hemodialysis. In patients with liver disease, the pharmacokinetics of meropenem does not change.

Studies in children have shown that the pharmacokinetics of meropenem in children and adults are similar. Half-life (T_1/2)) of meropenem in children under 2 years is approximately 1.5-2.3 hours, a linear dependence of pharmacokinetic parameters is observed in the dose range of 10-40 mg / kg.

Indications:

Infectious and inflammatory diseases in adults and children over 3 months caused by sensitive pathogens, including in cases of polymicrobial infections (as a monotherapy or a combination with other.antibacterial, antiviral and antifungal drugs):

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

- urinary tract infection (including pyelonephritis, pyelitis);

- infection of the abdominal cavity (complicated appendicitis, peritonitis, pelvioperitonitis);

- infections of the pelvic organs (including endometritis);

- infection of the skin and its structures (incl. rye, impetigo, again infected dermatoses);

- bacterial meningitis;

- septicemia;

- suspicion of bacterial infection in adults with febrile neutropenia (empirical treatment in in the form of 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:

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 penicillins or cephalosporins). Children up to 3 months.

Carefully:

-Simultaneous appointment with nephrotoxic drugs;

Patients with colitis.

Pregnancy and lactation:

The safety of Meropenem-Vero during pregnancy has not been studied.

Meropenem-Vero should not be used during pregnancy, except when the potential benefit from its use justifies the possible risk to the fetus.

If you need to use Meropenem-Vero during lactation, you should consider the possibility of stopping breastfeeding.

Dosing and Administration:

Intravenously.

The dose and duration of therapy are determined depending on the severity of the infection and the patient's condition.

The following doses are recommended:

Adults:

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

- with hospital pneumonia, peritonitis, septicemia, suspected bacterial infection in patients with neutropenia - 1000 mg every 8 hours;

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

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

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 of introduction
26-50	100%	in 12 hours
10-25	50%	in 12 hours
<10	50%	in 24 hours

Meropenem is excreted in hemodialysis and hemofiltration. If continuation of treatment 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 an effective concentration in the blood plasma. Currently, there is no evidence of experience with the use of meropenem in patients on peritoneal dialysis.

Children:

- at the age of 3 months. up to 12 years, a single dose of 10-20 mg / kg every 8 hours;

- Children weighing more than 50 kg are given doses for adults;

- with meningitis - 40 mg / kg every 8 hours. The safety of taking a dose of 40 mg / kg in the form of a bolus injection is not well understood. There is no experience of using the drug in children with impaired liver function.

Experience with children with impaired renal function is absent.Use in children younger than 3 months is not recommended (there are no data on efficacy and tolerability).

Rules for the preparation and administration of a solution for intravenous administration:

To prepare a solution for intravenous bolus injections, the drug should be dissolved with sterile water for injection (5 ml per 250 mg), with a solution concentration of 50 mg / ml; enter for at least 5 minutes.

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 should be dissolved with 0.9% sodium chloride solution or 5% dextrose solution, with a solution concentration of 1 to 20 mg / ml; enter within 15-30 minutes.

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 a 5% dextrose solution should be used immediately.

Intravenous prolonged infusion: 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. If a decision is made to treat the patient with the method of prolonged infusion, attention should be paid to the stability data of compatible infusion liquids (see the table of instructions).

Meropenem is compatible with the following infusion liquids:

- water for injections;

- 0.9% solution of sodium chloride;

- 5% solution of dextrose.

When diluting the drug should follow the standard mode of asepsis.

Shake the diluted solution before use.

For intravenous injections and infusions, a freshly prepared solution of meropenem is recommended. Meropenem, diluted as described above, retains efficacy when stored at room temperature (up to 25 ° C) or when stored in a refrigerator (2-8 ° C) for the time indicated in the following table:

Solvent	Duration of storage (h)
	before 25 ° С	2-8 ° С
Solution (50 mg / ml), prepared with sterile water for injection	3	16
Solutions (1-20 mg / ml), prepared with:
0,9 % sodium chloride	3	24
5% dextrose	use immediately!

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. Meropenem should not be mixed or added to other medicinal products. The solution of meropenem should not be frozen.

Side effects:

Gastrointestinal tract: Nausea, vomiting, diarrhea, increased activity of "liver" transaminases, alkaline phosphatase, lactate dehydrogenase and serum bilirubin concentration. There are isolated reports of constipation *, cholestatic hepatitis *, pseudomembranous colitis.

The cardiovascular system: possible cases of heart failure *, cardiac arrest *, tachycardia *, bradycardia *, myocardial infarction *, decrease or increase in blood pressure (BP) *, thromboembolism of the branches of the pulmonary artery *.

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

Skin and subcutaneous tissue: single data - rash, hives, itching, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

The immune system: individual reports - angioedema, manifestations of anaphylaxis.

Nervous system: Headache, paresthesia, fainting *, hallucinations *, depression *, anxiety *, increased excitability *, insomnia *; in isolated cases, convulsions.

The system of hematopoiesis: thrombocytosis. Single reports on eosinophilia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia. Decrease in partial thromboplastin time, positive direct or indirect Coombs test.

Respiratory tract: single data - dyspnea *.

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

* - It is not possible to determine the reliable relationship between the occurrence of adverse reactions and therapy with meropenem.

Overdose:In case of an overdose, which is possible mainly in the treatment of patients with impaired renal function, symptomatic treatment is performed. Hemodialysis is possible.

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. are 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 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:

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 other antibiotics, when using meropenem in monotherapy in patients who are in critical condition with an identified lower respiratory tract infection caused by Pseudomonas aeruginosa, or if it is suspected, regular testing of sensitivity is recommended.

In rare cases, with the use of meropenem, as with almost all antibiotics, pseudomembranous colitis develops, which can vary in severity from mild to life-threatening forms. It is important to remember the possibility of developing pseudomembranous colitis in the occurrence ofdiarrhea on the background of the use of meropenem. With the development of pseudomembranous colitis should cancel the drug. Contraindicated use of drugs that inhibit intestinal peristalsis.

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

There are clinical and laboratory signs of cross-allergic reactions between other carbapenems and beta-lactam antibiotics, penicillins and cephalosporins. There are rare reports of cases of hypersensitivity reactions (including fatal outcome) with the use of meropenem, as well as other beta-lactam antibiotics (see the "Side effect" section). Before starting therapy with meropenem, the patient should be thoroughly 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.

The use of meropenem in patients with liver disease should be conducted under careful control of the activity of transaminases and bilirubin concentrations.

As with other antibiotics, excessive growth of insensitive microorganisms is possible, and therefore, constant monitoring of the patient is necessary. 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. If the resistance is such that the effectiveness of the drug against at least some infections becomes questionable, you should consult an expert. 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 section "Interaction with other drugs").

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:There have been no studies of the effect of meropenem on the ability to drive a car and other equipment. Nevertheless, it should be taken into account that when taking Meropenem-Vero, headache, paresthesia and convulsions can occur.

Form release / dosage:Powder for the preparation of a solution for intravenous administration of 500 mg or 1000 mg of active substance.

Packaging:In bottles with a capacity of 15 ml and 30 ml respectively. For 1 or 10 bottles together with instructions for use in a pack of cardboard. For 25 or 35 bottles with an equal number of instructions for use in a cardboard box (for hospitals).

Storage conditions:

Store at a temperature not exceeding 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:LSR-002592/09

Date of registration:02.04.2009 / 02.12.2015

Expiration Date:Unlimited

The owner of the registration certificate:Shenzhen Haibin Pharmaceutical Co., Ltd.Shenzhen Haibin Pharmaceutical Co., Ltd. China

Manufacturer: & nbsp

SHENZHEN HAIBIN PHARMACEUTICAL, Co. Ltd. China

Representation: & nbspVEROPHARM, AO VEROPHARM, AO Russia

Information update date: & nbsp01.05.2018

Illustrated instructions

Instructions

Meropenem Vero (Meropenem-Vero)