Meropenem Jodas - 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 an inhibitor of DHP-1.

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,high level of stability to the majority of beta-lactamases and significant affinity for various penicillin bondsprotein (PSB). 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 hthen the measureEnema 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 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 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
Enterococcus⁵	-	-
Staphylococcus²	Depends on the availability of sensitivity to methicillin
Haemophilius influenzae¹	≤ 2	>2

Moraxella catarrhalis
Neisseria meningitidis^2,3	≤ 0,25	>0,25
Dramp-positive anaerobes	≤ 2	>8
DREM-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 MICs 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 the reference laboratory, the strain is considered resistant after receiving confirmation of the confirmed clinical effect 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 - 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 faecalis¹,

Staphylococcus aureus (methicillin-sensitive)².

Staphylococcus spp. (methicillin-sensitive), including Staphylococcus epidermidis; Streptococcus agalactiae (group B),

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

Streptococcus pneumoniae,

Streptococcus pyogenes (Group A).

Gram-negative aerobes:

Citrobactcr freundii,

Citrobacteur 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,

Peptostrcptocoeeus spp. (including P. micros, P. anaerobius, P. magnus). Gram-negative anaerobes:

Bacteroides caccae,

Bacteroides fragilis,

Prcvotella bivia,

Prevotella disiens

Pathogens for which the problem of acquired resistance is relevant:

Gram-positive aerobes:

Enterococcus faecium¹

Gram-negative aerobes:

Acinetobacter spp.,

Burkholderia cepacia,

Pseudomonas aeruginosa.

Pathogens with natural resistance:

Stenotrophomonas maltophilia,

Legionella spp.

Other pathogens:

Chlamydophila pneumoniae,

Chlamidophila psittaci,

Coxiella burnettii,

Mycoplasma pneumoniae.

1- pathogens with intermediate sensitivity;

2- all methicillin-resistant staphylococci are resistant to meropenem

Pharmacokinetics:

With a single intravenous (IV) administration within 30 minutes, the maximum concentration in the plasma (C_mOh) is 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 C_max 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 with increasing doses from 250 mg to 2 g.

With iv bolus administration for 5 minutes, the dose of 500 mg C_maxis 52 μg / ml; The dose of 1 g is 112 μg / ml.

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

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

With the standard 30-minute infusion of two doses of 500 and 2000 mg every 8 hours in healthy volunteers, the value of% T> MIC (ratio between the period of time when the drug concentration exceeds the MIC, and the dosing interval; MIC = 4 ug / ml) was respectively 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. For IV bolus doses of 1000 mg during K) min, the average plasma concentration in healthy volunteers exceeded MIC 4 μg / ml for 42% of the dosing interval and compared to 59% for a 3-hour infusion of 1000 mg.

Meropenem penetrates well into most tissues and body fluids, incl. into the cerebrospinal fluid (S'MZH) of patients with bacterial meningitis, reaching concentrations exceeding those required for the suppression of most bacteria. Binding to plasma proteins is approximately 2%. Exposed to a slight metabolism in the liver with the formation of a single inactive metabolite. The half-life period (T1 / 2) in patients with normal renal function is approximately 1 hour, in children under 2 years - 1.5 - 2.3 hours. In the dose range of 10-40 mg / kg in adults and children, a linear dependence of pharmacokinetic parameters is observed.

Do not cumulate.

It is excreted by the kidneys - 70% unchanged for 12 hours. The concentration of meropenem in the urine, exceeding 10 μg / ml, is maintained for 5 hours after the administration of 500 mg.

Renal insufficiency

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 pharmacodynamics in elderly people revealed a decrease in the clearance of meropenem, which correlated with the age-related decrease in creatinine clearance. Meropenem is derived 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:

Infectious-inflammatory diseases in children (over 3 months old) and adults caused by one or several susceptible to meropenem 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 the regimenmonotherapy or in combination with antiviral or antifungal agents.

The effectiveness of the drug Meropenem Jodas is 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 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:

When used simultaneously with potentially nephrotoxic drugs, with diseases of the gastrointestinal tract (including 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.

The drug should not be used during pregnancy, except when the potential benefit of its use for the mother 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:Dose and duration of therapy should be established in accordance from type and severity of infection and condition patient.

The following daily subsistence allowance is recommendedPS:

Adults

500 mg intravenously every 8 hours with lepneumonia, urinary infectionsgynecological infectionssuch as endometritis, infections skin and skin structures. 1 g intravenously every 8 hours in the treatment of nocomixpneumonia, peritonitis, suspectedon bacterial infection in painwith symptoms of neutropenia, and septicemia.

In the treatment of meningitis and certain types of infections, in particular, infections caused by less sensitive bacterial species (such as Enterobacteriaceae, Pseudomonas aeruginosa and / or Acinetobacter spp.), or very serious infections, 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.

Special categories of patients

Patients with impaired renal function

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

Clearance creatinineon	Dose	Frequency introduction of
26-50 ml / min	500 mg - 1.0 g - 2.0 g	Every 12 hours
10-25	250 mg -	Every 12
ml / min	500 mg - 1.0 g	hours
<10 ml / min	250 mg - 500 mg - 1.0 g	Every 24 hours

Meropenem is excreted by hemodialysis and hemofiltration. If prolonged treatment is required, it is recommended to administer a dose (determined according to the type and severity of the infection) at the end of hemodialysis to restore the effective concentration in the blood plasma.

There are currently no experience data available application of the drug for administration of paon peritonealdialysis.

Patients with impaired hepatic function

Patients with hepatic insufficiencyThere is no need to correctShl.

Elderly patients

In elderly patients with normal kidney function or creatine clearancenin more than 50 ml / min.dose reductions.

Children

For children aged 3 months to 12 years recommended dose for intravenoustion is 10-20 mg / kg every 8 hours depending on type and weighttensity of infection, sensitivity of the pathologygene microorganism and the state of pacient. Children with a body weight of more than 50 kg dosages should be used for adults.In meningitis, the recommended the dose is 40 mg / kg every 8 hours.Safety of application of a dose of 40 mg / kg in the form of a bolus injection is not enough studied. Experience in the use of the drug in children with impaired liver function and there is no kidney.

Preparation of solutions and methodthe

Meropenem for intravenous administrationcan enter as intravenousbolus injection, either in the form intravenous infusion.

To prepare a solution for insidevenous bolus injection drug should be dissolved with sterile water for injections (5 ml per 250 mg), while the conthe solution concentration is 50 mg / ml(enter for at least 5 minutes). ByThe solution remains stablefor 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 insideInfusion of the drug follows the racescreate 0.9% solution of sodium chloride or 5% solution of dextrose, with the concentration of the solution should be from 1 to 20 mg / ml (administered for 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.

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. The drug solution 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 frequency of adverse reactions listed below,was determined according to the following criteria: Very often (not less than 1/10), often (more than 1/100, less than 1/10); sometimes (more than 1/1000, less than 1/100); rarely (more than 1/10000, less than 1/1000); very rarely (less than 1/10000), including individual messages.

From the digestive system: often: nausea, vomiting, diarrhea, increased activity of "liver" transaminases, alkaline phosphatase, lactate dehydrogenase and serum bilirubin concentration. Infrequent: constipation **, cholestatic hepatitis **. Very rarely: pseudomembranous colitis.

Allergic reactions: infrequently: itching of the skin, skin rash, hives. Very rarely: erythema multiforme, Stephen-Johnson syndrome, toxic epidermal necrolysis.

From the nervous system: infrequently: headache, paresthesia, fainting **,hallucinations **, depression **, anxiety **, increased excitability **, insomnia **. Rarely: convulsions.

From the laboratory indicators: often: thrombocytosis. Infrequently: eosinophilia, thrombocytopenia. Rarely: leukopenia, neutropenia, agronolocytosis. Very rarely: hemolytic anemia.

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

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

From the side of the urinary system: infrequently: increasing the concentration of creatinine in the blood, increasing the concentration of urea in the blood.

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

* - reported cases of positive direct or indirect Coombs test, as well as cases of partial thromboplastin time decrease.

** - cause-and-effect withdrawal with taking meropenem is not established.

Overdose:

Accidental overdose is possible during treatment, especially in patients with impaired function of the nights. Treatment in case of an overdose should be symptomatic. When hemodialysis occurs, rapid elimination of the drug.

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, a compatible 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 the connection with plasma proteins, is not expected. The combined use 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. In connection with a rapid and significant decrease in the concentration of valproic acid, the combined use of meropenem and valproic acid preparations is not recommended.

There are no specific data on possible drug interactions (with the exception of probenecid).

The use of meropenem during the administration of other drugs was not accompanied by the development of unfavorable pharmacological interactions.

Repeatedly reported cases of increased anticoagulant effect in the joint use of indirect anticoagulants (for example, 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). With the simultaneous use 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 pediatric practice in patients with neutropenia or primary or secondary immunodeficiency is not present.

As with the use of other antibiotics 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 suspected, regular testing of sensitivity is recommended.

In rare cases, when using the drug Meropenem Jodas, as with almost all antibiotics, pseudomembranous colitis develops, which can vary but the severity of the lungs to life-threatening forms.It is important to remember the possibility of developing pseudomembranous colitis when diarrhea occurs when the drug Meropenem Jodas is used. With the development of pseudomembranous colitis should be canceled Meropenem Jodas. 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 Meropenem Jodas 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 Jodas should be used with caution in patients with a history of hypersensitivity reactions to beta-lactam antibiotics (ie 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 Jodas in patients with liver disease should be carried out under careful monitoring of the activity of "liver" 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 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. And 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 the joint drug Meropenem Jodas 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"). 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 using Meropenem Jodas, headache, paresthesia and convulsions can occur.

Form release / dosage:

Powder for the preparation of a solution for intravenous administration of 500 mg and 1000 mg.

Packaging:For 500 mg of active substance in glass bottles with a capacity of 10 ml and 20 ml and 1000 mg of active substance in glass bottles with a capacity of 30 ml (type 1 Evr.Pharm.), Closed by a rubber stopper, crimped with an aluminum ring and a plastic lid.

One bottle together with the instruction but application in a pack of cardboard with the control of the first autopsy.

For hospitals: 5, 10, 25, 48 or 100 vials, together with the instruction, are placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use but expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-010476/08

Date of registration:24.12.2008 / 12.03.2015

Expiration Date:Unlimited

The owner of the registration certificate:Jodas Expo Pvt.LtdJodas Expo Pvt.Ltd India

Manufacturer: & nbsp

JODAS EXPOIM, Pvt. Ltd. India

Representation: & nbspJodas Expoim, Open CompanyJodas Expoim, Open Company

Information update date: & nbsp27.11.2016

Illustrated instructions

Instructions

Meropenem Jodas (Meropenem Jodas)