Janem - instructions for use, doses, side effects, contraindications

	"500 mg"	"1000 mg"
Merenenema trihydrate equivalent to meropenem free	500.0 mg	1000.0 mg
Auxiliary component:
Sodium carbonate anhydrous	45.1 mg	90.2 mg

Description:White or white with a yellowish tint 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 the majority of β-lactamases and significant affinity for various penicillin-binding proteins (PSBs). The minimum bactericidal concentrations (MBC) are usually the same. as well as minimal inhibitory concentrations (MICs). For 76% of the tested bacterial species, the MBC / MIC ratio was 2 or less.

Tests in vitro show that meropenem acts synergistically with various antibiotics. In the tests in vitro and in vivo shown, that meropenem has a post-antibiotic effect.

Microorganisms may possess one or more of the listed mechanisms of resistance to meropenem: a violation of the permeability of the cell wall of Gram-negative bacteria due to a violation of the synthesis of porins; decrease in affinity for the target PSB; activation of efflux mechanisms; production of beta-lactamases, under the action of which hydrolysis of carbapenems takes place.

The only recommended criteria for sensitivity to meropenem are based on the pharmacokinetics of the drug and on the 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 threshold values of MIC meropenem for various bacterial pathogens in clinical settings (adopted in the European Union (EU)

Pathogens	Sensitivityь (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 thresholds meanings⁷	≤ 2	> 8

¹: Sensitivity threshold for Streptococcus pneumoniae and Haemophilus influenzae when meningitis - 0.25 mg / l.

²: Strains for which 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 the reference laboratory, and the strain is considered resistant before obtaining a confirmed clinical effect on it.

³: Values used only for meningitis.

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

⁵: The sensitivity test is not recommended, since this agent is not the optimal target for meropenem.

The sensitivity to meropenem should be determined using standard methods.Interpretation of results should be carried out in accordance with local guidelines.

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

Pathogens sensitive to meropenem:

Gram-positive aerobes:

Enterococcus faecalis¹

Staphylococcus aureus [methicillin-sensitive]²; Genus Staphylococcus (methicillin-sensitive), including Staphylococcus epidermidis, Streptococcus agalactiae group B.

Group Streptococcus milleri (S.anginosus, 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 P. anaerobius, P. magnus, P. micros).

Gram-negative anaerobes:

Bacteroides fragilis, Bacteroides caccae, Prevotella bivia, Prevotella disiens.

Pathogens, for the problem is urgent acquired resistance:

Gram-positive aerobes:

Enterococcus faecium¹^,³

Gram-negative aerobes:

clan 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;

³ - the level of resistance is ≥ 50% in one or more EU countries.

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

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

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

Extended (up to 3 hours) infusion of carbapenems can lead to optimization of their pharmacokinetic and pharmacodynamic parameters. With a standard 30-minute infusion in healthy volunteers, two doses of 500 and 2000 mg every 8 hours, the value of% T> MIC (the ratio between the period of time when the concentration of the drug 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 a normal function of cumulation nights of the drug 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 a slight renal excretion is detected.

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 (T_1/2) meropenem in children under 2 years 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, clearance of meropenem correlates with creatinine clearance (CC). Such patients need dose adjustment.

A study of pharmacokinetics in elderly people revealed a decrease in the clearance of meropenem, which correlated with the age-related decrease in creatinine clearance. Meropenem is derived in hemodialysis with a clearance of about 4 times the clearance of meropenem in patients with anuria.

Liver failure

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

Indications:

The Janem drug is indicated for treatment in children (over 3 months old) and adults of the following infectious and inflammatory diseases,induced by one or more meropenem-sensitive excitable gels:

- pneumonia, including nosocomial pneumonia;

- infection of the abdominal cavity;

- urinary tract infection;

- 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 or other drugs of the carbapenem group in the anamnesis; severe hypersensitivity (anaphylactic reactions, severe skin reactions) to any antibacterial agent having 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 those suffering from colitis.

Pregnancy and lactation:

Pregnancy

The safety of the use of meropenem in women during pregnancy has not been studied. Studies in animals have not shown any adverse effects on the developing fetus. Meropenem should not be used during pregnancy, except when the potential 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.

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 meropenem.

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, at particularly 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.

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:

Creatinine clearance	Dose (based on	Frequency of administration
(ml / min)	vine units 500 mg, 1 g, 2 g)
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 treatment with meropenem is required,so that the drug (depending on the type and severity of the infection) was introduced 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 weighing more than 50 kg should use doses for adults.

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

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

Preparation and administration of the solution

Method of administration

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

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

To prepare the solution for intravenous bolus injections, the Gene drug 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 infusions, Gene should be diluted with 0.9% sodium chloride solution for infusion, or 5% dextrose solution (glucose) for infusion, with the solution concentration being 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.

The drug solution of Janem 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:

Meropenem is characterized by good tolerability. In rare cases, side effects led to the abolition of therapy. Serious adverse reactions are rare.

The frequency of adverse reactions is given in the table as a gradation: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000).

Organs and Systems	Side effects
Hematology system *	Often: thrombocytosis
	Infrequently: eosinophilia, thrombocytopenia.
	Rarely: leukopenia, neutropenia, agranulocytosis
	Rarely: hemolytic anemia
Nervous system	Infrequently: headache, paresthesia, syncope , hallucinations , depression , anxiety , increased excitability , insomnia
Nervous system	Rarely: convulsions
Gastrointestinal tract	Often: nausea, vomiting, diarrhea, increased activity of "liver" transaminases, alkaline phosphatase, lactate dehydrogenase and serum bilirubin concentration
	Infrequently: constipation , cholestatic hepatitis
	Rarely: pseudomembranous colitis
Skin and subcutaneous tissue	Infrequently: rash, hives, itching
Skin and subcutaneous tissue	Rarely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
The immune system	Rarely: angioedema, manifestations of anaphylaxis
The cardiovascular system	Infrequently: heart failure , cardiac arrest , tachycardia . bradycardia , myocardial infarction , decrease or increase of arterial pressure (BP) . thromboembolism of the branches of the pulmonary artery **
Kidneys and urinary tract	Infrequently: increasing the concentration of creatinine in the blood, increasing the concentration of urea in the blood.
Respiratory tract	Infrequently: dyspnoea **
Other	Often: Local reactions - inflammation, thrombophlebitis, pain at the injection site
Other	Rarely: vaginal candidiasis, 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 the drug 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 metabolites.

Interaction:

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

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

The combined administration of carbapenems and valproic acid preparations led to a decrease in the concentration of valproic acid in blood plasma by 60-100% after 2 days of therapy. Due to the rapid and significant decrease in the concentration of valproic acid, joint administration of meropenem and valproic acid preparations is not recommended.

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

Studies to study the interaction of meropenem with other drugs (with the exception of probenecid) were not conducted.

Repeatedly reported cases of increased anticoagulant effect in the joint administration of indirect anticoagulants (eg, warfarin) and antibacterial drugs. The risk of 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 the use of 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 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 when diarrhea occurs against the background of the use of meropenem. With the development of pseudomembranous colitis should be canceled meropenem. Contraindicated use of drugs that inhibit intestinal peristalsis.

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

There are clinical and laboratory signs of cross-allergic reactions between other carbanenems 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 treatment with meropenem, the patient should be thoroughly questioned, paying special attention to hypersensitivity reactions to beta-lactam antibiotics in the anamnesis. 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. In case the resistance is such that the efficacy of the drug against at least some infections becomes questionable, an expert should be consulted.

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

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 vehicles and mechanisms. Nevertheless, it should be taken into account that when taking Jenem's drug, headache, paresthesia and convulsions can occur.

Form release / dosage:Powder for the preparation of a solution for intravenous administration, 500 mg and 1000 mg.

Packaging:

500 mg or 1000 mg in a glass bottle sealed with sulfur butyl rubber stopper, covered with an aluminum cap with additional packaging in the form of a plastic cap: 1, 3, 5, 6 or 10 bottles together with instructions for medical use in a cardboard box.

For hospitals: 30, 50 or 100 vials, together with an equal number of instructions for medical use in a box of cardboard.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2.5 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001177

Date of registration:11.11.2011 / 14.11.2016

Expiration Date:Unlimited

The owner of the registration certificate:Jepak InternationalJepak International India

Manufacturer: & nbsp

GEPACH INTERNATIONAL India

Representation: & nbspJEPAK INTERNATIONALJEPAK INTERNATIONALRussia

Information update date: & nbsp25.04.2017

Illustrated instructions

Instructions

Janem (Genem)