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

	Saeronym 0.5 g	Saeronym 1.0 g
Active substance:
meropenem trihydrate,	570 mg	1140 mg
equivalent to anhydrous meropenem	500 mg	1000 mg
Excipient:
sodium carbonate	104 mg	208 mg

Description:The powder is white or 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:

Meropenem is an antibiotic of the carbapenem class, intended for parenteral use, relatively resistant to human dehydropeptidase-1 (DHP-1), does not require additional administration of DHP-1 inhibitor.

Meropenem has a bactericidal effect due to the effect on the synthesis of the bacterial cell wall. The high bactericidal activity of meropenem against a wide range of aerobic and anaerobic bacteria is due to the high capacity of meropenem to penetrate the bacterial cell wall,a high level of stability to most beta-lactamases and significant affinity for various penicillin-binding proteins (PSBs). The minimum bactericidal concentrations (MBC) are usually the same as minimum inhibitory concentrations (MIC). 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 sensitivity criteria to meropenem based on the pharmacokinetics of the drug and on the correlation of clinical and microbiological data - the diameter of the zone and MIC, determined for the respective pathogens.

Categories pathogens	Diameter of the zone (mm)
Sensitive	≥ 14
Intermediate	From 12 to 13
Resistant	≤11

The following table shows the threshold values of MIC meropenem for various bacterial pathogens in clinical settings:

Pathogens	Sensitivity	Resistance
	(mg / L)	(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 meningitides^2,3	≤0,25	>0,25
Gram-positive anaerobes	≤2	>8
Gram-negative anaerobes	≤2	>8
Nonspecific thresholds⁴	≤2	>8

1: Sensitivity threshold for Streptococcus pneumoniae and Haemophilus influenzae with 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 a reference laboratory, and the strain is considered resistant until a confirmed clinical effect is obtained with respect to 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 pathogen is not an optimal target for meropenem.

The sensitivity to meropenem should be determined using standard methods.

The effectiveness of the drug against the pathogens listed below is confirmed by clinical experience:

Pathogens sensitive to meropenem:

Gram-positive aerobes:

Enterococcus faecalis¹, Staphylococcus aureus (methicillin-sensitive)²

The genus Staphylococcus (methicillin sensitive), vklyuchayaStaphylococcus epidermidis, Streptococcus agalactiae group B

Group Streptococcus milleri (S. anginosus, S. constellatus, S. intermedins), Streptococcus pneumoniae, Streptococcus pyogenes group A

Gram-negative aerobes:

Citrobacter freudii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenza, 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. micros, P anaerobius, P. magnus)

Gram-negative anaerobes:

Sassae Bacteroides, Bacteroides fragilis, Prevotella bivia, Prevotella disiens

Pathogens for which the problem of acquired resistance is relevant:

Gram-positive aerobes:

Enterococcus faecium¹

Gram-negative aerobes:

Genus Acinetobacter, Burkholderia cepacia, Pseudomonas aeruginosa

Pathogens with natural resistance:

Gram-negative aerobes:

Stenotrophomonas maltophilia, Legionella spp.

Other pathogens:

Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae

1: pathogens with intermediate sensitivity

2: all methicillin-resistant staphylococci resistant to meropenem.

Pharmacokinetics:Intravenous jet infusion over 30 minutes of meropenem to healthy volunteers leads to a maximum concentration (Cmax) in blood plasma of about 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 Cmand the area under the pharmacokinetic curve "concentration-time" (AUC) there is no absolute pharmacokinetic proportional to the dose administered. There was a decrease in plasma clearance from 287 ml / min to 205 ml / min for doses from 250 mg to 2 g. Intravenous bolus injection of the drug meropenem healthy volunteers for 5 min leads to a maximum plasma concentration of about 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 below.

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 mg 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 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. Average plasma concentration in healthy volunteers after intravenous bolus administration for 10 min 1000 mgexceeded MIC 4 μg / ml for 42% of the dosing interval compared to 59% with 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. In small amounts penetrates into breast milk.

With repeated administration of meropenem with an interval of 8 h, patients with normal renal function of cumulation are not observed. In patients with normal renal function, the half-life period is approximately 1 hour.

Binding to plasma proteins is approximately 2%.

The only metabolite of meropenem is microbiologically inactive.

About 70% of the intravenous dose of meropenem is excreted by the kidneys unchanged for 12 hours, after which insignificant renal excretion is determined. Concentrations of meropenem in the 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 urine in healthy volunteers with normal liver function.

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, in the dose range of 10-40 mg / kg linear dependence is observed.

Renal insufficiency

Studies of pharmacokinetics in patients with renal insufficiency showed that the clearance of meropenem correlates with the clearance of creatinine (CC). Such patients need dose adjustment. A study of pharmacokinetics in elderly patients revealed a decrease in the clearance of meropenem, which correlated with the age-related decrease in QC.

Meropenem is excreted in hemodialysis with a clearance of about 4 times the clearance of meropenem in patients with anuria.

Liver failure

Studies of pharmacokinetics in patients with liver disease have shown that these pathological changes do not affect the pharmacokinetics of meropenem.

Indications:Adultslivers and children older than 3 months:

Infectious-inflammatory diseasecaused by microorganisms sensitive to meropenem (the effectiveness of the drug has been proven both in monotherapy,and in combination with other antimicrobial agents in the treatment of polymicrobial infections):

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

- intra-abdominal infections (complicated appendicitis, peritonitis);

- infection of the urinary system (pyelonephritis, pyelitis);

- infections of the skin and soft tissues (erysipelas, impetigo, secondarily infected dermatoses);

- bacterial meningitis;

- septicemia;

Infectious-inflammatory diseases of the pelvic organs (including endometritis).

Empirical treatment (in monotherapy or in combination with antiviral or antifungal agents) with suspected bacterial infection in adult patients with febrile episodes on neutropenia.

Contraindications:Hypersensitivity to meropenem, other components of the drug and other carbapenems, pronounced sensitivity (anaphylactic reactions, severe skin reactions) to other beta-lactam antibiotics (ie penicillins or cephalosporins); children's age (up to 3 months).

Carefully:When used simultaneously with nephrotoxic drugs, patients with complaints from the gastrointestinal tract, especially with colitis.

Pregnancy and lactation:

The safety of the use of the drug by Sairon during pregnancy has not been studied.

The preparation of Cyronem should not be used during pregnancy, except when the potential benefit from its use for the mother exceeds the possible risk to the fetus. In each case, the drug should be administered under strict medical supervision.

If you need to use the drug during lactation, you should decide whether to stop breastfeeding. Data were obtained on the isolation of meropenem with breast milk.

Dosing and Administration:Intravenous bolus for at least 5 minutes, or as an intravenous infusion for 15-30 minutes.

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

Doses and duration of therapy should be determined depending on the type and severity of the infection, and the patient's condition.

The following daily doses are recommended:

Adults and children over 12 years of age:

0.5 g intravenously every 8 hours for pneumonia, infections of the urinary system, infectious and inflammatory diseases of the pelvic organs, infections of the skin and soft tissues.

1 g intravenously every 8 hours with hospital pneumonia, peritonitis, suspected bacterial infection in patients with neutropenia, and septicemia.

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

The safety of administering a dose of 2 g as a bolus injection has not been sufficiently studied. In chronic renal insufficiency, the dose is adjusted depending on KK: with KK 26-50 ml / min - but 0.5-1-2 g 2 times a day, 10-25 ml / min - 250-500-1000 mg 2 times a day, less than 10 ml / min - but 250-500-1000 mg once a day.

Meropenem is excreted in hemodialysis. If long-term treatment is required, it is recommended that the dose unit (determined depending on the type and severity of the infection) be introduced but completed hemodialysis procedure to restore the effective concentration in the blood plasma. At present, there is no data on the experience of using the preparation of Cyronem in patients on peritoneal dialysis.

In patients with hepatic insufficiency, dose adjustment is not required.

In elderly patients with normal renal function or KK more than 50 ml / min dose adjustment is not required.

Children from 3 months to 12 years:

The recommended dose for intravenous administration is 10-20 mg / kg body weight 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 be given doses for adults.

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

The safety of administering a dose of 40 mg / kg as a bolus injection has not been sufficiently studied. There is no experience of using the drug in children with impaired liver and kidney function.

Preparation of solutions

To prepare a solution for intravenous

bolus injections should be dissolved with sterile water for injection (5 ml per 250 mg), with a solution concentration of 50 mg / ml. The resulting solution remains stable for 3 hours at a temperature of up to 25 ° C and for 16 hours when stored in a refrigerator (2-8 ° C). To prepare a solution for intravenous infusion, the drug should be dissolved with 0.9% sodium chloride solution, or 5% dextrose (glucose) solution, 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 solution was used for its preparation chloride. Solution,cooked with using 5% solution of dextrose (glucose), should be used 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. The preparation of Cyronem should not be mixed with solutions containing other drugs.

When breeding the drug should observe the standard aseptic mode.

All vials are for single use only.

Side effects:In general, meropsnem 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 in the form of the following gradation: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000) according to the classification of the World Health Organization.

Organs and Systems	Side effects
Hemopoietic 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 Rarely: convulsions
Digestive system	Often: nausea, vomiting, diarrhea, increased activity of "liver" transaminases, alkaline phosphatase, lactate dehydrogenase, hyperbilirubinemia Infrequently: constipation *, cholestatic hepatitis * Very rarely: pseudomembranous colitis
Skin and subcutaneous tissue	Infrequently: skin rash, hives, itchy skin Rarely: multiform exudative erythema, syndrome Stevens-Johnson, toxic epidermal necrolysis
The immune system	Rarely: angio-neurotic edema, manifestation of anaphylaxis
The cardiovascular system	Infrequently: heart failure, stop heart , tachycardia, bradycardia , infarction myocardium , decrease or rise arterial pressure , thromboembolism branches pulmonary artery **
Kidneys and urinary tract	Infrequently: hypercreatininaemia, rise concentrations urea in blood plasma
Respiratory system	Infrequently: dyspnoea
Other	Often: local reactions inflammation, thrombophlebitis, soreness at the site of administration 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 meropepem not established.

Overdose:

Accidental overdose is possible during treatment, especially in patients with impaired renal function, it is possible that dose-dependent side effects effects.

Treatment in case of an overdose should be symptomatic. When hemodialysis occurs fast elimination meropenem.

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

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

Meropenem can reduce the concentration of valproic acid in the blood serum. In some patients, concentrations below therapeutic may be achieved. The combined use of carbapenems and valproic acid 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, the combined use of meropenem and valproic acid is not recommended.

In patients receiving antibacterial drugs, the anticoagulant effect of concomitantly taken oral anticoagulants was frequently noted, including warfarin. The risk of this effect varies depending on the type of infection, age and general condition of the patient, so it is difficult to assess the effect of antibiotics on increasing the international standardized ratio (INR).With the simultaneous use of antibiotics and oral anticoagulants, it is recommended to carefully monitor MPO during and immediately after application of these drugs.

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

Special instructions:The experience of using the preparation of Cyronem in pediatric practice in patients with neutropenia or with primary or secondary immunodeficiency is not present.

In monotherapy of a known or suspected lower respiratory tract infection of severe course caused by Pseudomonas aeruginosa, it is recommended to regularly determine the sensitivity of the pathogen. Pa treatment with carbapenems, including meropenem, infrequently reported the occurrence of seizures, so caution should be exercised when using the drug in patients with a reduced seizure threshold.

With the use of the preparation, the development of pseudomembranous colitis can be observed (toxin produced Clostridium difficile, is one of the main causes of colitis associated with antibiotic therapy), which can vary in severity from mild to life-threatening forms.It is important to remember the possibility of developing pseudomembranous colitis when diarrhea occurs on the background of treatment. With the development of pseudomembranous colitis should cancel the drug. Contraindicated use of drugs that inhibit intestinal peristalsis.

Against the background of the use of carbapenems, in that number of meropenem, infrequently reported the occurrence of seizures. Care should be taken when using the preparation of Cyronem in patients with a reduced threshold of convulsive readiness.

Patients with a history of hypersensitivity to carbapenems, penicillins, or other beta-lactam antibiotics may show increased sensitivity to meropenem. Before starting treatment, you should carefully question the patient for any history of allergic reactions. If there is an allergic reaction to meropenem, it is necessary to stop the introduction of the drug and take appropriate measures.

Treatment of patients with liver disease should be conducted under careful monitoring of the activity of "liver" transaminases and bilirubin concentrations.

As with other antibacterial drugs, excessive growth is possible insensitive microorganisms, in connection with which constant monitoring of the patient is necessary. Prevalence acquired antibiotic resistance of different pathogens may vary depending on the region and over time, preferably availability of current information about resistance common pathogens in a particular region, especially when treating severe infections. If 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 use the drug Sairon at infections caused by methicillin-resistant strains Staphylococcus spp.

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.

Form release / dosage:Powder for solution for intravenous administration, 0.5 g, 1.0 g.

Packaging:The amount of the preparation containing 0.5 g of meropenem in a colorless glass bottle of 10 ml or 20 ml; or 1.0 g of meropenem in a colorless glass bottle of 20 ml or 30 ml, closed with a rubber stopper,Crimped with an aluminum cap and plastic lid.

1 or 10 bottles in a pack of cardboard along with instructions for use.

In the case of packaging, JSC "Chemical-Pharmaceutical Plant" Akrihin ":

1 or 10 vials with instructions for application is placed in a pack of cardboard for consumer tare subgroups chrome or chrome-ersatz but GOST 7933-89.

Storage conditions:

In a dry, 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 the product after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-004345/09

Date of registration:01.06.2009 / 27.08.2015

Expiration Date:Unlimited

The owner of the registration certificate: Simpex Pharma Pvt Ltd. Simpex Pharma Pvt Ltd. India

Manufacturer: & nbsp

SIMPEX PHARMA, Pvt. Ltd. India

Representation: & nbspAKRIKHIN OJSC AKRIKHIN OJSC Russia

Information update date: & nbsp10.12.2016

Illustrated instructions

Instructions

Saeronym (Syronem)