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

	Meronem® 0.5 g	Meronem®1 g
Active Ingredient:
meropenem trihydrate	570 mg	1140 mg
equivalent to anhydrous meropenem	500 mg	1000 mg
Auxiliary ingredient:
Sodium carbonate (anhydrous)	104 mg	208 mg

Description:Powder from white to light yellow color.

Pharmacotherapeutic group:Antibiotic, carbapenem.

ATX: & nbsp

J.01.D.H.02 Meropenem

J.01.D.H Carbapenems

Pharmacodynamics:Meropenem - 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 DTP-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,a high level of stability to most p-lactamases and a significant affinity for various penicillin-binding proteins (PSBs). 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.
In vitro tests show that meropenem acts synergistically with various antibiotics. In tests in vitro and in vivo it was 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 causative agent	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)
Enterobacteriac eae	≤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 thresholds⁴	≤2	> 8

¹Sensitivity threshold for Streptococcus pneumoniae and

Haemophilus influenzae when meningitis - 0.25 mg / l.

²Strains for which the 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 until confirmed the clinical effect of it.

³Values used only for meningitis.

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

⁵The 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

The genus Staphylococcus (methicillin-sensitive), including Staphylococcus epidermidis

Group B Streptococcus agalactiae

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

Streptococcus pneumoniae

Streptococcus pyogenes groups A

Gramotryatelьaerobes:

Citrobacter freudii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Morganella morganii

Neisseria meningitidis

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

GrampolozhiteьAnaerobes:

Clostridium perfringens

Peptoniphilus asaccharolyticus

Genus Peptostreptococcus (including P. micros, P anaerobius, P. magnus)

GramotryatelьAnaerobes:

Bacteroides caccae

Bacteroides fragilis

Prevotella bivia

Prevotella disiens

Pathogens for which the problem of acquired resistance is relevant:

Grampolozhiteьaerobes:

Enterococcus faecium¹

Gramotryatelьaerobes:

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

¹Pathogens with intermediate sensitivity.

²All methicillin-resistant staphylococci are resistant to meropenem.

Pharmacokinetics:Intravenous administration of Meronem® for 30 minutes to healthy volunteers 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_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 for doses from 250 mg to 2 g.
An intravenous bolus injection of Meronem® 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 drug concentration 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 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 normal renal function do not observe cumulation of the drug. In patients with normal renal function, the elimination half-life is approximately 1 hour. Binding to plasma proteins is approximately 2%.
About 70% of the intravenous dose of Meronem® 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 the drug Meronem® in children and adults is similar. The half-life of meropenem in children under 2 years is approximately 1.5-2.3 hours, a linear dependence is observed in the dose range of 10-40 mg / kg.
Renal insufficiency
Studies of pharmacokinetics in patients with renal insufficiency showed that the clearance of meropenem correlates with creatinine clearance. 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 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:Meronem® is indicated for treatment in children (over 3 months of age) and adults of the following infectious-inflammatory diseases caused by one or more meropenem-sensitive 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 monotherapy or in combination with antiviral or antifungal agents.
The effectiveness of the drug Meronem® 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 the anamnesis.
Severe hypersensitivity (anaphylactic reactions, severe skin reactions) to any antibacterial agent having a beta-lactam structure (ie to penicillins or cephalosporins).
Children up to 3 months.

Carefully:Simultaneous use with potentially nephrotoxic drugs. Patients with gastrointestinal complaints (diarrhea), especially those suffering from colitis.

Pregnancy and lactation:Pregnancy
The safety of the use of the drug Meronem® in women during pregnancy has not been studied. Studies in animals have not shown any adverse effects on the developing fetus. Meronem® should not be used during pregnancy, except when the potential benefit to 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. Meronem® should not be used during breastfeeding,when the potential advantage for the mother from the use of the drug exceeds the possible risk for the child. After evaluating the advantage for the mother, a decision should be made to stop breastfeeding or to cancel the drug Meronem®.

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, particularly those caused by less sensitive pathogens (such as Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp.), Or in very serious 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:

Clearance creatinine (ml / min)	Dose (based on a unit dose of 500 mg, 1 g, 2 g)	Frequency introduction of
26-50	aboutbottom dose unit		toevery 12 hours
10-25	0.5 unit dose		toevery 12 hours
< 10	0.5 unit dose		toevery 24 hours

Meropenem is excreted in hemodialysis and hemofiltration. If prolonged treatment with Meronem® 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 to restore the effective concentration in the blood plasma.
At present, there is no evidence of the use of MERONEM® for administration to patients on peritoneal dialysis.
Dosing in adult patients with impaired hepatic function
Patients with hepatic insufficiency do not need
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,sensitivity of the pathogenic microorganism 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, particularly those caused by less sensitive pathogens (such as Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp.), Or in 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.
Method of administration
Meronem® 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 a solution for intravenous bolus injections, Meronem® should be dissolved with sterile water for injection (5 ml per 250 mg of meropenem), with a solution concentration of 50 mg / ml. The resulting solution remains stable for 3 hours at a temperature of up to 25 ° C and for 16 hours when stored in a refrigerator (2-8 ° C). To prepare a solution for intravenous infusion, Meronem® should be dissolved with 0.9% sodium chloride solution for infusion or 5% dextrose solution (glucose) for infusion, with the solution concentration being between 1 and 20 mg / ml. The resulting solution remains stable for 3 hours at
temperature 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 solution of the preparation Meronem® 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:

Organs and Systems	Side effects
System hemopoiesis *	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
Cardiovascular system	Infrequently: heart failure , cardiac arrest , tachycardia , bradycardia , myocardial infarction , decreased or increased blood pressure (BP) , thromboembolism of the pulmonary artery branches **
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 and candidiasis of the oral mucosa

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

** Cause-and-effect relationship with taking Meronem® is not established. Side effects were observed in a study involving 2904 immunocompetent adult patients treated with Meronem® (500 mg or 1000 mg every 8 hours) due to infections not affecting the CNS. In 36 patients, therapy was discontinued due to adverse events. In 5 cases, the relationship of death to ongoing therapy is not excluded. Against the backdrop of the severe condition of patients, numerous diseases and multiple concomitant therapy with other medications, it was not possible to conclude that the side effect was related to Méronem® therapy.

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 metabolite.

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 the Meronem® drug administered without probenecid is adequate, co-administration of probenecid with Meronem® is not recommended. The possible effect of the drug Meronem® on the degree of association of other drugs with blood plasma proteins or metabolism has not been studied. The association of the drug Meronem® 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 administration of carbapenems and valproic acid preparations led to a decrease in the concentration of valproic acid in blood plasma by 60-100% after 2 days of therapy.Due to the rapid and significant decrease in the concentration of valproic acid, it is not recommended to take the MERONEM® and valproic acid preparations together. The use of the drug Meronem 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 suspected of it, regular testing of sensitivity is recommended.
In rare cases, when using the drug Meronem®, as with almost all antibiotics, pseudomembranous colitis develops, which can vary in severity from lungs to life-threatening forms. It is important to remember the possibility of developing pseudomembranous colitis in the event of diarrhea when using the drug Meronem®. When developing pseudomembranous colitis should be canceled Meronem®. 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 with the use of the drug Meronem® 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 the drug Meronem®, as well as other beta-lactam antibiotics (see section "Side effect"). Before starting therapy with meropenem, the patient should be thoroughly questioned, paying special attention to the history of hypersensitivity reactions to beta-lactam antibiotics. Meronem® 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 MERONEM® in patients with liver disease should be carried out 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 effectiveness
the drug in regard to at least some infections becomes questionable, you should consult an expert. It is not recommended to take Meroonem® together with valproic acid because of a possible decrease in 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 the drug Meronem® on the ability to drive a car and other equipment. Nevertheless, it should be taken into account that when taking Meronem®, headache, paresthesia and convulsions can occur.

Form release / dosage:Powder for the preparation of a solution for intravenous injection of 0.5 g and 1 g.

Packaging:0.5 g of active substance in glass bottles with a capacity of 10 ml and 20 ml and 1 g of active substance in glass bottles with a capacity of 30 ml (type 1 Hearth.Pharm.) Closed with a rubber stopper, crimped with an aluminum ring and plastic lid. On the outer surface of the bottle, the AZ logo is painted with paint. For 10 vials with instructions for use in a cardboard box with the control of the first autopsy.

Storage conditions:Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.

Shelf life:4 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N 013294/01

Date of registration:04.02.2010 / 20.10.2011

Expiration Date:Unlimited

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

ACS DOBFAR, S.p.A. Italy

DAINIPPON SUMITOMO PHARMA, Co., Ltd. Japan

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp2016-12-09

Illustrated instructions

Instructions

Meronem® (Meronem®)