International non-proprietary name:Meropenem

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Composition
Active ingredient:1 vial contains 1140 mg of meropenem trihydrate equivalent to 1 g of meropenem. 
Auxiliary substance:  sodium carbonate.

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Description
It is a white or light yellowish powder.

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Pharmacotherapeutic group
Antibiotic – Carbapenem.

ATC code:J01DH02.

pharmacological properties
Pharmacodynamics
Meropenem is a broad-spectrum, β-lactamase-resistant carbapenem antibiotic. It has a bactericidal effect by inhibiting the synthesis of the cell wall of bacteria. Meropenem's high bactericidal effect against most gram-positive and gram-negative aerobic and anaerobic bacteria is explained by its easy penetration (penetration) of the bacterial cell wall and its significant affinity for penicillin-binding proteins (PBPs). The highest affinity is for PBP 2 of Escherichia coli, PBP 2 and 3 of Pseudomonas aeruginosa and PBP 1, 2 and 4 of Staphylococcus aureus. 
It interacts with receptors on the surface of the cytoplasmic membrane - specific PBPs - inhibits the synthesis of the peptidoglycan layer of the cell wall (due to the structural similarity with D-alanine-D-alanine, it inhibits transpeptidase and prevents the formation of cross-links between peptidoglycan chains), the release of autolytic enzymes from the cell wall creates conditions for its occurrence, damages and destroys bacteria. 
The minimum bactericidal concentration (MBC) is almost the same as the minimum inhibitory concentration (MIC). 76% of the tested bacteria had an MBK/MIC ratio of 2 or less.
In vitro studies have shown synergistic effect of meropenem with various antibiotics.
Meropenem has been shown to have a postantibiotic effect in in vitro and in vivo studies.
Spectrum of influence
Gram-positive aerobes
Enterococcus faecalis (excluding vancomycin-resistant strains); Staphylococcus aureus; Streptococcus agalactiae; Streptococcus pneumoniae (only strains sensitive to penicillin); Streptococcus pyogenes; Streptococcus viridans; Staphylococcus epidermidis.
Gram-negative aerobes 
Escherichia coli; Haemophilus influenzae; Klebsiella pneumoniae; Neisseria meningitidis; Proteus mirabilis; Pseudomonas aeruginosa.
Gram-positive anaerobes 
Acinetobacter spp., Aeromonas hydrophila, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobacter cloacae, Haemophilus influenzae (ampicillin resistant, not synthesizing penicillinase), Hafnia alvei, Klebsiella oxytoca, Moraxella catarrhalis (synthesizing penicillinase and not synthesizing penicillinase), Morganella morganii , Pasteurella multocida, Proteus vulgaris, Salmonella spp., Serratia marcescens, Shigella spp., Yersinia enterocolitica.
Anaerobic microorganisms
Bacteroides fragilis; Peptostreptococcus spp., Bacteroides theraiotaomicron.
Anaerobic bacteria
Bacteroides distasonis, Bacteroides ovatus, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus, Clostridium difficile, Clostridium perfringens, Eubacterium lentum, Fusobacterium spp., Prevotella bivia, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas asaccharolytica, Propionibacterium acnes.
Pharmacokinetics
Being asked
When administered intravenously in the form of infusion in doses of 500 mg and 1 g, the maximum plasma concentration (Сmax) in 30 minutes is 23 μg/ml for a dose of 500 mg, 49 μg/ml for a dose of 1 g, and 115 μg/ml for a dose of 2 g._cc781905- 5cde-3194-bb3b-136bad5cf58d_
After rapid (bolus) intravenous administration of 500 mg and 1 g, the maximum concentration (Сmax) in 5 minutes is 52 mcg/ml for 500 mg dose and 112 mcg/ml for 1 g. 
The maximum concentration of meropenem falls below 1 μg/ml 6 hours after intravenous administration of 500 mg.
When the dose of meropenem is increased from 250 mg to 2 g, the plasma clearance decreases from 287 to 205 ml/min.
Its combination with plasma proteins is 2%.
Prolonged (up to 3 hours) infusion of carbapenems (including meropenem) leads to optimization of their pharmacokinetic and pharmacodynamic parameters.
%T>MIC value (the ratio between the time at which the drug concentration is higher than the minimal inhibitory concentration (MIC) against susceptible microorganisms) and the dosing interval with a standard 30-minute infusion of 0.5 g and 2 g every 8 hours in healthy volunteers; MIC value 4 taken as mg/ml) were 30% and 58%, respectively. When the same doses were administered as a 3-hour infusion every 8 hours, the %T>MIC increased to 43% and 73% for the 500 mg and 2 g doses, respectively. After a rapid (bolus) intravenous injection of 1 g of meropenem over 10 minutes in healthy volunteers, the mean plasma concentration exceeded the MIC=4 mcg/ml for 42% of the dose interval, compared to 59% after a 3-hour infusion of the same dose.
Distribution
Accumulation of the drug was not observed when meropenem was re-injected at 8-hour intervals in patients with normal renal function.
Penetration into tissue and fluids
It penetrates well into most tissues and fluids of the body, as well as into the cerebrospinal fluid of patients with bacterial meningitis, and reaches a concentration higher than the concentration required for the destruction of most sensitive bacteria (bactericidal concentration occurs 0.5-1.5 hours after the start of infusion).
Metabolism
It undergoes insignificant metabolism in the liver and the only microbiologically inactive metabolite is formed.
Exclusion
Meropenem is mainly excreted through the kidneys. In patients with normal renal function, the elimination half-life of meropenem is 1 hour. Approximately 70% of the administered dose is excreted unchanged by the kidneys within 12 hours, after which little renal excretion is determined. When meropenem is administered at a dose of 500 mg, it remains in the urine for 5 hours at a concentration higher than 10 μg/ml. When meropenem is administered at a dose of 0.5 g every 8 hours or 1 g every 6 hours to healthy volunteers with normal liver function, accumulation of the drug in blood serum and urine is not observed.
Patients with renal failure
Meropenem clearance is correlated with creatinine clearance in patients with renal failure. In such patients, the dose of meropenem and the interval between injections should be adjusted.
Patients with liver failure
The pharmacokinetics of meropenem in patients with liver disease does not change.
Pediatric patients
Studies have shown that meropenem pharmacokinetics is similar in children and adults. 
The elimination half-life in children up to 2 years old is 1.5-2.3 hours. In the dose range of 10-40 mg/kg, a linear dependence is noted in the pharmacokinetic parameters.
Elderly patients
Decreased meropenem clearance in elderly patients correlates with age-related decrease in creatinine clearance. Meropenem is eliminated during dialysis.

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Instructions for use
It is indicated in the treatment of infectious-inflammatory diseases caused by microorganisms sensitive to meropenem (monotherapy or in combination with other antimicrobial agents):
•    lower respiratory tract infections (including pneumonias, nosocomial pneumonia);
•   lower respiratory tract infections during cystic fibrosis (mucoviscidosis);
•    infections of the urinary tract (including complicated pyelonephritis, pyelitis); 
•    intra-abdominal infections (including complicated appendicitis, peritonitis);
•    skin and soft tissue infections (including rubella, impetigo, secondary infected dermatoses);
•    pelvic infections (including endometritis, pelvioperitonitis);
•    bacterial meningitis;
•    septicemia;
•     in empiric treatment (as monotherapy or in combination with antiviral or antifungal drugs) when infectious diseases accompanied by febrile neutropenia in adults are suspected.

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Contraindications
Hypersensitivity to meropenem or other antibacterial agents from the carbapenem group.
Hypersensitivity to other antibacterial agents with a beta-lactam structure (including penicillin and cephalosporins) in the anamnesis.
Children up to 3 months.

Special instructions and precautions
At the same time as potential nephrotoxic drugs; Care should be taken when prescribing to patients with a history of inflammatory diseases of the large intestine, especially ulcerative colitis, pseudomembranous colitis.
There are no data on the experience of using the drug in pediatric patients with neutropenia, primary or secondary immunodeficiency.
When meropenem is used as monotherapy in critically ill patients with lower respiratory tract infections caused by Pseudomonas aeruginosa, susceptibility testing should be performed regularly.
Overgrowth of non-susceptible microorganisms is possible during the use of antibacterial drugs. The prevalence of acquired antibiotic resistance of various pathogens may vary by region and time. It is desirable to have accurate information about the resistance of the agents prevalent in a region, especially in the treatment of severe infections. If resistance, at least against some infections, raises doubts about the effectiveness of the drug, it is recommended to consult with specialists. As with the use of other antibacterial drugs, the occurrence of pseudomembranous colitis, which can range from mild to life-threatening, is rarely observed with the use of meropenem.
If diarrhea occurs during the use of meropenem, the possibility of developing pseudomembranous colitis should be considered. When the diagnosis of pseudomembranous colitis is suspected or confirmed, the use of the drug should be stopped and appropriate treatment (metronidazole, vancomycin per os, enterosorbents, infusion therapy) should be started. In such cases, the use of drugs that slow down intestinal peristalsis is contraindicated.
Carbapenems, including meropenem, may very rarely cause seizures.
Meropenem should be used with caution in patients with reduced seizure readiness.
Patients with hypersensitivity to carbapenem, penicillin or other antibacterial agents with beta-lactam structure may show hypersensitivity to meropenem. Meropenem should be used with caution in patients with a history of hypersensitivity to beta-lactam antibacterial agents (including penicillin and cephalosporins).
In case of allergic reactions, drug intake should be stopped immediately and appropriate treatment should be started.
Treatment of patients with liver diseases should be carried out under the control of the activity of "liver" transaminases and the concentration of bilirubin.

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Interaction with other drugs 
In particular, tell your doctor, pharmacist or nurse if you are taking any of the following medicines:
• Probenecid (used to treat gout).
• Valproic acid/sodium valproate (used to treat epilepsy). 
• Oral anticoagulants.
Probenecid
Probenecid reduces the renal excretion of meropenem, increases its half-life and plasma concentration.
Valproic acid
When carbapenems are used together with valproic acid preparations, the plasma concentration of valproic acid decreases by 60-100% after 2 days of treatment. It is not recommended to use Meropenem together with valproic acid preparations.
The effect of meropenem on the extent of binding to plasma proteins or metabolism of other medicinal products has not been studied.
The binding of meropenem to plasma proteins is low (about 2%), therefore, interactions with other drugs based on binding to plasma proteins are not expected. There is no information about unwanted pharmacological interactions when Meropenem is used together with other drugs. Studies have not been conducted to study the interaction of meropenem with other drugs (except probenecid).
Cases of increased anticoagulant effect have been reported during the simultaneous use of indirect anticoagulants (for example, warfarin) and antibacterial drugs. The risk of increased anticoagulant effect may depend on the type and severity of the infection, as well as the age and general condition of the patient, therefore, it is difficult to assess the effect of the antibacterial drug on increasing the international normalized ratio (INR). Frequent monitoring of MHO is recommended during the joint use of antibacterial drugs and indirect anticoagulants and for some time after treatment.
Sodium
Each 1 g of this medicine contains 90 mg of sodium (the main component of table salt).
This is equivalent to 4.5% of the maximum recommended daily intake of sodium for adults. 
Tell your doctor if you have a medical condition that requires sodium intake to be controlled.

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Use during pregnancy and lactation
Pregnancy
Consult your doctor before taking any medication during pregnancy.
Before starting to use the drug, inform your doctor that you are pregnant or planning to become pregnant.
Meropenem should not be used during pregnancy. As an exception, its use may be used if the benefit to the mother outweighs the potential risk to the fetus.

Lactation period
The drug penetrates into breast milk in a small concentration. Meropenem should not be used during lactation. As an exception, it can be used if the benefit to the mother outweighs the potential risk to the baby. If it is necessary to use the drug during lactation, breastfeeding should be stopped.

Effects on the ability to drive vehicles and other potentially dangerous mechanisms
The effect on the ability to drive vehicles and other potentially dangerous mechanisms has not been studied. During treatment with meropenem, side effects such as headache, paresthesia and convulsions may be observed. When these reactions occur, patients are not recommended to use vehicles and other types of activities that require special attention and psychomotor reactions.

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Method of use and dosage
Always use this medication as directed by your doctor.
It is administered intravenously as a direct (bolus) injection or infusion. Dissolves in solutions suitable for infusion. Meropenem should not be mixed or added to other drugs. 
Meropenem can be administered intravenously over about 5 minutes or over 15 to 30 minutes. The duration of the injection will be determined by your doctor. The injection should be done at the same time every day.
To adults
The dose and duration of treatment are selected depending on the type and severity of the infection, as well as the patient's condition.
Recommended daily doses 
The recommended dose for adults is 500 mg to 1 g intravenously every 8 hours. During the treatment of meningitis and lower respiratory tract infections during cystic fibrosis, meropenem is prescribed in a dose of 2 g every 8 hours. 
Adults are prescribed intravenously at a dose of 500 mg every 8 hours in pneumonia, urinary tract infections, infectious-inflammatory diseases of small pelvic organs, abdominal cavity infections, skin and soft tissue infections. 
In case of nosocomial pneumonias, complicated infections of the urinary tract, complicated infections of the small pelvic organs, complicated infections of the skin and soft tissues, peritonitis, septicemia, when bacterial infections are suspected in patients with symptoms of febrile neutropenia, it is prescribed intravenously in a dose of 1 g every 8 hours._cc781905-5cde- 3194-bb3b-136bad5cf58d_
The recommended dose in the treatment of broncho-pulmonary infections and acute bacterial meningitis in patients with cystic fibrosis (mucoviscidosis) is 2 g every 8 hours.
For the treatment of certain infections, especially those caused by less susceptible pathogens (Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp.) or very severe infections, the recommended dose is up to 2 g every 8 hours. 
Meropenem is usually administered as an intravenous infusion over about 15 to 30 minutes. Alternatively, doses of up to 1 g can be administered as an intravenous bolus injection over approximately 5 minutes. The safety of a 2 g bolus injection has not been adequately studied. 
Additional information on special groups of patients
Patients with renal failure
Dosage regimen in patients with renal insufficiency (creatinine clearance ≤51 ml/min):