Meropenem-Vista powder for solution for injection 1000 mg vial No. 10

Instructions Meropenem-Vista powder for solution for injection 1000 mg vial No. 10

Composition

active ingredient: meropenem;

1 vial contains 570 mg of meropenem trihydrate, which corresponds to 500 mg of meropenem on an anhydrous basis;

1 vial contains 1140 mg of meropenem trihydrate, which corresponds to 1000 mg of meropenem on an anhydrous basis;

excipient: sodium carbonate.

Dosage form

Powder for preparation of solution for injection.

Main physicochemical properties: white to light yellow powder.

Pharmacotherapeutic group

Antimicrobials for systemic use. Carbapenems. ATX code J01D H02.

Pharmacological properties

Pharmacodynamics

Meropenem exerts its bactericidal action by inhibiting bacterial cell wall synthesis of Gram-positive and Gram-negative bacteria by binding to penicillin-binding proteins (PBPs).

As with other beta-lactam antibacterial agents, the time at which meropenem concentrations exceeded the minimum inhibitory concentration (MIC) showed a high degree of correlation with efficacy. In preclinical models, meropenem demonstrated activity at plasma concentrations that exceeded the MIC for infecting organisms by approximately 40% over the dosing interval. This target value has not been established clinically.

Bacterial resistance to meropenem may arise as a result of:

- decreased permeability of the outer membrane of gram-negative bacteria (due to decreased production of porins);

- decreased affinity for target PBPs;

- increased expression of efflux pump components;

- production of beta-lactamases that can hydrolyze carbapenems.

Cases of infectious diseases caused by bacteria resistant to carbapenems have been recorded.

There is no cross-resistance between meropenem and drugs belonging to the quinolone, aminoglycoside, macrolide and tetracycline classes, taking into account the target microorganisms. However, bacteria may exhibit resistance to more than one class of antibacterial drugs when the mechanism of action involved involves cell membrane impermeability and/or the presence of efflux pump(s).

Table 1

MIC breakpoints determined during clinical trials by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

1Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25 mg/L (susceptible) and 1 mg/L (resistant).

2Strains with MIC values above the S/R breakpoints are very rare or have not been reported to date. Identification and antimicrobial susceptibility testing for any such isolate should be repeated and, if confirmed, the isolate should be sent to a reference laboratory. Until clinical response data are available for verified isolates with MIC values above the current resistance breakpoints (indicated in italics), isolates should be reported as resistant.

3Staphylococcal susceptibility to carbapenems is predicted based on cefoxitin susceptibility data.

4Meropenem breakpoints for Neisseria meningitidis apply only to meningitis.

5Non-species breakpoints were derived primarily from PK/PD data and are independent of the MIS distribution of individual species. They are intended for use with species not listed in the table and footnotes. Non-species breakpoints are based on the following doses: EUCAST breakpoints apply to meropenem 1000 mg 3 times daily intravenously over 30 minutes as the lowest dose. Doses of 2 g 3 times daily have been considered for severe infections and for intermediate/resistant breakpoints.

6 Beta-lactam susceptibility of streptococci groups A, B, C, and G is predicted based on penicillin susceptibility.

The prevalence of acquired resistance may vary geographically and over time for individual species, therefore it is advisable to rely on local information on resistance patterns, particularly in the treatment of severe infections. Expert advice should be sought when the local prevalence of resistance is such that the benefit of the medicinal product in at least some types of infections is questionable.

Below are the pathogenic microorganisms identified based on clinical experience and therapeutic disease treatment protocols.

7Species that have shown natural intermediate sensitivity.

8All methicillin-resistant staphylococci are resistant to meropenem.

9Resistance rate > 50% in one or more EU countries.

Pharmacokinetics

In healthy volunteers, the mean plasma half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 l/kg (11–27 l); the mean clearance is 287 ml/min at a dose of 250 mg, with a decrease in clearance to 205 ml/min at a dose of 2 g. When the drug is used in doses of 500, 1000 and 2000 mg, administered as an infusion over 30 minutes, the mean Cmax values were approximately 23, 49 and 115 μg/ml, respectively; the corresponding AUC values were 39.3, 62.3 and 153 μg×h/ml. After a 5-minute infusion, the Cmax values were 52 and 112 μg/ml at doses of 500 and 1000 mg, respectively. When multiple doses of the drug were administered every 8 hours in patients with normal renal function, no accumulation of meropenem was observed.

In a study of 12 patients receiving meropenem 1000 mg every 8 hours after surgery for intra-abdominal infections, Cmax and half-life were similar to those in healthy volunteers, but the volume of distribution (27 L) was larger.

Distribution.

The binding of meropenem to plasma proteins averaged approximately 2% and was independent of drug concentration. After rapid administration of the drug (5 minutes or less), the pharmacokinetics are biexponential, but this is much less pronounced after a 30-minute infusion. Meropenem has been shown to penetrate well into several body fluids and tissues, including lungs, bronchial secretions, bile, cerebrospinal fluid, female genital tissues, skin, fascia, muscle, and peritoneal exudates.

Metabolism.

Meropenem is metabolised by hydrolysis of the beta-lactam ring to a microbiologically inactive metabolite. In vitro, meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, and there is no need for concomitant use of a DHP-I inhibitor.

Breeding.

Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50–75%) of a dose is excreted unchanged within 12 hours. A further 28% is excreted as a microbiologically inactive metabolite. Faecal excretion accounts for only approximately 2% of the dose. Renal clearance and the effect of probenecid indicate that meropenem is subject to both filtration and tubular secretion.

Kidney dysfunction.

Renal impairment results in increased plasma AUC and prolonged half-life of meropenem. AUC values were increased 2.4-fold in patients with moderate renal impairment (creatinine clearance (CC) 33-74 ml/min), 5-fold in patients with severe renal impairment (CC 4-23 ml/min) and 10-fold in patients on haemodialysis (CC 80 ml/min). AUC values of the microbiologically inactive ring-open metabolite were also significantly increased in patients with renal impairment. Dose adjustment is recommended in patients with moderate and severe renal impairment (see section 4.2).

Meropenem is removed by hemodialysis with clearance approximately 4 times higher during hemodialysis than in anuric patients.

A study in patients with alcoholic cirrhosis showed no effect of liver disease on the pharmacokinetics of meropenem after repeated doses.

Adult patients.

Pharmacokinetic studies in patients did not reveal significant pharmacokinetic differences compared to healthy volunteers with similar renal function. A population model developed from data from 79 patients with intra-abdominal infection or pneumonia showed a dependence of basal volume on body weight, creatinine clearance and patient age.

Children.

Pharmacokinetic studies in infants and children with infection at doses of 10, 20 and 40 mg/kg demonstrated Cmax values close to those observed in adults at doses of 500, 1000 and 2000 mg, respectively. The pharmacokinetic relationships between doses and half-lives were similar to those observed in adults, except in the youngest patients (1/2 1.6 hours). The mean clearance values for meropenem were 5.8 ml/min/kg (6–12 years), 6.2 ml/min/kg (2–5 years), 5.3 ml/min/kg (6–23 months) and 4.3 ml/min/kg (2–5 months). Approximately 60% of the dose is excreted in the urine within 12 hours as meropenem and another 12% as metabolite. The concentration of meropenem in the cerebrospinal fluid of children with meningitis is approximately 20% of the simultaneously detected plasma level, although there is considerable interindividual variability.

The pharmacokinetics of meropenem in neonates treated with antibacterial agents showed higher clearance in neonates of older chronological or gestational age with an overall mean half-life of 2.9 hours. Monte Carlo simulations using a population PK model showed that a dosing regimen of 20 mg/kg every 8 hours achieved a T>MIC 60% against P. aeruginosa in 95% of preterm neonates and 91% of term neonates.

Elderly patients.

Pharmacokinetic studies in healthy elderly volunteers (65–80 years) have shown a decrease in plasma clearance, which correlates with the age-related decrease in creatinine clearance, as well as a slight decrease in non-renal clearance. No dose adjustment is required in elderly patients, except in cases of moderate to severe renal impairment.

Indication

Meropenem is indicated for the treatment of the following infections in adults and children aged 3 months and older:

· pneumonia, including community-acquired and hospital-acquired pneumonia;

bronchopulmonary infections in cystic fibrosis; complicated urinary tract infections; complicated intra-abdominal infections; infections during childbirth and postpartum infections; complicated skin and soft tissue infections; acute bacterial meningitis.

Meropenem can be used to treat patients with neutropenia and fever if a bacterial infection is suspected.

Treatment of patients with bacteremia that is associated or may be associated with any of the above infections.

Consideration should be given to providing official guidance on the appropriate use of antibacterial drugs.

Contraindication

Hypersensitivity to the active or auxiliary substances of the drug.

Hypersensitivity to any other carbapenem antibacterial agent.

Severe hypersensitivity (e.g. anaphylactic reactions, severe skin reactions) to any other type of beta-lactam antibacterial agent (e.g. penicillins or cephalosporins).

Interaction with other medicinal products and other types of interactions

Studies of drug interactions with individual drugs, except probenecid, have not been conducted.

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal secretion of meropenem, leading to an increase in the half-life and increased plasma concentrations of meropenem. Caution should be exercised when probenecid is used concomitantly with meropenem.

The potential effect of meropenem on the protein binding or metabolism of other drugs has not been studied. However, protein binding is so low that interactions with other compounds based on this mechanism are not expected.

Concomitant use of antibiotics with warfarin may increase its anticoagulant effect. There have been many reports of increased anticoagulant effects of oral anticoagulants, including warfarin, in patients receiving concomitant antibacterial agents. The risk may vary depending on the underlying infection, age, and general condition of the patient, so the role of antibacterial agents in increasing INR (international normalized ratio) levels is difficult to assess. Frequent monitoring of INR levels is recommended during and shortly after concomitant use of antibiotics with an oral anticoagulant.

Children

All drug interaction studies were conducted only in adults.

Application features.

When choosing meropenem as a treatment, the appropriateness of using a carbapenem antibacterial agent should be considered, taking into account factors such as the severity of the infection, the prevalence of resistance to other appropriate antibacterial agents, and the risk of selecting the drug for carbapenem-resistant bacteria.

Resistance to Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter

Penem resistance in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter varies in the European Union. It is recommended that local penem resistance of these bacteria be taken into account when prescribing the drug.

Hypersensitivity reactions

As with other beta-lactam antibiotics, serious and sometimes fatal hypersensitivity reactions have been reported (see sections 4.3 and 4.8).

Patients with a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be sensitive to meropenem. Careful inquiry should be made regarding previous hypersensitivity reactions to beta-lactam antibiotics before initiating therapy with meropenem.

If a severe allergic reaction occurs, use of the drug should be discontinued and appropriate measures should be taken.

Severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and acute generalised exanthematous pustulosis have been reported in patients receiving meropenem. If signs and symptoms suggestive of these reactions occur, meropenem should be discontinued immediately and alternative treatment considered.

Antibiotic-associated colitis

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents, including meropenem, and may range in severity from mild to life-threatening. Therefore, caution should be exercised in patients who develop diarrhoea during or after the use of meropenem (see section 4.8). Discontinuation of meropenem and specific treatment against Clostridium difficile should be considered. Medicinal products that inhibit intestinal motility should not be administered.

Convulsions

Convulsions have been reported rarely during treatment with carbapenems, including meropenem (see section 4.8).

Liver function monitoring

Due to the risk of developing hepatic toxicity (liver dysfunction with cholestasis and cytolysis), liver function should be closely monitored during treatment with meropenem (see section "Adverse reactions").

Liver function should be closely monitored during treatment with meropenem in patients with pre-existing liver disease. No dose adjustment is required (see section 4.2).

Treatment with meropenem may cause a positive direct or indirect Coombs test.

The concomitant use of meropenem and valproic acid/sodium valproate/valpromide is not recommended.

Meropenem contains approximately 2.0 mEq or 4.0 mEq of sodium per 500 mg or 1 g dose, respectively, which should be taken into account when prescribing the drug to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

There are no or limited amount of data from the use of meropenem in pregnant women.

Animal studies do not indicate direct or indirect reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of meropenem during pregnancy.

It is not known whether meropenem is excreted in human milk. Meropenem is found in very low concentrations in animal milk. A decision should be made whether to discontinue breast-feeding or to discontinue meropenem therapy, taking into account the benefit of therapy to the woman.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies of the effect of the drug on the ability to drive vehicles and work with other mechanisms have not been conducted.

When driving or operating machinery, special caution is recommended, given the possibility of developing headache, paresthesia or seizures, which have been reported with the use of meropenem.

Method of administration and doses

Tables 2-4 below provide general recommendations for dosing the drug.

The dose of meropenem and the duration of treatment depend on the type of pathogen, the severity of the disease and the individual sensitivity of the patient.

Meropenem at a dose of up to 2 g three times a day in adults and children weighing more than 50 kg and at a dose of up to 40 mg/kg three times a day in children is best suited for the treatment of certain types of infections caused by less susceptible species of bacteria (e.g. Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter species), or for very severe infections.

Additional dosing recommendations should be followed when treating patients with renal impairment (see below).

Table 2.

Recommended doses for adults and children weighing more than 50 kg.

Meropenem should usually be administered as an intravenous infusion over 15 to 30 minutes.

Alternatively, doses of up to 1 g can be administered as an intravenous bolus injection over approximately 5 minutes. There is limited safety data on the administration of 2 g as an intravenous bolus injection in adults.

Kidney dysfunction.

Table 3.

Recommended doses for adults and children weighing more than 50 kg

creatinine clearance less than 51 ml/min

Data on the use of the drug doses indicated in Table 3, adjusted for a dose unit of 2 g, are limited.

Meropenem is removed by hemodialysis and hemofiltration, therefore the required dose of the drug should be administered after the hemodialysis procedure is completed.

There are no established dosage recommendations for patients receiving peritoneal dialysis.

Liver dysfunction.

For patients with impaired liver function, dose adjustment of the drug is not required (see section "Special instructions").

Dosage for elderly patients.

No dose adjustment is required for elderly patients with normal renal function or with creatinine clearance values above 50 ml/min.

Children under 3 months of age

There are no data on the safety and efficacy of meropenem in children under 3 months of age and the optimal dosage regimen has not been established. There are limited pharmacokinetic data to support the use of a dose of meropenem of 20 mg/kg every 8 hours (see section 5.2).

Table 4.

Recommended doses of the drug for children aged 3 months to 11 years and weighing up to 50 kg.

There is no experience with the use of the drug in children with impaired renal function.

Children weighing more than 50 kg should be dosed as for adult patients.

Method of administration and doses

Meropenem is usually administered as an intravenous infusion over 15 to 30 minutes. Alternatively, doses of meropenem up to 20 mg/kg can be administered as an intravenous bolus injection over approximately 5 minutes. There are limited safety data supporting the use of 40 mg/kg as an intravenous bolus injection in children.

Performing an intravenous bolus injection.

The solution for bolus injection should be prepared by dissolving Meropenem-Vista in water for injection to a concentration of 50 mg/ml.

Chemical and physical stability of the prepared solution for bolus injection was maintained for 3 hours at room temperature (15-25°C).

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the medicinal product should be used immediately.

If the medicine is not used immediately, the doctor is responsible for the period and conditions of its storage after preparation.

The infusion solution should be prepared by dissolving Meropenem-Vista in 0.9% sodium chloride solution for infusion or 5% glucose (dextrose) solution for infusion to a concentration of 1-20 mg/ml.

Chemical and physical in-use stability of the reconstituted solution for infusion using 0.9% sodium chloride solution has been demonstrated for 6 hours at room temperature (15-25°C) or for 24 hours at 2-8°C. The reconstituted solution, if refrigerated, should be used within 2 hours of storage in a refrigerator. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, the physician is responsible for the storage time and conditions after reconstitution.

Meropenem solution prepared with 5% glucose (dextrose) solution should be used immediately, i.e. within 1 hour after preparation.

Do not freeze prepared solutions.

Children.

The drug is used in children aged 3 months and older.

Overdose

Relative overdose is possible in patients with impaired renal function if the dose of the drug is not adjusted. Limited post-marketing experience indicates that adverse reactions that occur after overdose are consistent with the profile of these adverse reactions and are usually mild and resolve after drug withdrawal or dose reduction. Symptomatic treatment should be considered.

In individuals with normal kidney function, the drug is rapidly excreted by the kidneys.

Meropenem and its metabolites are removed from the body during hemodialysis.

Adverse reactions

In a review of 4872 of 5026 patients treated with meropenem, the most common adverse reactions associated with meropenem were diarrhoea (2.3%), rash (1.4%), nausea/vomiting (1.4%), and injection site inflammation (1.1%). The most common laboratory adverse events were thrombocytosis (1.6%) and elevated liver enzymes (1.5–4.3%).

In Table 5, all adverse reactions are listed by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to rare (≥ 1/10,000 to

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5

There is no evidence to suggest an increased risk of adverse events in children based on the limited data available. All reports received were consistent with adverse reactions observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorised is essential. This ensures continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions as required by law.

Expiration date

4 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 30 ° C. Keep out of the reach of children.

It is recommended to use freshly prepared solutions of Meropenem-Vista for intravenous injections and infusions.

Each vial is intended for single use only.

Standard aseptic techniques should be used when preparing the solution and during its administration.

The solution should be shaken before use.

Any unused product or waste material should be disposed of in accordance with local requirements.

Incompatibility

Meropenem to be used for bolus intravenous injection should be reconstituted in sterile water for injection.

Meropenem in intravenous infusion vials can be directly reconstituted in 0.9% sodium chloride solution or 5% glucose solution for infusion.

Packaging

500 mg or 1000 mg of powder in glass vials. 1 or 10 vials in a cardboard box.

Vacation category

According to the recipe.

Producer

АСС DOBFAR S.P.A.

Address

Nucleo Industriale S. Atto (loc. S. Nicolo' A Tordino), 64100, Teramo (TE), Italy.