Meropenem-Darnitsa powder for solution for injection and infusion 1000 mg vial No. 1

Instructions Meropenem-Darnitsa powder for solution for injection and infusion 1000 mg vial No. 1

Composition

active ingredient: meropenem trihydrate;

1 vial contains meropenem trihydrate 1140 mg, equivalent to meropenem 1000 mg;

excipient: sodium carbonate.

Dosage form

Powder for solution for injection and infusion.

Main physicochemical properties: white to light yellow powder.

Pharmacotherapeutic group

Antimicrobials for systemic use. Other β-lactam antibacterials. Carbapenems. Meropenem. ATC code J01D H02.

Pharmacological properties

Pharmacodynamics.

Meropenem exerts its bactericidal action by inhibiting bacterial cell wall synthesis in 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) (T > MIC) showed a high degree of correlation with efficacy. In preclinical models, meropenem demonstrated activity at plasma concentrations that exceeded the MIC for the infecting organisms by approximately 40% over the dosing range. This target value has not been established clinically.

Bacterial resistance to meropenem may arise as a result of: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to decreased production of porins), (2) decreased affinity for target PBPs, (3) increased expression of efflux pump components, and (4) production of beta-lactamases that can hydrolyze carbapenems.

Outbreaks of infections caused by carbapenem-resistant bacteria have been reported in the European Union.

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 involved involves cell membrane impermeability and/or the presence of efflux pump(s).

The MIC breakpoints that have been established in clinical trials by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are listed below.

1Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25/L 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 should be repeated for any such isolate and, if confirmed, the isolate should be referred to an expert laboratory. Until clinical response data are available for verified isolates with MIC values above the current resistance breakpoints, isolates should be recorded as resistant.

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

4Breakpoints apply to meningitis only.

5Non-species breakpoints were derived primarily from pharmacokinetic/pharmacodynamic data and are independent of the distribution of MICs within individual species. They are intended for use with species not listed in the table and notes. 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.

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

The prevalence of acquired resistance to individual species may vary geographically and over time, and 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.

The pathogenic microorganisms are listed below, based on clinical experience and therapeutic protocols for treating diseases.

Typically sensitive species

Gram-positive aerobes

Enterococcus faecalis7

Staphylococcus aureus (methicillin-susceptible)8

Staphylococcus species (methicillin-susceptible), including Staphylococcus epidermidis

Streptococcus agalactiae (group B)

Streptococcus milleri group (S. anginosus, S. constellatus and S. intermedius)

Streptococcus pneumoniae

Streptococcus pyogenes (group 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

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

Gram-negative anaerobes

Bacteroides caccae

Bacteroides fragilis group

Prevotella bivia

Prevotella disiens

Species that may acquire resistance

Gram-positive aerobes

Enterococcus faecium7,9

Gram-negative aerobes

Species of Acinetobacter Burkholderia cepacia

Pseudomonas aeruginosa

Naturally resistant microorganisms

Gram-negative aerobes

Stenotrophomonas maltophilia

Legionella species

Other microorganisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetii

Mycoplasma pneumoniae

7Species that have shown natural intermediate sensitivity.

8All methicillin-resistant staphylococci are resistant to meropenem.

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

Gangrene and melioidosis: The use of meropenem in humans is based on in vitro susceptibility data for B. mallei and B. pseudomallei and limited human data. Physicians should refer to national and/or international consensus documents regarding the treatment of gangrene and melioidosis.

Pharmacokinetics.

In healthy subjects, 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 clearance decreasing to 205 ml/min at a dose of 2 g. At doses of 500, 1000 and 2000 mg administered as a 30-minute infusion, 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 to 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 subjects, but the volume of distribution was larger (27 L).

Distribution

The mean plasma protein binding of meropenem was approximately 2% and was independent of drug concentration. After rapid administration (5 minutes or less), the pharmacokinetics are biexponential, but this is much less evident 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 the dose is excreted unchanged within 12 hours. A further 28% is excreted as a microbiologically inactive metabolite. Faecal excretion represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid indicate that meropenem undergoes both filtration and tubular secretion.

Kidney failure

Renal impairment results in high plasma AUC values and a longer 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). The 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 subjects 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 age.

Children

Pharmacokinetic studies in infants and children with infection at doses of 10, 20 and 40 mg/kg demonstrated Cmax values approaching those observed in adults after doses of 500, 1000 and 2000 mg, respectively. The pharmacokinetic characteristics depending on the dose of the drug and the half-life were similar to those observed in adults in all but the youngest patients (1/2 = 1.6 h). The mean clearance values of 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 metabolites. Meropenem concentrations in cerebrospinal fluid in children with meningitis are approximately 20% of the simultaneously detected plasma levels of the drug, although there is considerable intersubject 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 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 subjects (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-Darnitsa 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;

- 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-Darnitsa can be used to treat patients with neutropenia and fever suspected to be caused by a bacterial infection.

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

Official recommendations regarding the appropriate use of antibacterial drugs should be considered.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

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

No interaction studies have been conducted with meropenem and other drugs other than probenecid.

Probenecid competes with meropenem for active tubular secretion, thereby inhibiting the renal excretion 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 with carbapenems has been reported to decrease blood levels of valproic acid, resulting in a 60-100% decrease in valproic acid levels within approximately 2 days. Due to the rapid onset of action, concomitant use of valproic acid/sodium valproate/valpromide and carbapenems is considered to be non-adjusting and should be avoided (see section 4.4).

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

Children

All drug interaction studies were conducted only in adults.

Application features

The choice of meropenem as a treatment should take into account the appropriateness of using a carbapenem antibacterial agent, taking into account factors such as the severity of the infection, the prevalence of resistance to other relevant antibacterial agents, and the risk of selecting the drug for carbapenem-resistant bacteria.

Resistance of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter species

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, 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 cutaneous adverse 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 treated with meropenem (see section 4.8). 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, it is important to consider the possibility of this diagnosis 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, particularly 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").

Use of meropenem in patients with liver disease: patients should have their liver function closely monitored. No dose adjustment is required (see section 4.2).

Seroconversion of direct antiglobulin test (Coombs reaction)

Treatment with meropenem may result in a positive direct/indirect Coombs test.

The concomitant use of meropenem and valproic acid/sodium valproate/valpromide is not recommended (see section “Interaction with other medicinal products and other types of interactions”).

Important information about excipients.

This medicinal product contains 90 mg sodium per 1000 mg vial, equivalent to 4.5% of the WHO recommended maximum daily intake of sodium for an adult (2 g).

Use during pregnancy or breastfeeding

Pregnancy: 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.

Breastfeeding: Small amounts of meropenem have been reported to pass into human breast milk. Meropenem should be used in nursing mothers only if the expected benefit to the mother outweighs the potential risk to the infant.

Ability to influence reaction speed when driving vehicles or other mechanisms

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

The vial with the medicine is intended for single use only.

The solution should be shaken before use.

Dosage

The following tables provide general recommendations for the dosage of the drug.

The dose of meropenem and the duration of treatment depend on the type of pathogen, the severity of the disease and the response to treatment.

Meropenem-Darnitsa, when used 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 particularly suitable for the treatment of certain types of infections caused by less susceptible species of bacteria (e.g. Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter species), or very severe infections.

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

Table 1

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.

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

Kidney dysfunction

Table 2

Recommended doses for adults and children weighing more than 50 kg if creatinine clearance is less than 51 ml/min

Data supporting the use of the drug doses specified in Table 2, adjusted for a 2 g dose unit, 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

No dose adjustment is required for patients with impaired liver function (see section "Special warnings and precautions for use").

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 3

Recommended doses for children aged 3 months to 11 years with a body weight of up to 50 kg

Children weighing more than 50 kg

The dose should be used as for adult patients.

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

Method of administration and doses

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

Performing an intravenous bolus injection

Chemical and physical in-use stability of the prepared solution for bolus injection has been demonstrated for 3 hours at temperatures up to 25°C or 12 hours at 2–8°C.

Performing an intravenous infusion

The infusion solution should be prepared by dissolving Meropenem-Darnitsa 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 3 hours at 25°C or 24 hours at 2-8°C. From a microbiological point of view, the medicinal product should be used immediately. If the medicinal product is not used immediately, the shelf life and storage conditions of the reconstituted solution should be closely monitored.

Meropenem-Darnitsa solution prepared with 5% glucose (dextrose) solution should be used immediately.

Do not freeze prepared solutions.

Children.

The medicine should be used in children over 3 months of age.

Overdose

Relative overdose is possible in patients with impaired renal function if the dose of the drug is not adjusted as described in the section "Method of administration and dosage". Limited experience of post-marketing use of the drug indicates that adverse reactions that occur after overdose are consistent with the profile of adverse reactions listed in the section "Adverse reactions" and are usually mild in severity and resolve after drug withdrawal or dose reduction. The need for symptomatic treatment should be considered.

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

Hemodialysis removes meropenem and its metabolites from the body.

Adverse reactions

In 4872 of 5026 patients exposed to 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 adverse laboratory changes associated with meropenem reported were thrombocytosis (1.6%) and increased liver enzymes (1.5-4.3%).

All adverse reactions are listed below by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to

Infections and infestations - uncommon: oral and vaginal candidiasis.

Gastrointestinal disorders: Common: diarrhea, abdominal pain, vomiting, nausea; uncommon: colitis associated with the use of antibiotics (see section "Special warnings and precautions for use").

Hepatobiliary disorders: Common: increased transaminase levels, increased alkaline phosphatase levels in the blood, increased lactate dehydrogenase levels in the blood; uncommon: increased bilirubin levels in the blood.

Renal and urinary disorders: uncommon: increased blood creatinine levels, increased blood urea levels.

Nervous system disorders: Common: headache; uncommon: paresthesia; rare: convulsions (see section "Special warnings and precautions for use").

From the psyche: - rarely: delirium.

Blood and lymphatic system disorders: Common: thrombocythemia; uncommon: agranulocytosis, hemolytic anemia, thrombocytopenia, neutropenia, leukopenia, eosinophilia.

On the part of the immune system - infrequently: anaphylactic reaction (see sections "Contraindications" and "Special instructions for use"), angioedema.

Skin and subcutaneous tissue disorders: Common: rash, pruritus; uncommon: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria; frequency unknown: drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis (see section "Special warnings and precautions for use").

General disorders and administration site conditions: - common: inflammation, pain; uncommon: thrombophlebitis, injection site pain.

There is no evidence to suggest an increased risk of adverse events in children. According to some available data, adverse reactions in children were consistent with those observed in adult patients.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after the registration of a medicinal product is of great importance. This allows monitoring the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the link: https://aisf.dec.gov.ua/.

Expiration date

4 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach of children.

Incompatibility.

Meropenem-Darnitsa should not be mixed or added to other medicines.

If the solution is to be used for bolus intravenous injections, it should be prepared in sterile water for injection.

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

Packaging

1000 mg per vial; 1 vial per pack.

Vacation category

According to the recipe.

Producer

ANFARM HELLAS SA/ANFARM HELLAS SA

Location of the manufacturer and address of its place of business.

61 km National Rd. Athens-Lamia, Skimatari Vioti, 32009, Greece /

61st km Nat. Rd. Athens-Lamia, Schimatari Viotias, 32009, Greece

Applicant.

PrJSC "Pharmaceutical Company "Darnitsa".

Location of the applicant and address of the place of business.

Ukraine, 02093, Kyiv, Boryspilska St., 13.