Meropenem-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Meropenem-Darnitsa (Meropenem-Darnitsa)

Composition:

active substance: meropenem trihydrate;

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

excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection and infusion.

Main physicochemical properties: powder from white to light yellow color.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other beta-lactam antibacterial agents. Carbapenems. Meropenem. ATC code J01D H02.

Pharmacological properties.

Pharmacodynamics.

Meropenem exerts a bactericidal effect by inhibiting the synthesis of bacterial cell walls in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

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

Bacterial resistance to meropenem may arise due to: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to reduced porin production), (2) decreased affinity for target PBPs, (3) increased expression of efflux pump components, and (4) production of beta-lactamases capable of hydrolyzing carbapenems.

In the European Union, outbreaks of infections caused by carbapenem-resistant bacteria have been reported.

Cross-resistance between meropenem and medicinal products belonging to the classes of quinolones, aminoglycosides, macrolides, and tetracyclines is absent with regard to the target microorganisms. However, bacteria may exhibit resistance to more than one class of antibacterial agents when the mechanism involved includes membrane impermeability and/or the presence of efflux pumps.

The following are the MIC breakpoints established during clinical studies by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Microorganism	Susceptible (S) (mg/l)	Resistant (R) (mg/l)
Enterobacteriaceae	≤ 2	> 8
Pseudomonas species	≤ 2	> 8
Acinetobacter species	≤ 2	> 8
Streptococcus, groups A, B, C, G	Note 6	Note 6
Streptococcus pneumoniae1	≤ 2	> 2
Other streptococci2	≤ 2	> 2
Enterococcus species
Staphylococcus species	Note 3	Note 3
Haemophilus influenzae1,2 and Mo2	≤ 2	> 2
Neisseria meningitidis2,4	≤ 0.25	> 0.25
Gram-positive anaerobes, except Clostridium difficile	≤ 2	> 8
Gram-negative anaerobes	≤ 2	> 8
Listeria monocytogenes	≤ 0.25	> 0.25
Non-species related breakpoints5	≤ 2	> 8

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

2Microorganism strains with MIC values exceeding the S/R breakpoint are very rare or have not been reported to date. Testing for identification and antimicrobial susceptibility of any such isolate should be repeated, and if the result is confirmed, the isolate should be referred to a reference laboratory. Until clinical response data are available for verified isolates with MIC values exceeding the current resistance breakpoints, such isolates should be reported as resistant.

3Susceptibility of staphylococci to carbapenems is predicted based on susceptibility data to cefoxitin.

4Breakpoints apply only to meningitis.

5Non-species-related breakpoints have been primarily defined based on pharmacokinetic/pharmacodynamic data and do not depend on the MIC distribution of individual species. They are intended for use with species not listed in the table and footnotes. Non-species-related breakpoints are based on the following dosing regimens: EUCAST breakpoints apply to meropenem administered intravenously at 1000 mg three times daily over 30 minutes as the lowest dose. Doses of 2 g three times daily were considered for severe infections and for intermediate/resistant breakpoints.

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

«–» Performance of susceptibility testing is not recommended, as the organism is a poor target for treatment with this medicinal product. Isolates may be categorized as resistant without prior testing.

The prevalence of acquired resistance in individual species may vary geographically and over time; therefore, it is advisable to rely on local information regarding microbial resistance, especially when treating severe infections. If necessary, when the local prevalence of microbial resistance is such that the benefit of using the medicinal product, at least for certain types of infections, is questionable, expert consultation should be sought.

The following lists pathogenic microorganisms based on clinical experience and therapeutic treatment guidelines.

Usually susceptible species

Gram-positive aerobes

Enterococcus faecalis 7

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 with potential for acquired resistance

Gram-positive aerobes

Enterococcus faecium 7,9

Gram-negative aerobes

Acinetobacter species

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 exhibiting intrinsic intermediate susceptibility.

8All methicillin-resistant staphylococci are resistant to meropenem.

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

Glanders 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 glanders and melioidosis.

Pharmacokinetics.

In healthy individuals, the mean plasma elimination 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 when the drug is administered at a dose of 250 mg, decreasing to 205 mL/min at a dose of 2 g. After administration of doses of 500, 1000, and 2000 mg as a 30-minute infusion, mean Cmax values were approximately 23, 49, and 115 µg/mL, respectively; corresponding AUC values were 39.3, 62.3, and 153 µg×h/mL. After a 5-minute infusion, Cmax values were 52 and 112 µg/mL following administration of 500 and 1000 mg doses, respectively. With multiple dosing every 8 hours in patients with normal renal function, accumulation of meropenem was not observed.

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

Distribution

The mean extent of meropenem binding to plasma proteins is approximately 2% and is 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 certain body fluids and tissues, including lungs, bronchial secretions, bile, cerebrospinal fluid, female genital tract tissues, skin, fascia, muscle, and peritoneal exudates.

Metabolism

Meropenem is metabolized by hydrolysis of the beta-lactam ring, forming 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 administration of a DHP-I inhibitor.

Excretion

Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50–75%) of the administered dose is excreted unchanged within 12 hours. An additional 28% is excreted as the microbiologically inactive metabolite. Fecal excretion accounts for only about 2% of the dose. Measured renal clearance and the effect of probenecid indicate that meropenem undergoes both glomerular filtration and tubular secretion.

Renal impairment

Renal dysfunction leads to higher plasma AUC values and a prolonged elimination half-life of meropenem. AUC values increased by 2.4-fold in patients with moderate renal impairment (creatinine clearance (CrCl) 33–74 mL/min), by 5-fold in patients with severe renal impairment (CrCl 4–23 mL/min), and by 10-fold in patients undergoing hemodialysis (CrCl < 2 mL/min), compared to healthy individuals (CrCl > 80 mL/min). AUC values of the microbiologically inactive open-ring metabolite were also significantly increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate to severe renal impairment (see section "Dosage and administration").

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

Hepatic impairment

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

Adult patients

Pharmacokinetic studies in patients revealed no significant pharmacokinetic differences compared to healthy individuals with similar renal function. A population model developed from data of 79 patients with intra-abdominal infection or pneumonia showed dependence of key parameters on body weight, creatinine clearance, and age.

Children

Pharmacokinetic studies in infants and children with infection receiving doses of 10, 20, and 40 mg/kg demonstrated Cmax values approaching those observed in adults after administration of 500, 1000, and 2000 mg doses, respectively. Dose-dependent pharmacokinetic characteristics and elimination half-life were similar to those observed in adults in all except the youngest patients (< 6 months, t1/2 = 1.6 hours). Mean meropenem clearance values 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 was excreted in urine within 12 hours as meropenem and an additional 12% as metabolite. Meropenem concentrations in cerebrospinal fluid in children with meningitis are approximately 20% of simultaneous plasma levels, although considerable inter-individual variability exists.

Pharmacokinetics of meropenem in neonates receiving antibacterial therapy demonstrated higher clearance in neonates with greater chronological or gestational age, with an overall mean elimination half-life of 2.9 hours. Monte Carlo simulation based on the population pharmacokinetic model showed that with a regimen of 20 mg/kg every 8 hours, T > MIC of 60% was achieved against P. aeruginosa in 95% of preterm neonates and 91% of term neonates.

Elderly patients

Pharmacokinetic studies in healthy elderly individuals (65–80 years) showed reduced plasma clearance, correlating with age-related reduction in creatinine clearance, as well as a slight decrease in non-renal clearance. Dose adjustment is not required for elderly patients, except in cases of moderate or severe renal impairment.

Clinical characteristics.

Indications.

Meropenem-Darnitsia 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-Darnitsia may be used for the treatment of patients with neutropenia and fever suspected to be caused by a bacterial infection.

For treatment of patients with bacteremia associated or potentially associated with any of the above-mentioned infections.

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

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

Hypersensitivity to any other antibacterial agent of the carbapenem class.

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 forms of interaction.

Interaction studies of meropenem with other medicinal products, except probenecid, have not been conducted.

Probenecid competes with meropenem for active tubular secretion, thereby inhibiting renal excretion of meropenem, which leads to an increased elimination half-life and higher plasma concentrations of meropenem. Caution should be exercised when probenecid is administered concomitantly with meropenem.

The potential effect of meropenem on protein binding or metabolism of other drugs has not been studied. However, since protein binding is minimal, interactions based on this mechanism are unlikely.

Decreased blood levels of valproic acid have been reported when administered concomitantly with carbapenems, resulting in a 60–100% reduction in valproic acid levels within approximately 2 days. Due to the rapid onset of this interaction, concomitant administration of valproic acid / sodium valproate / valpromide and carbapenems is considered non-adjustable; therefore, such combination should be avoided (see section "Special precautions for use").

Oral anticoagulants

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

Children

All drug interaction studies have been conducted in adults only.

Special precautions for use.

When selecting meropenem as a treatment option, consideration should be given to the appropriateness of using a carbapenem-class antibacterial agent, taking into account factors such as the severity of infection, prevalence of resistance to other relevant antibacterial agents, and the risk of selecting for carbapenem-resistant bacteria.

Resistance of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter

In the European Union, resistance to penems among Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter varies. When prescribing the drug, local resistance patterns of these bacteria to penems should be taken into account.

Hypersensitivity reactions

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

Patients with a history of hypersensitivity to carbapenems, penicillins, or other beta-lactam antibiotics may also have an increased risk of hypersensitivity to meropenem. A thorough patient history regarding previous hypersensitivity reactions to beta-lactam antibiotics should be obtained prior to initiating meropenem therapy.

If a severe allergic reaction occurs, the drug should be discontinued immediately and appropriate measures initiated.

Serious skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, and acute generalized exanthematous pustulosis, have been reported in patients receiving meropenem (see section "Adverse reactions"). If signs or symptoms suggestive of these reactions occur, meropenem should be discontinued immediately and alternative therapy considered.

Antibiotic-associated colitis

Cases of antibiotic-associated colitis, including pseudomembranous colitis, have been reported with the use of nearly all antibacterial agents, including meropenem, with severity ranging from mild to life-threatening. It is therefore important to consider this diagnosis in patients who develop diarrhea during or after treatment with meropenem (see section "Adverse reactions"). Consideration should be given to discontinuing meropenem therapy and initiating specific treatment against Clostridium difficile. Medicinal products that inhibit intestinal peristalsis should not be prescribed.

Seizures

Seizures have been rarely reported during treatment with carbapenems, including meropenem (see section "Adverse reactions").

Liver function monitoring

Due to the risk of hepatotoxicity (liver function abnormalities with cholestasis and cytolysis) during meropenem therapy, liver function should be closely monitored (see section "Adverse reactions").

Use of meropenem in patients with liver disease: liver function should be closely monitored in these patients. Dose adjustment of the drug is not required (see section "Dosage and administration").

Serum conversion in the direct antiglobulin test (Coombs test)

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

Concomitant use of meropenem and valproic acid / sodium valproate / valpromide is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Important information on excipients.

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

Pregnancy and breastfeeding.

Pregnancy. Data on the use of meropenem in pregnant women are lacking or limited in number.

Animal studies have not shown direct or indirect effects of reproductive toxicity. As a precautionary measure, it is advisable to avoid the use of meropenem during pregnancy.

Breastfeeding. It has been reported that small amounts of meropenem pass into human breast milk. Meropenem may be used in breastfeeding mothers only if the expected benefit to the mother outweighs the potential risk to the infant.

Ability to affect driving and operating machinery.

Studies on the effect of the drug on the ability to drive vehicles or operate machinery have not been conducted.

When driving vehicles or operating machinery, particular caution is recommended, considering the possibility of developing headache, paresthesia, or seizures, which have been reported during meropenem use.

Dosage and Administration

The vial of the medicinal product is intended for single use only.

The solution should be shaken before use.

Dosage

The tables below provide general recommendations for dosage of the medicinal product.

The dose of meropenem and duration of treatment depend on the causative pathogen, severity of the infection, and the patient's response to therapy.

Meropenem-Darnitsa, administered at a dose of up to 2 g three times daily in adults and children with body weight over 50 kg, and up to 40 mg/kg three times daily in children, is particularly suitable for the treatment of certain infections caused by less susceptible bacterial species (e.g. Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter) or severe infections.

Additional dosage recommendations must be followed when treating patients with renal impairment (see below).

Table 1

Recommended doses for adults and children with body weight over 50 kg

Infection	Single dose administered every 8 hours
Pneumonia, including community-acquired and hospital-acquired pneumonia	500 mg or 1 g
Respiratory tract infections in cystic fibrosis	2 g
Complicated urinary tract infections	500 mg or 1 g
Complicated intra-abdominal infections	500 mg or 1 g
Infections during childbirth and postpartum infections	500 mg or 1 g
Complicated skin and soft tissue infections	500 mg or 1 g
Acute bacterial meningitis	2 g
Treatment of patients with febrile neutropenia	1 g

Meropenem-Darnytsia is usually administered as an intravenous infusion over 15 to 30 minutes.

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

Renal impairment

Table 2

Recommended doses for adults and children with body weight over 50 kg when creatinine clearance is less than 51 ml/min

Creatinine clearance (ml/min)	Single dose (see table 1)	Frequency
26–50	full single dose	every 12 hours
10–25	half the single dose	every 12 hours
< 10	half the single dose	every 24 hours

Data supporting the use of doses of the medicinal product adjusted to the 2 g unit dose as indicated in Table 2 are limited.

Meropenem is removed by hemodialysis and hemofiltration; therefore, the required dose of the medicinal product should be administered after completion of the hemodialysis procedure.

There are no recommendations regarding established dosing for patients undergoing peritoneal dialysis.

Hepatic impairment

Dose adjustment of the medicinal product is not required in patients with hepatic impairment (see section "Special warnings and precautions for use").

Dosage in elderly patients

Dose adjustment is not required in 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 dosing regimen has not been established. There are limited pharmacokinetic data justifying the use of a meropenem dose of 20 mg/kg every 8 hours (see section "Pharmacokinetics").

Table 3

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

Infection	Single dose administered every 8 hours
Pneumonia, including community-acquired and hospital-acquired pneumonia	10 or 20 mg/kg body weight
Respiratory tract infections in cystic fibrosis	40 mg/kg body weight
Complicated urinary tract infections	10 or 20 mg/kg body weight
Complicated intra-abdominal infections	10 or 20 mg/kg body weight
Complicated skin and soft tissue infections	10 or 20 mg/kg body weight
Acute bacterial meningitis	40 mg/kg body weight
Treatment of patients with febrile neutropenia	20 mg/kg body weight

Children with body weight over 50 kg

The dose for adult patients should be used.

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

Method of administration

Meropenem-Darnitsia is usually administered as an intravenous infusion over 15 to 30 minutes. Additionally, doses of meropenem up to 20 mg/kg may be administered as an intravenous bolus injection over approximately 5 minutes. Safety data supporting administration of the medicinal product at a dose of 40 mg/kg as an intravenous bolus injection in children are limited.

Administration of intravenous bolus injection

The solution for bolus injection should be prepared by dissolving Meropenem-Darnitsia in water for injections to obtain a concentration of 50 mg/mL.

Chemical and physical stability of the prepared solution for bolus injection was maintained for 3 hours at temperatures up to 25 °C or for 12 hours at temperatures of 2–8 °C.

Administration of intravenous infusion

The infusion solution should be prepared by dissolving the medicinal product Meropenem-Darnitsia in 0.9 % sodium chloride solution for infusions or in 5 % glucose (dextrose) solution for infusions to obtain a concentration of 1–20 mg/mL.

Chemical and physical stability of the prepared infusion solution using 0.9 % sodium chloride solution was maintained for 3 hours at 25 °C or for 24 hours at 2–8 °C. From a microbiological standpoint, the medicinal product should be used immediately. If the medicinal product is not used immediately, the storage period and conditions of the prepared solution should be carefully controlled.

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

Prepared solutions should not be frozen.

Children.

The medicinal product may be administered to children aged from 3 months.

Overdose.

Relative overdosage is possible in patients with impaired renal function if the dose of the medicinal product is not adjusted as described in the section "Dosage and method of administration". Limited post-marketing experience suggests that adverse reactions occurring after overdosage are consistent with the profile of adverse reactions listed in the section "Adverse reactions" and are generally mild in severity and resolve after discontinuation or dose reduction of the medicinal product. Symptomatic treatment should be considered as necessary.

In individuals with normal renal function, the medicinal product is rapidly eliminated by the kidneys.

Haemodialysis removes meropenem and its metabolites from the body.

Adverse Reactions

Based on data from 4,872 out of 5,026 patients regarding the effects of meropenem treatment, the most commonly reported adverse reactions associated with meropenem use were diarrhea (2.3%), rash (1.4%), nausea/vomiting (1.4%), and injection site inflammation (1.1%). The most frequently reported laboratory test abnormalities associated with meropenem use were thrombocytosis (1.6%) and elevated liver enzymes (1.5–4.3%).

The following lists all adverse reactions by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated based on available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Infections and infestations — uncommon: oral and vaginal candidiasis.

Gastrointestinal disorders — common: diarrhea, abdominal pain, vomiting, nausea; uncommon: antibiotic-associated colitis (see section "Special precautions for use").

Hepatobiliary disorders — common: increased levels of transaminases, increased alkaline phosphatase levels in blood, increased lactate dehydrogenase levels in blood; uncommon: increased blood bilirubin levels.

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

Nervous system disorders — common: headache; uncommon: paresthesia; rare: seizures (see section "Special precautions for use").

Psychiatric disorders — rare: delirium.

Blood and lymphatic system disorders — common: thrombocytosis; uncommon: agranulocytosis, hemolytic anemia, thrombocytopenia, neutropenia, leukopenia, eosinophilia.

Immune system disorders — uncommon: anaphylactic reaction (see sections "Contraindications" and "Special precautions for use"), angioneurotic edema.

Skin and subcutaneous tissue disorders — common: rash, pruritus; uncommon: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria; frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (see section "Special precautions for use").

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

There are no data indicating an increased risk of adverse events in children. According to limited available data, adverse reactions in pediatric patients were consistent with those observed in adult patients.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance 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 through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua/.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach and sight of children.

Incompatibilities.

Meropenem-Darnytsia should not be mixed or combined with other medicinal products.

If the solution is intended for intravenous bolus injection, it should be prepared using sterile water for injections.

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

Packaging.

1000 mg in a vial; 1 vial per pack.

Prescription status. Prescription only.

Manufacturer.

Anfarm Hellas S.A.
Anfarm Hellas S.A.

Manufacturer's address.

61st Km National Road Athens-Lamia, Schimatari, Viotias, 320 09, Greece

Marketing Authorization Holder.

JSC "Pharmaceutical Company Darnitsya"

Address of the Marketing Authorization Holder.

13 Boryspylska Street, Kyiv, 02093, Ukraine