Europenem

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUROPENEM

Composition:

Active substance: meropenem;

1 vial contains meropenem trihydrate equivalent to anhydrous meropenem 500 mg or 1.0 g;

Excipient: sodium carbonate monohydrate equivalent to anhydrous sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white to pale yellow powder.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Carbapenems. ATC code J01D H02.

Pharmacological properties.

Pharmacodynamics.

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

As with other beta-lactam antibacterial agents, the duration of time during which meropenem concentrations exceed the minimum inhibitory concentrations (MIC) (T>MIC) has been shown to correlate highly with efficacy. In preclinical models, meropenem demonstrated activity when plasma concentrations exceeded the MIC for the infecting microorganisms for approximately 40% of the dosing interval. This target value has not been clinically established.

Bacterial resistance to meropenem may occur due to:

• reduced outer membrane permeability in Gram-negative bacteria (due to decreased porin production);
• reduced affinity for target PBPs;
• increased expression of efflux pump components;
• production of beta-lactamases capable of hydrolyzing carbapenems.

In the European Union, outbreaks of infection 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 reduced membrane permeability and/or presence of efflux pump(s).

The MIC breakpoint values established during clinical studies by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are listed below.

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 species2	note 3	note 3
Haemophilus influenzae1,2 and MoRaxella catarrhalis2	≤ 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
Species-unrelated breakpoints5	≤ 2	> 8

1. The breakpoint values for meropenem against Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25 mg/L and 1 mg/L (resistant), respectively.

2. Microbial isolates with MIC values above the S/I breakpoint are very rare or have not yet been reported. Testing for identification and antimicrobial susceptibility for any such isolate should be repeated. 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 (indicated in italics), such isolates should be reported as resistant.

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

4. Breakpoints apply only to meningitis.

5. Non-species-related breakpoints were primarily established based on PK/PD 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.

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

"–" Susceptibility testing is not recommended, as the organism is a poor target for treatment with the agent. Isolates may be designated as resistant without prior testing.

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local data on microbial resistance should be consulted whenever possible, especially when treating severe infections. When the local prevalence of resistance is such that the utility of the medicinal product is questionable—even for certain types of infections—expert consultation should be sought.

Listed below are 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) Group Streptococcus milleri (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 Group Bacteroides fragilis 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

Inherently resistant microorganisms

Gram-negative aerobes

Stenotrophomonas maltophilia Legionella species

Other microorganisms

Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetii Mycoplasma pneumoniae

7Species that have demonstrated natural intermediate susceptibility.

8All methicillin-resistant staphylococci are resistant to meropenem.

9Resistance rate > 50 % in one or more European Union countries. Glanders and melioidosis: the use of meropenem in humans is based on in vitro susceptibility data for B. mallei and B. pseudomallei and on 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 following a 250 mg dose, decreasing to 205 mL/min with a 2 g dose. Following administration of doses of 500, 1000, and 2000 mg infused over 30 minutes, 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 5-minute infusions, Cmax values were 52 and 112 µg/mL following 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 values were consistent with those in healthy individuals, but with a larger volume of distribution (27 L).

Distribution

The mean degree of meropenem binding to plasma proteins is approximately 2 % and is independent of drug concentration. After rapid administration (5 minutes or less), 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 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 demonstrates reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, and thus does not require co-administration of a DHP-I inhibitor.

Excretion

Meropenem is primarily excreted unchanged by the kidneys; approximately 70 % (50–75 %) of the 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 impairment leads to higher plasma AUC values and a prolonged elimination half-life for meropenem. AUC 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 volunteers (CrCl >80 mL/min). AUC values for the microbiologically inactive open-ring metabolite were also significantly increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate and 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

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

Adult patients

Pharmacokinetic studies in patients have not revealed significant pharmacokinetic differences compared to healthy volunteers with similar renal function. A population model developed from data in 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, using doses of 10, 20, and 40 mg/kg, demonstrated Cmax values approaching those observed in adults after 500, 1000, and 2000 mg doses, respectively. Comparative analyses revealed pharmacokinetic characteristics between doses and elimination half-lives similar to those observed in adults, except in 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 is 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 concentrations, although considerable inter-individual variability exists.

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

Geriatric patients

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

Clinical characteristics.

Indications.

Eurepenem 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.

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

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 group.

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

Interaction with other medicinal products and other forms of interaction.

Studies on the interaction of the drug with individual medicinal products, except probenecid, have not been conducted.

Probenecid competes with meropenem for active tubular secretion and thereby inhibits renal excretion of meropenem, resulting in prolonged elimination half-life and increased plasma concentrations of meropenem. Caution should be exercised when probenecid is used concomitantly with meropenem.

The potential effect of Eurepenem on protein binding or metabolism of other drugs has not been studied. However, since protein binding is so minimal, interactions with other compounds via this mechanism are not expected.

Decreased serum levels of valproic acid have been reported when co-administered with carbapenems, resulting in approximately 60–100% reduction in valproic acid levels within about 2 days. Due to the rapid onset and extent of this reduction, concomitant administration of valproic acid and carbapenems cannot be compensated by dose adjustment; 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 effect of oral anticoagulants, including warfarin, in patients receiving antibiotics concomitantly. The risk may vary depending on the underlying infection, age, and general condition of the patient, thus making it difficult to assess the exact contribution of antibacterial agents to the increase in INR (International Normalized Ratio). Frequent monitoring of INR levels is recommended during and shortly 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 be at increased risk of hypersensitivity to meropenem. A careful patient history regarding previous hypersensitivity reactions to beta-lactam antibiotics should be obtained prior to initiating therapy with meropenem.

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

Severe skin 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 therapy (see section "Adverse reactions"). If signs or symptoms suggesting these reactions occur, meropenem should be discontinued immediately and alternative therapy should be considered.

Antibiotic-associated colitis

Cases of antibiotic-associated colitis and pseudomembranous colitis, with severity ranging from mild to life-threatening, have been reported during treatment with nearly all antibacterial agents, including meropenem. Therefore, this diagnosis should be considered in patients who develop diarrhea during or after meropenem therapy (see section "Adverse reactions"). Discontinuation of meropenem therapy and initiation of specific treatment directed against Clostridium difficile should be considered. Antiperistaltic medicinal products 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 in patients with liver disease: liver function should be closely monitored in patients with pre-existing liver disease during meropenem therapy. Dose adjustment is not required (see section "Method of administration and dosage").

Seroconversion in the direct antiglobulin test (Coombs test)

Treatment with meropenem may result in a positive direct 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").

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

Use during pregnancy or breastfeeding

Pregnancy

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

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

Breastfeeding period

It has been reported that a small amount of meropenem passes into human breast milk. Meropenem may be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

Ability to affect the speed of reactions when driving or 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, it is recommended to exercise particular caution, considering the possibility of developing headache, paresthesia, or seizures, which have been reported during meropenem use.

Method of Administration and Dosage.

Dosage

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

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

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

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

Table 1

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

Euvopenem should usually be administered as an intravenous infusion lasting from 5 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 administration of a 2 g dose as an intravenous bolus injection in adults are limited.

Renal impairment

Recommended doses of the medicinal product for adults and children with body weight above 50 kg when patients' creatinine clearance is less than 51 ml/min

Table 2

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

The data supporting the use of the doses of the drug indicated in Table 2, adjusted to the 2 g dose unit, are limited.

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

There are no recommendations regarding established dosing of the drug for patients receiving peritoneal dialysis.

Hepatic impairment

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

Dosing 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 supporting the use of a meropenem dose of 20 mg/kg every 8 hours (see section "Pharmacokinetics").

Recommended doses of the drug for children aged 3 months to 11 years and with body weight below 50 kg.

Table 3

Infection	Single dose to be administered every 8 hours
Pneumonia, including community-acquired and hospital-acquired	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 more than 50 kg

The dose should be applied as for adult patients.

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

Route of administration

Europenem is usually administered as an intravenous infusion lasting from 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 drug to children at a dose of 40 mg/kg as an intravenous bolus injection are limited.

Administration of intravenous bolus injection

The solution for bolus injection should be prepared by dissolving the medicinal product Europenem in water for injections to obtain a concentration of 50 mg/mL.

Chemical and physical stability of the prepared bolus injection solution has been demonstrated for 3 hours at room temperature up to 25°C or 12 hours under refrigeration (2–8°C).

From a microbiological point of view, if the method of opening/reconstitution/dilution does not exclude the risk of microbiological contamination, 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.

Administration of intravenous infusion

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

Chemical and physical stability of the prepared infusion solution using 0.9% sodium chloride solution has been demonstrated for 3 hours at 25°C or for 24 hours at 2–8°C, or for 24 hours under refrigeration (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 storage period and conditions of the prepared solution should be carefully controlled.

The solution of Europenem prepared with 5% glucose (dextrose) solution should be used immediately. Prepared solutions should not be frozen.

Children.

The drug may be administered to children aged 3 months and older.

Overdose.

Relative overdose is possible in patients with impaired renal function if the drug dose is not adjusted as described in the section "Dosage and administration". Limited post-marketing experience indicates that if adverse reactions occur following overdose, they are consistent with the profile of the listed adverse reactions described in the section "Adverse reactions", are usually mild in severity and resolve after discontinuation of the drug or dose reduction. Symptomatic treatment should be considered as necessary.

In individuals with normal renal function, the drug is rapidly eliminated via the kidneys.

Haemodialysis removes meropenem and its metabolites from the body.

Adverse Reactions.

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

Below is a list of 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 group, adverse reactions are listed in decreasing order of severity.

Infections and infestations – uncommon: oral and vaginal candidiasis.

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»), angioneurotic edema.

Psychiatric disorders – rare: delirium.

Nervous system disorders – common: headache; uncommon: paresthesia; rare: seizures (see section «Special precautions»).

Gastrointestinal disorders – common: diarrhea, abdominal pain, vomiting, nausea; uncommon: antibiotic-associated colitis (see section «Special precautions»).

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

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»).

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

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

There are no data suggesting an increased risk of adverse reactions in children based on the limited available data. All reported cases corresponded to adverse reactions observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via 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 30 °C.

Keep out of reach and sight of children.

It is recommended to use freshly prepared solutions of Eupenem for intravenous injection and infusion.

Each vial is intended for single use only.

Standard aseptic techniques should be used during solution preparation and administration.

The solution should be shaken before use.

Unused product or waste material must be disposed of in accordance with local requirements.

Incompatibilities.

Eupenem must not be mixed or added to other medicinal products.

Eupenem intended for intravenous bolus injection should be reconstituted with sterile water for injections.

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

Packaging.

1 or 10 vials with powder in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ces Dofar S.p.A.

Manufacturer's address and location of operations.

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