Medopinem

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEDOPENEM | (MEDOPENEM)

Composition:

Active substance: meropenem;

1 vial contains meropenem trihydrate equivalent to 1 g of meropenem;

Excipient: anhydrous sodium carbonate.

Pharmaceutical form. Powder for solution for injection or infusion|administration|.

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

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

Pharmacological properties.

Pharmacodynamics.

Meropenem exerts bactericidal activity 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 at plasma concentrations exceeding 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 arise due to: (1) reduced permeability of the outer membrane in Gram-negative bacteria (associated with decreased porin production), (2) reduced 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, with regard to target microorganisms, is absent. 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.

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

2. Microbial isolates with MIC values exceeding the S/R breakpoints 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 confirmed, the isolate should be referred to a reference laboratory. Until clinical response data are available for confirmed isolates with MIC values above 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. The breakpoints apply only to meningitis.

5. Non-species-related breakpoints were primarily determined 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 1000 mg administered intravenously 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 groups 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 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 information on microbial resistance should be consulted, 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, consultation with an expert should be sought.

Listed below are pathogenic microorganisms based on clinical experience and therapeutic treatment guidelines.

Typically susceptible 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 for which acquired resistance may be a problem

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.

7. Species exhibiting intrinsic intermediate susceptibility.

8. All methicillin-resistant staphylococci are resistant to meropenem.

9. Resistance 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 about 0.25 L/kg (11–27 L); mean clearance is 287 mL/min following a 250 mg dose, decreasing to 205 mL/min with a 2 g dose. Following administration of 500, 1000, and 2000 mg doses infused over 30 minutes, mean C_max values are approximately 23, 49, and 115 µg/mL, respectively; corresponding AUC values are 39.3, 62.3, and 153 µg×h/mL. After 5-minute infusions, C_max values are 52 and 112 µg/mL for 500 and 1000 mg doses, respectively. With multiple dosing every 8 hours in patients with normal renal function, accumulation of meropenem is not observed.

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

Distribution. The mean plasma protein binding of meropenem 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 various 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 shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, and therefore does not require co-administration with 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. Impaired renal function results in higher plasma AUC values and 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 on hemodialysis (CrCl <2 mL/min), compared to healthy subjects (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 four times higher than in anuric patients.

Hepatic impairment. Studies in patients with alcoholic liver cirrhosis show no effect of liver disease on meropenem pharmacokinetics after repeated dosing.

Adult patients. Pharmacokinetic studies in patients have not revealed significant pharmacokinetic differences compared to healthy subjects 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 receiving doses of 10, 20, and 40 mg/kg demonstrated C_max 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 in adults, except in the youngest patients (<6 months, t_1/2 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 the metabolite. Meropenem concentrations in cerebrospinal fluid in children with meningitis are approximately 20% of simultaneously measured plasma levels, although considerable inter-individual variability exists. Meropenem pharmacokinetics in neonates receiving antibacterial therapy 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.

Elderly patients. Pharmacokinetic studies in healthy elderly subjects (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 in elderly patients unless moderate or severe renal impairment is present.

Clinical characteristics.

Indications.

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 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 on the 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 agent (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 thus inhibits renal excretion of meropenem, leading 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 the protein binding of other drugs or metabolism has not been studied. However, since protein binding is so low, interactions with other compounds via this mechanism are unlikely.

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

Oral anticoagulants. Concomitant use of antibiotics with warfarin may enhance its anticoagulant effect. Numerous reports have documented increased anticoagulant effect of orally administered 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 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 an oral anticoagulant.

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 suitable antibacterial agents, and the risk of selecting for carbapenem-resistant bacteria.

Resistance in 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 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, administration of the drug must be discontinued immediately and appropriate measures initiated.

Severe 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 treatment (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, with severity ranging from mild to life-threatening, have been reported during treatment with nearly all antibacterial agents, including meropenem. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after meropenem therapy (see section "Adverse reactions"). Discontinuation of meropenem and initiation of specific therapy directed against Clostridium difficile should be considered. Medicinal products that inhibit intestinal motility should not be prescribed.

Seizures. Seizures have been reported rarely 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 receiving meropenem. Dose adjustment 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 or indirect Coombs test. Concomitant administration of meropenem and valproic acid/sodium valproate/valpromide is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of meropenem in pregnant women are lacking or limited. Animal studies have not shown direct or indirect effects on reproductive toxicity. As a precautionary measure, it is advisable to avoid using meropenem during pregnancy.

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

Ability to affect reaction speed when driving vehicles or operating machinery.
No studies on the effect of the drug on the ability to drive vehicles or operate machinery have been conducted. When driving vehicles or operating machinery, particular caution is recommended due to 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 dosing 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 therapy.

Medopenem may be particularly appropriate when 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, 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.

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

Meropenem should usually be administered as an intravenous infusion lasting from 0.25 to 0.5 hours. Additionally, doses up to 1 g may be given as an intravenous bolus injection over approximately 5 minutes. Safety data supporting administration of the 2 g dose as an intravenous bolus injection in adults are limited.

Renal impairment.

Table 2

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

The data supporting the use of the doses of the medicinal product indicated in Table 2, adjusted per 2 g dose unit, are limited.

Meropenem is eliminated 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 for the established dose of the medicinal product in 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 supporting the use of a meropenem dose of 20 mg/kg every 8 hours (see section "Pharmacokinetics").

Table 3

Recommended doses of the medicinal product for children aged from 3 months to 11 years and with body weight up to 50 kg.

Children with body weight 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.

Administration method. Medopenem should usually be 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 the administration of the drug to children at a dose of 40 mg/kg as an intravenous bolus injection are limited.

Recommendations for reconstitution of the medicinal product prior to administration: standard aseptic techniques should be used during reconstitution. Freshly prepared solutions are recommended (see section "Storage conditions").

Injection: meropenem for intravenous bolus injection should be reconstituted with sterile water for injections.

Infusion: for intravenous infusion, meropenem may be directly reconstituted with 0.9% sodium chloride solution or 5% glucose infusion solution.

Children. The drug may be used in children aged from 3 months.

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 "Dosage and administration". Limited post-marketing experience indicates that if adverse reactions occur after overdose, they are consistent with the profile of the specified adverse reactions described in the section "Adverse reactions", and are generally 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 by the kidneys. Hemodialysis removes meropenem and its metabolites from the body.

Adverse Reactions

In a review of data from 4872 out of 5026 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 abnormalities associated with meropenem use were thrombocytosis (1.6%) and elevated liver enzyme levels (1.5–4.3%). The adverse reactions listed in the table below are categorized by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); 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.

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 warnings and precautions for use”), angioneurotic edema.

Psychiatric disorders – rare: delirium.

Nervous system disorders – common: headache; uncommon: paresthesia; rare: seizures (see section “Special warnings and precautions for use”).

Gastrointestinal disorders – common: diarrhea, abdominal pain, vomiting, nausea; uncommon: antibiotic-associated colitis (see section “Special warnings and precautions for use”).

Hepatobiliary disorders – common: increased transaminase levels, increased alkaline phosphatase levels in blood, increased lactate dehydrogenase levels in blood; uncommon: increased bilirubin levels 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 warnings and precautions for use”).

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 events in children based on the limited available data. All reported cases corresponded to adverse reactions observed in adult patients.

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued 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 suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Intravenous bolus administration

The solution for bolus injection is prepared by dissolving the medicinal product in water for injections to a final concentration of 50 mg/mL. Chemical and physical stability of the prepared bolus injection solution has been demonstrated for 3 hours at temperatures up to 25 °C or 12 hours under refrigerated conditions (2–8 °C).

From a microbiological standpoint, if the method of opening/reconstitution/dilution does not exclude the risk of microbial contamination, the product should be used immediately.

If the product is not used immediately, responsibility for the duration and conditions of storage lies with the user.

Intravenous infusion administration

The infusion solution is prepared by dissolving the medicinal product in 0.9% sodium chloride infusion solution or 5% dextrose infusion solution to a final concentration of 1 to 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 temperatures up to 25 °C or 24 hours under refrigerated conditions (2–8 °C).

From a microbiological standpoint, if the method of opening/reconstitution/dilution does not exclude the risk of microbial contamination, the product should be used immediately.

If the product is not used immediately, responsibility for the duration and conditions of storage lies with the user.

Reconstituted solution in 5% dextrose solution should be used immediately.

Prepared solutions must not be frozen.

Shake the prepared solution before administration.

All vials are intended for single use only.

Standard aseptic conditions must be observed during preparation and administration of the medicinal product.

Incompatibilities. Meropenem must not be mixed or combined with other medicinal products.

Meropenem intended for intravenous bolus injections should be reconstituted with 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. 1 g of powder in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Medochemie Limited / Medochemie Limited.

Manufacturer’s address and place of business.

Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus / Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.