Meropenem-mb

INSTRUCTIONS for medical use of the medicinal product MEROPEM-MB (MEROPENEM-MB)

Composition:

Active substance: meropenem;

1 vial contains 1000 mg of meropenem in the form of 1140 mg meropenem trihydrate;

Excipient: sodium carbonate anhydrous.

Pharmaceutical form. Powder for solution for injection and infusion.

Main physicochemical characteristics: white to slightly yellowish powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Carbapenems. ATC code J01DH02.

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 duration of time during which meropenem concentrations exceed the minimum inhibitory concentration (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 established clinically.

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

The MIC breakpoint values established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for clinical studies are presented in Table 1 below.

Table 1

MIC breakpoint values established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for clinical studies

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

2Strains of microorganisms with MIC values exceeding the S/R breakpoint are very rare or have not been reported so far. Testing for identification and antimicrobial susceptibility for any such isolate should be repeated, and if the result is confirmed, the isolate should be referred to a reference laboratory. Pending data on clinical response for verified isolates with MIC values exceeding the current resistance breakpoints (indicated in italics), isolates should be reported as resistant.

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

4Breakpoints apply only to meningitis.

5Non-species-related breakpoints were primarily determined 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 Table 1 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.

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

«–» Susceptibility testing is not recommended because the organism is a poor target for the drug. Isolates may be reported 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 taken into account, especially when treating severe infections. If necessary, when the local prevalence of microbial resistance is such that the benefit of using the drug, at least for certain types of infections, is questionable, consultation with an expert should be sought.

The following pathogens are listed 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 freudii

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

7Species exhibiting inherent 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 limited human data. Physicians should refer to national and/or international consensus documents regarding the treatment of glanders and melioidosis.

Pharmacokinetics.

In healthy volunteers, 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 after administration of a 250 mg dose, decreasing to 205 mL/min with a 2 g dose. After administration of doses of 500 mg, 1000 mg, and 2000 mg given as 30-minute infusions, mean maximum concentration (Cmax) values were approximately 23 µg/mL, 49 µg/mL, and 115 µg/mL, respectively; corresponding area under the concentration-time curve (AUC) values were 39.3 µg•h/mL, 62.3 µg•h/mL, and 153 µg•h/mL. After 5-minute infusions, Cmax values were 52 µg/mL and 112 µg/mL for 500 mg 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 (t1/2) values were consistent with those in healthy subjects, but the volume of distribution was higher—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), 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 via 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, thus eliminating the 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. Only about 2% of the dose is excreted in feces. Measured renal clearance and the effect of probenecid indicate that meropenem undergoes both glomerular filtration and tubular secretion.

Renal impairment

Impaired renal function leads to higher plasma AUC values and a prolonged t1/2 of meropenem. AUC values increased 2.4-fold in patients with moderate renal impairment (creatinine clearance (CrCl) 33–74 mL/min), 5-fold in patients with severe renal impairment (CrCl 4–23 mL/min), and 10-fold in patients undergoing hemodialysis (CrCl <2 mL/min), compared to healthy volunteers (CrCl >80 mL/min). AUC of the microbiologically inactive open-ring metabolite was also significantly increased in patients with impaired renal function. Dose adjustment is recommended for patients with moderate and severe renal impairment.

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 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 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 receiving doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg demonstrated Cmax values approaching those observed in adults after 500 mg, 1000 mg, and 2000 mg doses, respectively. Comparison revealed pharmacokinetic characteristics between doses and t1/2 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 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 the simultaneously measured plasma levels, although considerable inter-individual variability is observed.

Pharmacokinetics of meropenem in neonates receiving antibacterial treatment demonstrated higher clearance in neonates with greater chronological or gestational age, with a mean overall t1/2 of 2.9 hours. Monte Carlo simulations based on the population PK model showed that with a dosing regimen of 20 mg/kg every 8 hours, T>MIC of 60% against Pseudomonas aeruginosa was achieved in 95% of preterm neonates and 91% of term neonates.

Elderly patients

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

Clinical characteristics.

Indications.

Treatment of 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.

The medicinal product MEROPENEM-MB can be used for the treatment of patients with neutropenia and fever suspected of bacterial infection.

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

When prescribing the drug, it is necessary to follow official recommendations regarding the appropriate use of antibacterial agents.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the drug.

Hypersensitivity to any other antibacterial agent of the carbapenem group.

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

Interaction with other medicinal products and other types of interactions.

Studies 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 used concomitantly with meropenem.

The potential effect of the medicinal product MEROPENEM-MB 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, with reductions of approximately 60–100% occurring within about two 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.

Oral anticoagulants

Concomitant use of antibiotics with warfarin may enhance its anticoagulant effect. Increased anticoagulant effect of oral anticoagulants, including warfarin, has frequently been reported 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 predict the impact of antibacterial agents on the increase in international normalized ratio (INR). Frequent monitoring of INR levels 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 suitable antibacterial agents, and the risk of selecting for carbapenem-resistant bacterial strains.

Resistance of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species

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

Hypersensitivity reactions

Serious, and occasionally fatal, hypersensitivity reactions have been reported, as with other beta-lactam antibiotics.

Patients with a history of hypersensitivity to carbapenems, penicillins, or other beta-lactam antibiotics may also have increased sensitivity 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 should be taken.

Severe skin adverse reactions such as 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 colitis, including pseudomembranous colitis, associated with antibiotic use have been reported with 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. Discontinuation of meropenem therapy and initiation of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit intestinal peristalsis should not be prescribed.

Seizures

Seizures have been reported rarely during treatment with carbapenems, including meropenem.

Liver function monitoring

Due to the risk of hepatotoxicity (liver function abnormalities with cholestasis and cytolysis) during meropenem therapy, liver function should be carefully monitored.

Use in patients with liver disease: liver function should be closely monitored in patients with pre-existing liver disease during meropenem treatment. Dose adjustment is not required.

Seroconversion 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 is not recommended.

The medicinal product MEROPENEM-MB contains approximately 4.0 mEq of sodium per 1 g dose, which should be taken into account when prescribing the product 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 number.

Animal studies have not shown direct or indirect harmful effects with regard to reproductive toxicity.

As a precautionary measure, it is advisable to avoid using meropenem during pregnancy.

Breastfeeding

It has been reported that a small amount of meropenem passes into human 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 or operating machinery

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

It is recommended to exercise particular caution when driving or operating machinery, as headache, paresthesia, or seizures have been reported during meropenem therapy.

Dosage and Administration.

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 pathogen, severity of the infection, and the patient's response to therapy.

The medicinal product MEROPENEM-MB, when administered at a dose of up to 2 g three times daily in adults and children with body weight over 50 kg, or 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 species, Pseudomonas aeruginosa, Acinetobacter), or in cases of severe infections.

Additional dosage recommendations must be followed when treating patients with renal impairment (see Table 2).

Table 2

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

The medicinal product MEROPENEM-MB is usually administered as an intravenous infusion lasting from 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 a 2 g dose as an intravenous bolus injection in adults are limited.

Renal impairment

Recommended doses of the drug for adults and children with body weight above 50 kg are shown in Table 3.

Table 3

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

Data supporting the use of the doses of the drug indicated in Table 3, adjusted to a single dose of 2 g, 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 regimens for patients undergoing peritoneal dialysis.

Hepatic impairment

Dosage adjustment of the drug is not required for patients with hepatic impairment.

Dosing in elderly patients

Dosage adjustment is not 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 use in children under 3 months of age, therefore the optimal dosing regimen has not been established. Limited pharmacokinetic data support the use of a meropenem dose of 20 mg/kg every 8 hours (see section "Pharmacokinetics").

Recommended doses of the drug for children aged from 3 months to 11 years with body weight less than 50 kg are presented in Table 4.

Table 4

Recommended doses of the drug for children aged from 3 months to 11 years with body weight less than 50 kg

Children with body weight above 50 kg

The dose for adult patients should be used.

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

Method of administration

The medicinal product MEROPENEM-MB is usually administered as an intravenous infusion lasting from 15 to 30 minutes. In addition, 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 MEROPENEM-MB 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 temperatures 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 microbial contamination, the medicinal product should be used immediately.

If the medicinal product is not used immediately, the storage time 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 MEROPENEM-MB in 0.9% sodium chloride solution for infusion or in 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 24 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 microbial contamination, the medicinal product should be used immediately. If the medicinal product is not used immediately, the storage time and conditions of the prepared solution should be carefully controlled.

The MEROPENEM-MB solution prepared with 5% glucose (dextrose) solution should be used immediately.

Prepared solutions should not be frozen.

If the medicinal product is not used immediately, the physician is responsible for the storage time and conditions after preparation.

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

Children

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

Overdose

Relative overdosage 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 suggests that if adverse reactions occur after overdosage, they are consistent with the profile of the described adverse reactions and 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.

Hemodialysis removes meropenem and its metabolites from the body.

Adverse reactions

The most commonly reported adverse reactions in 4872 out of 5026 patients who received meropenem 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 administration were thrombocytosis (1.6%) and elevated liver enzymes (1.5–4.3%).

In the table 5 below, all adverse reactions are listed 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 group, adverse reactions are listed in order of decreasing severity.

Table 5

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Incompatibilities.

The medicinal product MEROPENEM-MB must not be mixed with or added to other medicinal products.

MEROPENEM-MB intended for intravenous bolus injections 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 vial or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer.

REMEDINA SA

REMEDINA SA

Manufacturer's address and place of business.

Gounari 23 & Areos, Kamatero Attiki, 13451, Greece

Gounari 23 & Areos, Kamatero Attiki, 13451, Greece

Marketing Authorization Holder.

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of the Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom