Meropenem

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MELOPENEM (MEROPENEM)

Composition:

active substance: meropenem;

1 vial contains meropenem (as meropenem trihydrate) 500 mg;

1 vial contains meropenem (as meropenem trihydrate) 1000 mg;

excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder ranging from white to slightly yellowish.

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 Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

As with other β-lactam antibacterial agents, the duration of time during which the concentration of meropenem exceeds the minimum inhibitory concentration (MIC) shows a high degree of correlation 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.

Bacterial resistance to meropenem may develop due to:

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

In the European Union, outbreaks of infection caused by bacteria resistant to carbapenems have been reported.

Cross-resistance between meropenem and medicinal products belonging to the classes of quinolones, aminoglycosides, macrolides, and tetracyclines, with respect to the 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).

MIC breakpoint values were defined during clinical studies by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Table 1

1The susceptibility 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 breakpoints are very rare or have not been reported to date. Testing for identification and antimicrobial susceptibility of any such isolate must be repeated, and if the result is confirmed, the isolate should be referred to a reference laboratory. Until clinical outcome data are available for verified isolates with MICs exceeding current resistance breakpoints (indicated in italics), isolates should be reported as resistant.

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

4Breakpoints apply only to meningitis.

5Non-species-related breakpoints have been primarily established based on PK/PD data and are independent of 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 at 1000 mg three times daily by intravenous infusion over 30 minutes as the lowest dose. Doses of 2 g three times daily were considered for severe infections and for intermediate/resistant breakpoints.

6β-lactam susceptibility of Groups 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 this agent. 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 data on microbial resistance should be taken into account, especially when treating severe infections. Where necessary, if the local prevalence of resistance is such that the benefit of using the medicinal product is at least questionable for certain types of infections, expert consultation should be sought.

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

Usually 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 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.

Intrinsically 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 volunteers, the mean plasma elimination half-life (t½) is approximately 1 hour; the mean volume of distribution is approximately 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 as 30-minute infusions, mean peak plasma concentrations (C_max) were approximately 23, 49, and 115 µg/mL, respectively, and corresponding area under the concentration-time curve (AUC) values were 39.3, 62.3, and 153 µg×h/mL. After 5-minute infusions, C_max values were 52 and 112 µg/mL for 500 and 1000 mg doses, respectively. With multiple dosing every 8 hours in patients with normal renal function, no accumulation of meropenem was observed.

In a study involving 12 patients who received meropenem 1000 mg every 8 hours after surgery for intra-abdominal infections, C_max and t½ values were similar to those in healthy volunteers, but the volume of distribution (27 L) was higher.

Distribution. Plasma protein binding of meropenem averages approximately 2% and is independent of drug concentration. Following rapid administration (5 minutes or less), the pharmacokinetics are biexponential, but this is much less pronounced 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 β-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.

Elimination. 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. Renal clearance and the effect of probenecid indicate that meropenem undergoes both glomerular filtration and tubular secretion.

Renal impairment. Impaired renal function leads to increased plasma AUC and prolonged t½ of 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 ring-opened 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 CrCl during hemodialysis approximately 4 times higher than in anuric patients.

Hepatic impairment. Studies in patients with alcoholic cirrhosis of the liver 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 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 patient 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. A pharmacokinetic relationship between dose and t½ similar to that observed in adults was confirmed, except in the youngest patients (<6 months, t½ 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 as meropenem and an additional 12% as metabolite within 12 hours. Cerebrospinal fluid concentrations of meropenem in children with meningitis are approximately 20% of the simultaneously measured plasma concentration, although there is considerable inter-individual variability.

Pharmacokinetics of meropenem in neonates receiving antibacterial treatment demonstrated higher clearance in neonates with greater chronological or gestational age, with a mean overall t½ of 2.9 hours. Monte Carlo simulation based on a population pharmacokinetic model showed 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 elderly healthy volunteers (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, except in cases of moderate to severe renal impairment.

Clinical characteristics.

Indications.

Meropenem 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.

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 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 β-lactam antibacterial agents (e.g., penicillins or cephalosporins).

Interaction with other medicinal products and other forms of interaction.

Drug interaction studies 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, resulting in an increased half-life (t½) and elevated 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 plasma protein binding is 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 2 days. Due to the rapid onset and extent of this reduction, concomitant administration of valproic acid and carbapenems is considered non-adjustable and should therefore 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 orally administered anticoagulants, including warfarin, in patients receiving antibacterial agents concomitantly. The risk may vary depending on the underlying infection, age, and general condition of the patient, making it difficult to assess the exact contribution of antibacterial agents to increased INR (International Normalized Ratio) levels. 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 suitable 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. Local resistance patterns of these bacteria to penems should be considered when prescribing the drug.

Hypersensitivity reactions. As with other β-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 β-lactam antibiotics may also be at increased risk of hypersensitivity to meropenem. A thorough patient history regarding previous hypersensitivity reactions to β-lactam antibiotics should be obtained before 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 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 therapy (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 remain vigilant for patients who develop diarrhea during or after treatment with meropenem. Consideration should be given to discontinuing meropenem therapy and initiating specific treatment directed against Clostridium difficile. Medicinal products that inhibit intestinal peristalsis 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 hepatic disease: liver function should be closely monitored in patients with pre-existing liver disease during meropenem therapy. Dose adjustment is not required (see section «Dosage and administration»).

Seroconversion in the direct antiglobulin test (Coombs test). Treatment with meropenem may result in a positive direct and/or indirect Coombs test.

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

Meropenem 500 mg: this medicinal product contains 45 mg of sodium per 500 mg vial, equivalent to 2.25% of the maximum daily sodium intake for an adult (2 g) recommended by WHO.

Meropenem 1000 mg: 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 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 reproductive toxicity. As a precautionary measure, it is advisable to avoid the use of meropenem during pregnancy.

Breastfeeding. It is unknown whether 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.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted.

When driving vehicles or operating machinery, caution is recommended due to the possibility of headache, paresthesia, or seizures, which have been reported during meropenem therapy.

Method of administration and dosage.

The general dosage recommendations for the medicinal product are provided in Tables 2–4 below.

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

Meropenem 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 species) or in cases of severe infections.

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

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

Table 2

Meropenem 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 on the administration of 2 g meropenem as an intravenous bolus injection in adults are limited.

Renal impairment.

Recommended doses of the drug for adults and children weighing over 50 kg

with creatinine clearance less than 51 ml/min

Table 3

Data on the use of the doses of the drug indicated in Table 3, adjusted to the 2 g dose unit, are limited.

Meropenem is removed 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 for patients undergoing peritoneal dialysis.

Hepatic impairment. Dose adjustment of the drug is not required in patients with hepatic impairment (see section «Special precautions»).

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. Limited pharmacokinetic data support the use of a meropenem dose of 20 mg/kg every 8 hours (see section «Pharmacokinetics»).

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

Table 4

Children with body weight over 50 kg. The dose should be used as for adult patients. There is no experience with use of the drug in children with renal impairment.

Administration method.

Meropenem is usually administered as an intravenous infusion over 15 to 30 minutes. Alternatively, meropenem doses 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 Meropenem medicinal product 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 room temperature (15–25 °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 Meropenem medicinal product 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 for 24 hours under refrigerated conditions (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 time and conditions of the prepared solution should be carefully controlled.

The prepared meropenem solution with 5% glucose (dextrose) should be used immediately.

Prepared solutions should not be frozen.

Children.

The drug 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 drug is not adjusted as described in the section «Administration and dosage». Limited post-marketing experience suggests that adverse reactions occurring after overdosage are consistent with the profile of the specified adverse reactions described in the section «Adverse reactions», and usually manifest in mild form and resolve after discontinuation of the drug or dose reduction. Symptomatic treatment should be considered.

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

Meropenem and its metabolites are removed from the body during hemodialysis.

Adverse reactions

The most common 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 common laboratory abnormalities were thrombocytosis (1.6%) and elevated liver enzymes (1.5–4.3%).

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 (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated based on available data).

Within each 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 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 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 indicating 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 of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Freshly prepared solutions of Meropenem for intravenous injection and infusion are recommended.

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

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

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

Packaging. 500 mg or 1000 mg powder in vials. 1, 10, or 50 vials per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lechem-Kharkiv".

Manufacturer's address and location of operations.

36 Severin Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.