Mepenam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEPENAM (MEPENAM)

Composition:

Active substance: meropenem;

1 vial contains meropenem trihydrate equivalent to meropenem – 0.5 g or 1.0 g;

Excipient: anhydrous sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group. Antimicrobial 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 concentrations (MICs) (T>MIC) has been shown to correlate highly with efficacy. Preclinical data indicate that meropenem demonstrates 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 develop due to: reduced permeability of the outer membrane of Gram-negative bacteria (due to decreased porin production), reduced affinity for target PBPs, increased expression of efflux pump components, and production of beta-lactamases capable of hydrolyzing carbapenems.

Cases of infections caused by bacteria resistant to carbapenems have been reported.

There is no cross-resistance between meropenem and medicinal products belonging to the classes of quinolones, aminoglycosides, macrolides, and tetracyclines, with respect to the target microorganisms. However, bacteria may exhibit resistance to more than one class of antibacterial agents when the mechanism involved includes membrane impermeability or the presence of efflux pump(s).

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

Table 1

Microorganism	Susceptible (S), (mg/l)	Resistant (R), (mg/l)
Enterobacteriaceae	≤ 2	> 8
Pseudomonas	≤ 2	> 8
Acinetobacter	≤ 2	> 8
Streptococcus, groups A, B, C, G	≤ 2	> 2
Streptococcus pneumoniae1	≤ 2	> 2
Other streptococci	2	2
Enterococcus
Staphylococcus2	Note 3	Note 3
Haemophilus influenzae1 and Мoraxella catarrhalis	≤ 2	> 2
Neisseria meningitidis2,4	≤ 0.25	> 0.25
Gram-positive anaerobes	≤ 2	> 8
Gram-negative anaerobes	≤ 2	> 8
Non-species related breakpoints5	≤ 2	> 8

1The breakpoint values of meropenem for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25 mg/L.

2Strains of microorganisms with MIC values exceeding the S/I breakpoint values are very rare or have not been reported to date. 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. Until data on clinical response for verified isolates with MIC values above the current resistance breakpoints become available, isolates should be reported as resistant.

3Susceptibility of staphylococci to meropenem is predicted based on methicillin susceptibility data.

4Meropenem breakpoint values for Neisseria meningitidis apply only to meningitis.

5Non-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.

"–" Susceptibility testing is not recommended, as the organism is a poor target for treatment with this medicinal product.

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. When the local prevalence of resistance is such that the benefit of using the medicinal product, at least for certain types of infections, is questionable, expert consultation should be sought.

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

Typically susceptible species

Gram-positive aerobes: Enterococcus faecalis⁶; Staphylococcus aureus (methicillin-susceptible)⁷; 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^6,8

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.

⁶ Species with inherent intermediate susceptibility.

⁷ All methicillin-resistant staphylococci are resistant to meropenem.

⁸ Resistance rate >50% in one or more EU countries.

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

Data indicate that after administration of 1000 mg meropenem every 8 hours to patients following surgery for intra-abdominal infections, Cmax and elimination half-life values correspond to those in healthy individuals, but with a larger volume of distribution (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 penetrates 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 co-administration with a DHP-I inhibitor is not required.

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 increases by a factor of 2.4 in patients with moderate renal impairment (creatinine clearance (CrCl) 33–74 mL/min), by 5 times in patients with severe renal impairment (CrCl 4–23 mL/min), and by 10 times in patients undergoing hemodialysis (CrCl <2 mL/min), compared to healthy volunteers (CrCl >80 mL/min). AUC values of the microbiologically inactive open-ring metabolite are also significantly higher in patients with renal impairment. 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. Data indicate no influence of liver disease on the pharmacokinetics of meropenem after repeated dosing.

Children. Pharmacokinetic data in children (including infants) with infection show that after doses of 10, 20, and 40 mg/kg, Cmax values approach those observed in adults after 500, 1000, and 2000 mg doses, respectively. Mean meropenem clearance values are 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 levels, although there is considerable inter-individual variability.

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 population pharmacokinetic modeling 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 data in healthy elderly volunteers (65–80 years) indicate 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 in elderly patients unless moderate or severe renal impairment is present.

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 and/or to any of the excipients of the medicinal product, and/or to any other antibacterial agent of the carbapenem class.

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

Interaction with other medicinal products and other forms of interaction.

Studies on interaction of the drug with other 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 prolonged elimination half-life and increased plasma concentration of meropenem. Caution should be exercised when probenecid is administered concomitantly with meropenem.

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

Decreased serum levels of valproic acid have been reported when co-administered with carbapenems. This reduction, which may occur within approximately two days, ranges from 60–100%. 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.

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 antibacterial agents concomitantly. The risk may vary depending on the underlying infection, age, and general condition of the patient. Thus, it is difficult to assess the exact contribution of antibacterial agents to increased 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 suitable antibacterial agents, and the risk of selecting 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.

Serious, and sometimes 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 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, the drug should be discontinued immediately and appropriate measures should be instituted.

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

Colitis associated with antibiotic use, including pseudomembranous colitis, has been reported with the use of nearly all antibacterial agents, including meropenem, with severity ranging from mild to life-threatening. Therefore, this diagnosis should be considered in patients who develop diarrhea during or after meropenem therapy. Discontinuation of meropenem and initiation of specific therapy directed against Clostridium difficile should be considered. Medicinal products that suppress gastrointestinal motility should not be administered.

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

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

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

Meropenem therapy may result in a positive direct or indirect Coombs test.

Concomitant administration of meropenem and valproic acid/sodium valproate is not recommended.

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

Use during pregnancy or breastfeeding

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

Available preclinical data indicate no direct or indirect effects of reproductive toxicity. As a precautionary measure, it is advisable to avoid using meropenem during pregnancy.

It has been reported that a small amount of meropenem is excreted 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 influence of the drug on the ability to drive vehicles or operate machinery have not been conducted.

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

Dosage and Administration.

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 individual patient sensitivity.

Meropenem 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 suitable for the treatment of certain types of infections, such as hospital-acquired infections caused by Pseudomonas aeruginosa or Acinetobacter spp.

Table 2

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

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

Meropenem should usually be administered as an intravenous infusion over 15 to 30 minutes.

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

Renal impairment.

Table 3

Recommended doses of the drug for adults and children weighing more than 50 kg with creatinine clearance less than 51 ml/min

Creatinine clearance (ml/min)	Single dose (see Table 2)	Frequency
26-50	full single dose	every 12 hours
10-25	half the single dose	every 12 hours
<10	half the single dose	every 24 hours

Data supporting the use of the doses of the drug indicated in Table 3, adjusted per 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 for patients with hepatic impairment.

Dosing for elderly patients. Dose adjustment is not required for elderly patients with normal renal function or with creatinine clearance values above 50 mL/min.

Table 4

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

Infection	Single dose administered every 8 hours
Pneumonia, including community-acquired and hospital-acquired	10 or 20 mg/kg body weight
Bronchopulmonary 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

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

Mepenam is usually administered as an intravenous infusion over 15 to 30 minutes. Additionally, doses of meropenem up to 20 mg/kg may be given 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.

Children with body weight over 50 kg. The dose should be the same as for adult patients.

Administration of intravenous bolus injection. The solution for bolus injection should be prepared by dissolving the Mepenam medicinal product in water for injections to obtain a concentration of 50 mg/ml (20 ml per 1 g of meropenem).

Chemical and physical stability of the prepared bolus injection solution was maintained for 3 hours at room temperature (15–25 °C). However, from a microbiological standpoint, the medicinal product should be used immediately.

If the medicinal product is not used immediately, responsibility for the storage duration and conditions after preparation lies with the physician.

Administration of intravenous infusion. The infusion solution should be prepared by dissolving the Mepenam 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 is maintained for 6 hours at room temperature (15–25 °C) or for 24 hours at 2–8 °C. The prepared solution, if cooled, should be used within 2 hours after removal from the refrigerator. From a microbiological standpoint, the medicinal product should be used immediately. If the medicinal product is not used immediately, responsibility for the storage duration and conditions after preparation lies with the physician.

The prepared Mepenam solution using 5% glucose (dextrose) solution should be used immediately, i.e., within 1 hour after preparation.

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.

Freshly prepared solutions are recommended.

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 dose of the drug is not adjusted as described in the section "Administration and dosage." Limited post-marketing experience indicates that if adverse reactions occur after overdose, they are consistent with the profile of the specified side effects 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 the review of data from 4872 out of 5026 patients regarding the impact of meropenem treatment, the most commonly 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 frequently reported laboratory-related adverse phenomena associated with meropenem use were thrombocytosis (1.6%) and elevated liver enzyme levels (1.5–4.3%).

In the table 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.

System organ class	Frequency	Adverse reaction
Infections and infestations	Uncommon	Oral and vaginal candidiasis.
Blood and lymphatic system disorders	Common	Thrombocytosis.
	Uncommon	Eosinophilia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia.
Immune system disorders	Uncommon	Angioneurotic edema, anaphylactic reaction.
Nervous system disorders	Common	Headache.
	Uncommon	Paraesthesia.
	Rare	Seizures.
Gastrointestinal disorders	Common	Diarrhea, vomiting, nausea, abdominal pain.
	Uncommon	Antibiotic-associated colitis.
Hepatobiliary disorders	Common	Elevated transaminase levels, elevated alkaline phosphatase levels in blood, elevated lactate dehydrogenase levels in blood.
	Uncommon	Elevated bilirubin levels in blood.
Skin and subcutaneous tissue disorders	Common	Rash, pruritus.
	Uncommon	Urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
	Frequency unknown	Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis.
Renal and urinary disorders	Uncommon	Elevated creatinine levels in blood, elevated urea levels in blood.
General disorders and administration site conditions	Common	Inflammation, pain.
	Uncommon	Thrombophlebitis, injection site pain.

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 suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions according to applicable legislation.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Incompatibilities.

Meropenem should not be added to or mixed with other medicinal products except those specified in the section "Method of administration and dosage".

Meropenem intended for intravenous bolus injection 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. 0.5 g or 1.0 g of meropenem in a glass vial, stoppered with a rubber stopper and sealed with an aluminum cap with or without a plastic overcap. A self-adhesive label is affixed to the vial.

1 vial per pack;

10 vials per pack;

In vials.

Prescription status. Prescription only.

Manufacturer/Marketing Authorization Holder. JSC "Kyivmedpreparat".

Address of manufacturer and location of its operations / address of marketing authorization holder and/or its representative. 139 Saksaganskogo Street, Kyiv, 01032, Ukraine.