MEROBAK

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

Composition:

Active substance: meropenem;

1 vial contains 570 mg meropenem trihydrate, equivalent to 500 mg anhydrous meropenem;

1 vial contains 1140 mg meropenem trihydrate, equivalent to 1000 mg anhydrous meropenem;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white to light yellow powder.

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

Pharmacological properties.

Pharmacodynamics.

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

Time values during which meropenem concentrations exceeded the minimum inhibitory concentrations (MIC) (T > MIC) indicated a high degree of correlation with efficacy. In preclinical models, meropenem demonstrated activity at plasma concentrations exceeding the MIC for microorganisms for approximately 40% of the dosing interval. This target value has not been clinically established.

Microbial resistance to meropenem.

Microbial resistance to meropenem may occur 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, and 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 target microorganisms. However, bacteria may exhibit resistance to more than one class of antibacterial agents when the mechanism involved includes reduced membrane permeability and/or presence of efflux pump(s).

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

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 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 the result is confirmed, the isolate should be referred to a reference laboratory. Until data on clinical response for verified isolates with MICs above the current resistance breakpoints (indicated in italics) become available, such 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 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.

6Beta-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 among individual species may vary geographically and over time; therefore, local information on microbial resistance should be consulted, especially when treating severe infections. If necessary, when local resistance rates are 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.

The following list of pathogenic microorganisms is based on clinical experience and therapeutic treatment guidelines.

Commonly 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 with potential for acquired resistance

Gram-positive aerobes

Enterococcus faecium^7,9

Gram-negative aerobes

Acinetobacter species

Burkholderia cepacia

Pseudomonas aeruginosa

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 data on human use. Physicians should refer to national and/or international consensus documents regarding the treatment of glanders and melioidosis.

Pharmacokinetics

In healthy individuals, the mean plasma elimination half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 L/kg (11–27 L); the mean clearance is 287 mL/min after a 250 mg dose, decreasing to 205 mL/min after a 2 g dose. After administration of 500, 1000, and 2000 mg doses infused over 30 minutes, mean Cmax values were approximately 23, 49, and 115 µg/mL, respectively; corresponding AUC values were 39.3, 62.3, and 153 µg×h/mL. After 5-minute infusions, Cmax values were 52 and 112 µg/mL for 500 and 1000 mg doses, respectively. With multiple dosing every 8 hours in patients with normal renal function, accumulation of meropenem was not observed.

In a study involving 12 patients who received meropenem 1000 mg every 8 hours after surgery for intra-abdominal infections, Cmax and elimination half-life values were consistent with those in healthy individuals, but a larger volume of distribution (27 L) was observed.

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 lung, bronchial secretions, bile, cerebrospinal fluid, female genital tract 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 there is no need for concomitant administration of a DHP-I inhibitor.

Excretion

Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50–75%) of the dose is excreted unchanged within 12 hours. An additional 28% is excreted as the microbiologically inactive metabolite. Fecal excretion accounts for only about 2% of the dose. Measured renal clearance and the effect of probenecid indicate that meropenem undergoes both glomerular filtration and tubular secretion.

Renal impairment

Renal dysfunction results in higher plasma AUC values and a prolonged elimination half-life of meropenem. AUC 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 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 and severe renal impairment (see section "Dosage and administration").

Meropenem is removed by hemodialysis, with a clearance during hemodialysis approximately 4 times higher than in anuric patients.

Hepatic impairment

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

Adult patients

Pharmacokinetic studies in patients have not revealed significant pharmacokinetic differences compared to healthy individuals with similar renal function. A population model developed from data in 79 patients with intra-abdominal infection or pneumonia showed dependence of primary 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 Cmax values approaching those in adults after 500, 1000, and 2000 mg doses, respectively. Comparison revealed a dose–half-life relationship similar to that observed in adults, except in the youngest patients (< 6 months: 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 plasma levels, although substantial inter-individual variability exists.

Pharmacokinetics of meropenem 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 PK 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 elderly healthy subjects (65–80 years) showed reduced plasma clearance, correlating with age-related reduction in creatinine clearance, and 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.

Merobak 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;
• obstetrical and postpartum infections;
• complicated skin and soft tissue infections;
• acute bacterial meningitis.

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

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

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Hypersensitivity to any other antibacterial agent of the carbapenem group.

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

Interaction with other medicinal products and other forms of interaction.

Interaction studies with other medicinal products, except probenecid, have not been conducted.

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

The potential impact of meropenem on protein binding or metabolism of other drugs has not been studied. However, since plasma protein binding is minimal, such interactions with other compounds are unlikely.

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

Oral anticoagulants

Concomitant use of antibiotics with warfarin may potentiate its anticoagulant effect. Numerous reports have documented increased anticoagulant effect of oral anticoagulants, including warfarin, in patients receiving antibiotics concomitantly. The risk may vary depending on the type of underlying infection, age, and general condition of the patient, thus making it difficult to assess the exact contribution of antibiotics to the increase in INR (International Normalized Ratio). Frequent monitoring of INR is recommended during and immediately after concomitant use of antibiotics with oral anticoagulants.

Children

All drug interaction studies have been conducted in adult patients only.

Special precautions for use

When selecting meropenem as a therapeutic agent, the following factors should be considered: severity of infection, prevalence of resistance to other appropriate antibacterial agents, and the risk of bacterial resistance to carbapenems.

Resistance in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter

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

Hypersensitivity reactions

Serious, and sometimes fatal, hypersensitivity reactions have been reported with the use of beta-lactam antibiotics (see sections "Contraindications" and "Side effects").

Patients with a history of hypersensitivity to carbapenems, penicillins, or other beta-lactam antibiotics may also have increased sensitivity to meropenem. A careful patient history regarding previous hypersensitivity reactions to beta-lactam antibiotics should be obtained prior to initiating therapy with meropenem.

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

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

Hypersensitivity reactions progressing to Kounis syndrome (acute allergic coronary artery spasm), which may lead to myocardial infarction, have been reported with other beta-lactam antibiotics (see section "Side effects").

Antibiotic-associated colitis

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

Seizures

Seizures have been rarely reported during treatment with carbapenems, including meropenem (see section "Side effects").

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 "Side effects").

Use in patients with hepatic impairment: liver function should be closely monitored in patients with liver disease during meropenem therapy. Dose adjustment is not required (see section "Method of administration and dosage").

Serum conversion in direct antiglobulin test (Coombs test)

Treatment with meropenem may result in a positive direct and/or indirect Coombs test.

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

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

Use during pregnancy or breastfeeding.

Pregnancy

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

Animal studies have not shown direct or indirect effects of reproductive toxicity. It is advisable to avoid the use of 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 influence of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted.

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

Dosage and Administration

Dosage

The following are general recommendations for dosing of the medicinal product.

The dose of meropenem and duration of treatment depend on the causative pathogen, severity of the infection, and the patient's response to therapy.

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

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

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

Table 1

Merobact should usually be administered as an intravenous infusion lasting from
15 to 30 minutes.

Additionally, doses of the drug up to 1 g may be given as an intravenous bolus injection over approximately 5 minutes. Data supporting the safety of administering a 2 g dose of the drug as an intravenous bolus injection to adults are limited.

Renal impairment

Recommended doses for adults and children with body weight of 50 kg or more,
in whom creatinine clearance is less than 51 ml/min

Table 2

Data supporting the use of doses of the drug indicated in Table 2, 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 of the drug 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 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 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 below 50 kg

Table 3

Children with body weight of 50 kg

The dose should be used as for adult patients.

There is no experience with the use of the medicinal product in children with renal impairment.

Method of administration

Merobact is usually 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. Data supporting the safety of administering the drug as an intravenous bolus injection at a dose of 40 mg/kg in children are limited.

Administration of intravenous bolus injection

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

Chemical and physical stability of the prepared bolus injection solution is maintained for 3 hours at a temperature up to 25 °C or for 12 hours at 2–8 °C (in the refrigerator).

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

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

Administration of intravenous infusion

The infusion solution should be prepared by dissolving the Merobact 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 3 hours at 25 °C or for 24 hours at 2–8 °C (in the refrigerator). From a microbiological point of view, the medicinal product should be used immediately. If the medicinal product is not used immediately, the physician is responsible for the duration and conditions of storage.

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

Prepared solutions should not be frozen.

Children

The medicinal product is indicated for use in children aged 3 months and older.

Overdose

Relative overdose is possible in patients with renal impairment 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 adverse reactions (see section "Adverse reactions") and are generally mild and resolve after discontinuation or dose reduction of the drug. Symptomatic treatment should be considered as necessary.

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

Haemodialysis removes meropenem and its metabolites from the body.

Adverse reactions.

In clinical trials involving 4872 patients, the most commonly reported adverse reactions associated with meropenem administration were diarrhea (2.3%), rash (1.4%), nausea/vomiting (1.4%), injection site inflammation (1.1%), thrombocytosis (1.6%), and elevated liver enzymes (1.5–4.3%).

Below is a list of adverse reactions 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 from available data). Within each frequency grouping, 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: eosinophilia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia.

Immune system disorders. Uncommon: angioedema, anaphylactic reaction (see sections "Contraindications" and "Special warnings and precautions for use").

Nervous system disorders. Common: headache; uncommon: paresthesia; rare: seizures (see section "Special warnings and precautions for use").

Psychiatric disorders. Rare: delirium.

Gastrointestinal disorders. Common: diarrhea, vomiting, nausea, abdominal pain; 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 blood bilirubin levels.

Skin and subcutaneous tissue disorders. Common: rash, pruritus; uncommon: urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme (see section "Special warnings and precautions for use"); frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), 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.

Description of selected adverse reactions

Kounis syndrome

Cases of acute coronary syndrome associated with allergic reaction (Kounis syndrome) have been reported with other beta-lactam antibiotics (see section "Contraindications").

Children

Merobact is approved for use in children aged 3 months and older. Based on limited available data, there is no evidence of increased risk of any adverse reactions in pediatric patients. All reported events corresponded to adverse reactions observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life. 4 years.

Each vial is for single use only.

Standard aseptic techniques should be used during reconstitution and administration.

The solution should be shaken before use.

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

Storage conditions.

Store at a temperature not exceeding 30 °C. Keep out of reach of children.

Incompatibilities. Merobact must not be mixed or added to other medicinal products.

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

Merobact 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 glass vials; 1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer.

ACS DOBFAR S.P.A.

Manufacturer's address and location of operations.

NUCLEO INDUSTRIALE S. ATTO (LOC. S. NICOLÒ A TORDINO), 64100 TERAMO (TE), Italy.

Date of last review.