LENALIDOL

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

Composition

active substance: meropenem; 1 vial contains meropenem trihydrate 570 mg, which corresponds to 500 mg of anhydrous meropenem; 1 vial contains meropenem trihydrate 1140 mg, which corresponds to 1000 mg of anhydrous meropenem; excipient: sodium carbonate.

Pharmaceutical Form

Powder for solution for injection.

Main Physical and Chemical Properties

Powder from white to light yellow in color.

Pharmacotherapeutic Group

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

Pharmacological Properties

Pharmacodynamics

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

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

Bacterial Resistance to Meropenem

Bacterial resistance to meropenem may occur as a result of: decreased permeability of the outer membrane of gram-negative bacteria (due to decreased production of porins), decreased affinity for target PBPs, increased expression of efflux pump components, and production of beta-lactamases that can hydrolyze carbapenems.

In the European Union, foci of infection caused by carbapenem-resistant bacteria have been registered.

Cross-resistance between meropenem and medicinal products belonging to the classes of quinolones, aminoglycosides, macrolides, and tetracyclines, taking into account the target microorganisms, is absent. However, bacteria may exhibit resistance to more than one class of antibacterial agents in cases where the mechanism of action involves membrane impermeability and/or the presence of an efflux pump(s).

Limiting Values of MIC

1The limiting values of meropenem for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25 mg/L (sensitive) and 1 mg/L (resistant).

2Strains of microorganisms with MIC values higher than the limiting values of S/R are very rare or have not been reported to date. Analyses for the identification and antimicrobial susceptibility of any such isolate should be repeated, and if the result is confirmed, the isolate should be sent to an expert laboratory. Until there is data on clinical response for verified isolates with MIC values higher than the current limiting values of resistance (indicated in italics), isolates should be registered as resistant.

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

4The limiting values apply only to meningitis.

5The limiting values not related to species of microorganisms were determined mainly based on PK/PD data and do not depend on the distribution of MIC of individual species. They are intended for use in relation to species not specified in the table and footnotes. The limiting values not related to species are based on such doses: EUCAST limiting values apply to meropenem at a dose of 1000 mg three times a day intravenously for 30 minutes as the lowest dose. Doses of 2 g three times a day were considered for severe infections and for intermediate/resistant limiting values.

6Beta-lactam susceptibility of streptococcal groups A, B, C, and G is predicted based on susceptibility to penicillin.

"-" Analysis to determine susceptibility is not recommended, as the species is a poor target for treatment with the agent. Isolates can be determined as resistant without prior testing.

The prevalence of acquired resistance for individual species may vary geographically and over time, so it is desirable to rely on local information about the resistance of microorganisms, especially when treating severe infections. If necessary, when the level of prevalence of resistance of microorganisms at the local level is such that the benefit of using the medicinal product, at least with regard to some types of infections, is in doubt, it is recommended to consult an expert.

Pharmacokinetics

In healthy individuals, the mean plasma 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 when the drug is administered at a dose of 250 mg, with a decrease in clearance to 205 mL/min when the drug is administered at a dose of 2 g. When the drug is administered at doses of 500, 1000, and 2000 mg, which are infused over 30 minutes, the mean Cmax values are approximately 23, 49, and 115 μg/mL, respectively; the corresponding AUC values are 39.3, 62.3, and 153 μg × hour/mL. After infusion over 5 minutes, the Cmax values are 52 and 112 μg/mL when the drug is administered at doses of 500 and 1000 mg, respectively. When multiple doses of the drug are administered every 8 hours to patients with normal renal function, no accumulation of meropenem is observed.

In a study involving 12 patients who received meropenem at a dose of 1000 mg every 8 hours after undergoing surgery for intra-abdominal infections, Cmax and half-life values were found that corresponded to those in healthy individuals, but with a larger volume of distribution (27 L).

Distribution

The mean value of meropenem binding to plasma proteins is approximately 2% and does not depend on the concentration of the drug. After rapid administration of the drug (5 minutes or less), the pharmacokinetics are bi-exponential, but this is much less evident after 30-minute infusion. It has been found that meropenem penetrates well into some fluids and tissues of the body, including the lungs, bronchial secretions, bile, cerebrospinal fluid, female genital tissues, skin, fascia, muscles, and peritoneal exudates.

Metabolism

Meropenem is metabolized by hydrolysis of the beta-lactam ring, forming a microbiologically inactive metabolite. In vitro, meropenem has been shown to have reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, and there is no need for concomitant use 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. Another 28% is excreted as a 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 filtration and tubular secretion.

Renal Insufficiency

Impaired renal function leads to high plasma concentrations of meropenem and a longer half-life. An increase in AUC values was observed in patients with moderate renal impairment (creatinine clearance (CC) 33-74 mL/min) by 2.4 times, in patients with severe renal impairment (CC 4-23 mL/min) by 5 times, and in patients on hemodialysis (CC <2 mL/min) by 10 times compared to healthy individuals (CC >80 mL/min). The AUC values of the microbiologically inactive metabolite with an open ring also increased significantly in patients with impaired renal function. Dose adjustment of the drug is recommended for patients with moderate and severe renal impairment (see "Method of administration and dosage").

Meropenem is excreted by hemodialysis with a clearance that is approximately 4 times higher than in patients with anuria.

Hepatic Insufficiency

A study involving patients with alcoholic liver cirrhosis showed no effect of liver disease on the pharmacokinetics of meropenem after repeated doses of the drug.

Adult Patients

Pharmacokinetic studies conducted in patients did not reveal significant pharmacokinetic differences compared to healthy individuals with similar renal function. A population model developed based on data from 79 patients with intra-abdominal infection or pneumonia showed a dependence of the main volume on body weight, creatinine clearance, and age.

Children

Pharmacokinetic studies in infants and children with infection after administration of the drug at doses of 10, 20, and 40 mg/kg demonstrated Cmax values similar to those in adults after administration of the drug at doses of 500, 1000, and 2000 mg, respectively. A comparison showed a dependence between the dose of the drug and the half-life similar to that observed in adults, in all patients except the youngest (<6 months, 1.6 hours). The mean clearance values of meropenem 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 the urine within 12 hours as meropenem and another 12% as a metabolite. Meropenem concentrations in cerebrospinal fluid in children with meningitis are approximately 20% of the levels in plasma, although there is significant intersubject variability in the indicators.

Elderly Patients

Pharmacokinetic studies in healthy elderly individuals (65-80 years) showed a decrease in plasma clearance, which correlates with the age-related decrease in creatinine clearance, as well as a slight decrease in non-renal clearance. Dose adjustment of the drug is not required for elderly patients, except in cases of moderate and severe renal impairment.

Clinical Characteristics

Indications

Merobac is indicated for the treatment of the following infections in adults and children aged 3 months and older:

• pneumonias, including non-hospital and hospital pneumonias;
• broncholegenerative 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.

Merobac can be used to treat patients with neutropenia and fever suspected to be caused by bacterial infection.

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

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

Contraindications

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

Hypersensitivity to any other antibacterial agent of the carbapenem group.

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

Interaction with Other Medicinal Products and Other Types of Interactions

Studies on the interaction of the drug with other medicinal products, except for probenecid, have not been conducted.

Probenecid competes with meropenem for active tubular excretion and thereby inhibits the renal excretion of meropenem, leading to an increase in the half-life and an increase in meropenem concentrations in the plasma. Caution should be exercised when co-administering probenecid with meropenem.

The potential impact of meropenem on the binding of other drugs to plasma proteins or metabolism has not been studied. However, the binding to plasma proteins is so low that a similar interaction with other compounds is not expected.

When co-administered with carbapenems, a decrease in valproate levels in the blood has been reported, resulting in a decrease in valproate levels of approximately 60-100% within 2 days. Due to the rapid onset of action and the significant degree of decrease in valproate levels, concomitant use of valproic acid/valproate sodium/valpromide and carbapenems is considered uncorrectable, so such interaction should be avoided (see "Special warnings and precautions for use").

Oral anticoagulants

Concomitant use of antibiotics with warfarin may enhance its anticoagulant effect. Many reports have been received about an increased anticoagulant effect of oral anticoagulant drugs, including warfarin, in patients who are also receiving antibacterial agents. The risk may vary depending on the type of underlying infection, age, and overall condition of the patient, so the contribution of antibacterial agents to increased INR (International Normalized Ratio) levels is difficult to assess. Frequent monitoring of INR is recommended during and immediately after concomitant use of antibiotics with oral anticoagulants.

Children

All studies of drug interactions were conducted only in adult patients.

Special Warnings and Precautions for Use

When choosing meropenem as a treatment, the following factors should be taken into account, such as the severity of the infection, the prevalence of resistance to other relevant antibacterial agents, and the risk of resistance of bacteria to carbapenems.

Resistance to Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter

In the European Union, resistance to penems of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter varies. When prescribing the drug, it is recommended to take into account the local resistance of these bacteria to penems.

Hypersensitivity Reactions

Serious, sometimes life-threatening hypersensitivity reactions have been reported with the use of beta-lactam antibiotics (see "Contraindications" and "Adverse reactions").

Patients who have a history of hypersensitivity to carbapenems, penicillins, or other beta-lactam antibiotics may also be hypersensitive to meropenem. A thorough inquiry about previous hypersensitivity reactions to beta-lactam antibiotics should be conducted before starting meropenem therapy.

In the event of a severe allergic reaction, the use of the drug should be discontinued and appropriate measures taken.

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

Hypersensitivity reactions that progress to Kounis syndrome (acute allergic coronary artery spasm) have been reported with the use of other beta-lactam antibiotics, which can lead to myocardial infarction (see "Adverse reactions").

Antibiotic-Associated Colitis

Almost all antibacterial agents, including meropenem, have been associated with antibiotic-associated colitis and pseudomembranous colitis, which can range in severity from mild to life-threatening. Therefore, it is essential to consider this diagnosis in patients who develop diarrhea during or after the use of meropenem (see "Adverse reactions"). The use of meropenem should be discontinued, and specific treatment directed against Clostridium difficile should be initiated. Drugs that suppress intestinal motility should not be prescribed.

Seizures

Seizures have been rarely reported during treatment with carbapenems, including meropenem (see "Adverse reactions").

Liver Function Monitoring

Due to the risk of developing liver toxicity (liver dysfunction with cholestasis and cytolysis) during meropenem treatment, liver function should be carefully monitored (see "Adverse reactions").

Use in Patients with Liver Disease

During meropenem treatment in patients with liver disease, liver function should be carefully monitored. Dose adjustment of the drug is not required (see "Method of administration and dosage").

Direct Antiglobulin Test (Coombs' Test) Seroconversion

Meropenem therapy may cause a positive direct/indirect Coombs' test.

Concomitant Use of Meropenem and Valproic Acid/Valproate Sodium/Valpromide

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

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

Use During Pregnancy or Breastfeeding

Pregnancy

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

Animal studies have not revealed any direct or indirect reproductive toxicity effects. It is recommended to avoid the use of meropenem during pregnancy.

Breastfeeding

It has been reported that a small amount of meropenem penetrates human breast milk. Meropenem can be used during lactation only if the expected benefit to the mother outweighs the potential risk to the child.

Ability to Affect the Speed of Reaction When Driving Vehicles or Operating Other Mechanisms

Studies on the effect of the medicinal product on the ability to drive vehicles or work with mechanisms have not been conducted.

When driving a vehicle or operating other mechanisms, it is recommended to exercise particular caution, taking into account the possibility of developing headache, paresthesia, or seizures, which have been reported with the use of meropenem.

Method of Administration and Dosage

Dosage

The following are general recommendations for dosing the medicinal product.

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

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

Special recommendations for dosing in patients with renal impairment should be followed (see below).

Renal Impairment

Data confirming the use of the doses of the drug adjusted for a unit dose of 2 g are limited.

Meropenem is excreted by hemodialysis and hemofiltration, so the necessary dose of the drug should be administered after the hemodialysis procedure.

There are no recommendations for the established dose of the medicinal product for patients undergoing peritoneal dialysis.

Hepatic Impairment

For patients with hepatic impairment, dose adjustment of the drug is not required (see "Special warnings and precautions for use").

Dosage for Elderly Patients

For elderly patients with normal renal function or with creatinine clearance values above 50 mL/min, dose adjustment is not required.

Children Under 3 Months

There are no data on the safety and efficacy of meropenem in children under 3 months of age, and the optimal dosing regimen has not been established. There are limited pharmacokinetic data that support the use of a meropenem dose of 20 mg/kg every 8 hours (see "Pharmacokinetics").

Recommended Doses for Children Aged 3 Months to 11 Years with a Body Weight of Up to 50 kg

Children with a body weight of 50 kg or more

The dose for adults should be used.

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

Method of Administration

Merobac is usually administered as an intravenous infusion over 15-30 minutes. In addition, meropenem doses of up to 20 mg/kg can be administered as an intravenous bolus injection over approximately 5 minutes. Data confirming the safety of administering 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 Merobac in water for injection to obtain a concentration of 50 mg/mL.

The chemical and physical stability of the prepared solution for bolus injection is maintained for 3 hours at a temperature of up to 25 °C or for 12 hours at a temperature of 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 must be used immediately.

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

Administration of Intravenous Infusion

The solution for infusion should be prepared by dissolving the medicinal product Merobac 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.

The chemical and physical stability of the prepared solution for infusion using 0.9% sodium chloride solution is maintained for 3 hours at a temperature of 25 °C or for 24 hours at a temperature of 2-8 °C (in the refrigerator). From a microbiological point of view, the medicinal product must be used immediately. If the medicinal product is not used immediately, the responsibility for the storage conditions and shelf life lies with the physician.

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

Prepared solutions should not be frozen.

Overdose

Relative overdose is possible in patients with renal impairment if the dose of the drug is not adjusted as described in the "Method of administration and dosage" section. Limited post-marketing experience with the drug suggests that if undesirable reactions occur after overdose, they are consistent with the adverse reaction profile (see "Adverse reactions") and are generally mild and transient, resolving after discontinuation of the drug or reduction of its dose. The need for symptomatic treatment should be considered.

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

Hemodialysis removes meropenem and its metabolites from the body.

Adverse Reactions

Based on the results of studies, the most common undesirable reactions associated with the use of meropenem in 4872 patients were diarrhea (2.3%), rash (1.4%), nausea/vomiting (1.4%), inflammation at the injection site (1.1%), thrombocytosis (1.6%), and elevated liver enzyme levels (1.5-4.3%).

Below are the adverse reactions, by system 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 from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations. Uncommon: oral and vaginal candidiasis.

Blood and lymphatic system disorders. Common: thrombocytosis; uncommon: eosinophilia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia.

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

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

Psychiatric disorders. Rare: delirium.

Gastrointestinal disorders. Common: diarrhea, vomiting, nausea, abdominal pain; uncommon: colitis, antibiotic-associated colitis (see "Special warnings and precautions for use").

Hepatobiliary disorders. Common: elevated transaminase levels, elevated alkaline phosphatase levels, elevated lactate dehydrogenase levels; uncommon: elevated bilirubin levels.

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

Renal and urinary disorders. Uncommon: elevated creatinine levels, elevated urea levels.

General disorders and administration site conditions. Common: inflammation, pain; uncommon: thrombophlebitis, pain at the injection site.

Description of Individual Adverse Reactions

Kounis syndrome

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

Children

Merobac is approved for use in children aged 3 months and older. Based on limited available data, there is no evidence of an increased risk of any adverse reactions to the drug in children. All reported adverse reactions were consistent with those observed in adult patients.

Reporting of Suspected Adverse Reactions

Reporting of adverse reactions after the registration of the medicinal product is essential. This allows for the monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals, as well as patients or their authorized representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the automated information system for pharmacovigilance at: https://aisf.dec.gov.ua/.

Shelf Life

4 years.

Each vial is intended for single use only.

When preparing and administering the solution, standard aseptic methods should be used.

The solution should be shaken before use.

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

Storage Conditions

Store at a temperature not exceeding 30 °C. Store in a place inaccessible to children.

Incompatibility

Merobac should not be mixed or added to other medicinal products.

Merobac intended for bolus intravenous injections should be reconstituted in sterile water for injection.

Merobac in vials for intravenous infusion can be directly reconstituted in 0.9% sodium chloride solution or 5% glucose solution for infusion.

Packaging

500 mg or 1000 mg of powder in glass vials; 1 or 10 vials in a cardboard box.

Release Category

Prescription only.

Manufacturer

ACS DOBFAR S.P.A.

Manufacturer's Location and Address

Nucleo Industriale S. Atto (Loc. S. Nicola a Tordino), 64100 Teramo (TE), Italy.

Date of Last Revision