Merapin 1000 mg powder for solution for injection and infusion 1000 mg vial No. 1

Instructions Merapin 1000 mg powder for solution for injection and infusion 1000 mg vial No. 1

Composition

active ingredient: meropenem;

1 vial contains meropenem trihydrate equivalent to meropenem 500 mg or 1000 mg;

excipients: sodium carbonate.

Dosage form

Powder for solution for injection.

Main physicochemical properties: white to slightly yellow crystalline powder.

Pharmacotherapeutic group

Antimicrobials for systemic use. Carbapenems. ATX code J01D H02.

Pharmacological properties

Pharmacodynamics.

Meropenem exerts its bactericidal action by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria by binding to penicillin-binding proteins (PBPs).

As with other β-lactam antibacterial agents, the time at which meropenem concentrations exceeded the minimum inhibitory concentration (MIC) (T>MIC) showed a high degree of correlation with efficacy. In preclinical models, meropenem demonstrated activity at plasma concentrations exceeding the MIC for infecting organisms over approximately 40% of the dosing interval. This target value has not been established clinically.

Bacterial resistance to meropenem may arise 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;

– production of β-lactamases that can hydrolyze carbapenems.

Outbreaks of infections caused by carbapenem-resistant bacteria have been reported in the European Union.

There is no cross-resistance between meropenem and drugs belonging to the quinolone, aminoglycoside, macrolide and tetracycline classes, taking into account the target microorganisms. However, bacteria may exhibit resistance to more than one class of antibacterial drugs when the mechanism involved involves cell membrane impermeability and/or the presence of efflux pump(s).

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

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

2Strains with MIC values above the S/R breakpoints are very rare or have not been reported to date. Identification and antimicrobial susceptibility testing for any such isolate should be repeated and, if confirmed, the isolate referred to an expert laboratory. Until clinical response data are available for verified isolates with MIC values above the current resistance breakpoints (indicated in italics), isolates should be recorded as resistant.

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

4Breakpoints apply to meningitis only.

5Non-species breakpoints were derived primarily from PK/PD data and are independent of the MIS distribution of individual species. They are intended to be used for species not listed in the table and footnotes. Non-species breakpoints are based on the following doses: EUCAST breakpoints apply to meropenem 1000 mg 3 times daily intravenously over 30 minutes as the lowest dose. Doses of 2 g 3 times daily have been considered for severe infections and for intermediate/resistant breakpoints.

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

The prevalence of acquired resistance may vary geographically and over time for individual species, therefore it is advisable to rely on local information on resistance patterns, particularly in the treatment of severe infections. Expert advice should be sought when the local prevalence of resistance is such that the benefit of the medicinal product in at least some types of infections is questionable.

The pathogenic microorganisms listed below are based on clinical experience and therapeutic protocols for treating diseases.

Typically sensitive 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 for which acquired resistance may be a problem

Gram-positive aerobes

Enterococcus faecium7,9

Gram-negative aerobes

Acinetobacter species

Burkholderia cepacia

Pseudomonas aeruginosa

Inherently resistant microorganisms

Gram-negative aerobes

Stenotrophomonas maltophilia

Legionella species

Other microorganisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetii

Mycoplasma pneumoniae

7Species that have shown natural intermediate sensitivity.

8All methicillin-resistant staphylococci are resistant to meropenem.

9Resistance rate > 50% in one or more EU countries.

Gangrene 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 gangrene and melioidosis.

Pharmacokinetics.

In healthy subjects, 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 at a dose of 250 mg, with clearance decreasing to 205 ml/min at a dose of 2 g. When the drug is administered at doses of 500 mg, 1000 mg and 2000 mg, administered as a 30-minute infusion, 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×h/ml. After a 5-minute infusion, the Cmax values are 52 and 112 μg/ml at doses of 500 and 1000 mg, respectively. When multiple doses of the drug were administered every 8 hours to patients with normal renal function, no accumulation of meropenem was observed.

A study in 12 patients receiving meropenem 1000 mg every 8 hours after surgery for intra-abdominal infections showed Cmax and half-life values similar to those in healthy subjects, but a larger volume of distribution (27 L).

Distribution

The mean plasma protein binding of meropenem was approximately 2% and was 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 several body fluids and tissues, including lung, bronchial secretions, bile, cerebrospinal fluid, female genitalia, skin, fascia, muscle, and peritoneal exudates.

Metabolism

Meropenem is metabolized by hydrolysis of the β-lactam ring to a microbiologically inactive metabolite. In vitro, meropenem exhibits 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.

Breeding

Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50-75%) of a dose is excreted unchanged within 12 hours. A further 28% is excreted as a microbiologically inactive metabolite. Faecal excretion represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid indicate that meropenem undergoes both filtration and tubular secretion.

Kidney failure

Renal impairment results in high plasma AUC values and a longer half-life for meropenem. AUC values were increased 2.4-fold in patients with moderate renal impairment (creatinine clearance (CC) 33-74 ml/min), 5-fold in patients with severe renal impairment (CC 4-23 ml/min) and 10-fold in patients on haemodialysis (CC 80 ml/min). The AUC values of the microbiologically inactive ring-open metabolite were also significantly increased in patients with renal impairment. Dose adjustment is recommended in patients with moderate and severe renal impairment (see section 4.2).

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

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

Adult patients

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

Children

Pharmacokinetic studies in infants and children with infection at doses of 10, 20 and 40 mg/kg demonstrated Cmax values approaching those observed in adults at doses of 500, 1000 and 2000 mg, respectively. Comparisons revealed pharmacokinetic profiles across doses and half-lives similar to those observed in adults in all but the youngest patients (1/2 1.6 hours). The mean clearance values for 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 metabolite. Meropenem concentrations in cerebrospinal fluid in children with meningitis are approximately 20% of the simultaneously detected plasma levels, although there is considerable interindividual variability.

The pharmacokinetics of meropenem in neonates treated with antibacterial agents showed higher clearance in neonates of older chronological or gestational age with an overall mean half-life of 2.9 hours. Monte Carlo simulations using a population PK model showed that a T>MIC 60% against P. aeruginosa was achieved in 95% of preterm neonates and 91% of term neonates at a dose of 20 mg/kg every 8 hours.

Elderly patients

Pharmacokinetic studies in healthy elderly subjects (65-80 years) have shown 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. No dose adjustment is required in elderly patients, except in cases of moderate to severe renal impairment.

Indication

The drug 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.

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

Treatment of patients with bacteremia that is associated or may be associated with any of the above infections.

Official recommendations regarding the appropriate use of antibacterial drugs should be considered.

Contraindication

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

Hypersensitivity to any other carbapenem antibacterial agent.

Severe hypersensitivity (e.g. anaphylactic reactions, severe skin reactions) to any other type of β-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 drugs, except probenecid, have not been conducted.

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem, leading to an increase in the half-life and increased plasma concentrations of meropenem. Caution should be exercised when probenecid is used concomitantly with meropenem.

The potential effect of meropenem on the protein binding or metabolism of other drugs has not been studied. However, protein binding is so low that interactions with other compounds based on this mechanism are not expected.

Concomitant use with carbapenems has been reported to decrease blood levels of valproic acid, resulting in a 60-100% decrease in valproic acid levels within approximately 2 days. Due to the rapid onset of action and the extent of the decrease, concomitant use of valproic acid/sodium valproate/valpromide and carbapenems is considered to be non-adjusting and should be avoided (see section 4.4).

Concomitant use of antibiotics with warfarin may enhance its anticoagulant effect. There have been many reports of increased anticoagulant effects of oral anticoagulants, including warfarin, in patients receiving concomitant antibacterial agents. The risk may vary depending on the type of underlying infection, age, and general 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 levels is recommended during and immediately after concomitant use of antibiotics with an oral anticoagulant.

Children

All drug interaction studies were conducted only in adults.

Application features

When choosing meropenem as a treatment, the appropriateness of using a carbapenem antibacterial agent should be considered, taking into account factors such as the severity of the infection, the prevalence of resistance to other appropriate antibacterial agents, and the risk of selecting the drug for carbapenem-resistant bacteria.

Resistance to Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter

Penem resistance in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter varies in the European Union. It is recommended that local penem resistance of these bacteria be taken into account when prescribing the drug.

Hypersensitivity reactions

As with other β-lactam antibiotics, serious and sometimes fatal hypersensitivity reactions have been reported (see sections 4.3 and 4.8).

Patients with a history of hypersensitivity to carbapenems, penicillins or other β-lactam antibiotics may also be sensitive to meropenem. Careful inquiry should be made regarding previous hypersensitivity reactions to β-lactam antibiotics before initiating therapy with meropenem.

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

Severe cutaneous adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme and acute generalised exanthematous pustulosis have been reported in patients treated with meropenem (see section 4.8). If signs and symptoms suggestive of these reactions occur, meropenem should be discontinued immediately and alternative treatment considered.

Antibiotic-associated colitis

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents, including meropenem, and may range in severity from mild to life-threatening. Therefore, it is important to consider the possibility of this diagnosis in patients who develop diarrhoea during or after the use of meropenem (see section 4.8). Discontinuation of meropenem and specific treatment against Clostridium difficile should be considered. Medicinal products that inhibit intestinal motility should not be administered.

Convulsions

Convulsions have been reported rarely during treatment with carbapenems, including meropenem (see section 4.8).

Liver function monitoring

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

Use in patients with liver disease: During treatment with meropenem in patients with pre-existing liver disease, liver function should be closely monitored. No dose adjustment is required (see section 4.2).

Seroconversion of direct antiglobulin test (Coombs reaction)

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

The concomitant use of meropenem and valproic acid/sodium valproate/valpromide is not recommended (see section 4.5).

The drug contains approximately 4.0 mEq of sodium per 1 g dose of the drug, which should be taken into account when prescribing the drug to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Pregnancy

There are no or limited amount of data from the use of meropenem in pregnant women.

Animal studies do not indicate direct or indirect reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of meropenem during pregnancy.

Breast-feeding

Small amounts of meropenem are excreted in human milk. Meropenem should be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

Ability to influence reaction speed when driving vehicles or other mechanisms

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

Method of administration and doses

Dosage

The tables below provide general recommendations for the dosage of the drug.

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

The drug, when used at a dose of up to 2 g three times a day in adults and children weighing more than 50 kg and at a dose of up to 40 mg/kg three times a day in children, may be particularly useful in the treatment of certain types of infections caused by less sensitive species of bacteria (e.g. Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter species), or in very severe infections.

Additional dosing recommendations should be followed when treating patients with renal impairment (see below).

Table 1. Recommended doses for adults and children weighing more than 50 kg

The drug should usually be administered as an intravenous infusion lasting 15 to 30 minutes.

Additionally, doses up to 1 g can be administered as an intravenous bolus injection over approximately 5 minutes. There are limited safety data supporting the administration of 2 g as an intravenous bolus injection in adults.

Kidney dysfunction

Table 2. Recommended doses for adults and children weighing more than 50 kg if the creatinine clearance in patients is less than 51 ml/min

Data supporting the use of the drug doses specified in Table 2, adjusted for a 2 g dose unit, are limited.

Meropenem is removed by hemodialysis and hemofiltration, therefore the required dose of the drug should be administered after the hemodialysis procedure is completed.

There are no established dosage recommendations for patients receiving peritoneal dialysis.

Liver dysfunction

For patients with impaired liver function, dose adjustment of the drug is not required (see section "Special instructions").

Dosage for elderly patients

No dose adjustment is 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 dosage regimen has not been established. There are limited pharmacokinetic data to support the use of a dose of meropenem of 20 mg/kg every 8 hours (see section 5.2).

Table 3. Recommended doses of the drug for children aged 3 months to 11 years and weighing up to 50 kg

Children weighing more than 50 kg

The dose should be used as for adult patients.

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

Method of application

The drug should usually be administered as an intravenous infusion over 15 to 30 minutes. Alternatively, doses of meropenem up to 20 mg/kg may be administered as an intravenous bolus injection over approximately 5 minutes. There are limited safety data supporting the administration of 40 mg/kg as an intravenous bolus injection in children.

Performing an intravenous bolus injection

The solution for bolus injection should be prepared by dissolving the drug in water for injection to obtain a concentration of 50 mg/ml.

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the medicinal product should be used immediately.

If the medicine is not used immediately, the shelf life and storage conditions of the prepared solution should be carefully monitored.

Performing an intravenous infusion

The infusion solution should be prepared by dissolving the medicinal product in 0.9% sodium chloride solution for infusion or 5% glucose (dextrose) solution for infusion to a concentration of 1-20 mg/ml.

Chemical and physical in-use stability of the reconstituted solution for infusion using 0.9% sodium chloride solution has been demonstrated for 3 hours at 25°C or for 24 hours in a refrigerator (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 shelf life and storage conditions of the reconstituted solution should be carefully monitored.

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

Do not freeze prepared solutions.

Children.

The drug should be used in 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 "Method of administration and dosage". Limited experience of post-marketing use of the drug indicates that if adverse reactions occur after overdose, they are consistent with the profile of these adverse reactions described in the section "Adverse reactions" and, as a rule, are mild in severity and resolve after discontinuation of the drug or reduction of its dose. The need for symptomatic treatment should be considered.

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

Hemodialysis removes meropenem and its metabolites from the body.

Adverse reactions

In a review of 4872 of 5026 patients exposed to meropenem, the most common adverse reactions associated with meropenem were diarrhoea (2.3%), rash (1.4%), nausea/vomiting (1.4%), and injection site inflammation (1.1%). The most common laboratory adverse events associated with meropenem reported were thrombocytosis (1.6%) and elevated liver enzymes (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 < 1/100);

Infections and infestations - uncommon: oral and vaginal candidiasis.

Blood and lymphatic system disorders: Common: thrombocythemia; 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: convulsions (see section "Special warnings and precautions for use").

On the part of the psyche - rarely: delirium.

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

Hepatobiliary disorders: Common: increased transaminase levels, increased blood alkaline phosphatase levels, increased blood lactate dehydrogenase levels; 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 unknown: 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.

There is no evidence to suggest an increased risk of adverse events in children based on the limited data available. All reports received were consistent with adverse reactions observed in adult patients.

Reporting of suspected adverse reactions

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Expiration date

2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 30 ° C. Keep out of the reach of children. Do not freeze the reconstituted solution.

Each vial is intended for single use only.

Standard aseptic techniques should be used when preparing the solution and during its administration.

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

Incompatibility.

The drug should not be mixed or added to other medicines.

The drug to be used for bolus intravenous injections should be reconstituted in sterile water for injection.

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

Packaging

1 bottle in a cardboard box.

Vacation category

According to the recipe.

Producer

Venus Remedies Limited.

Location of the manufacturer and address of its place of business

Hill Top Industrial Estate, Jarmajri, EPIP Phase-I (Extn), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India.