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

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

Composition

active ingredient: meropenem;

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

excipient: sodium carbonate anhydrous.

Dosage form

Powder for solution for injection or infusion.

Main physicochemical properties: white to yellowish 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 beta-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: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to decreased production of porins), (2) decreased affinity for target PBPs, (3) increased expression of efflux pump components, and (4) production of beta-lactamases that can hydrolyze carbapenems.

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

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 of action involved involves cell membrane impermeability and/or the presence of efflux pump(s).

The MIC breakpoints that were determined during clinical trials by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are listed below.

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

2 Strains with MIC values above the S/R breakpoints are very rare or have not been previously reported. Identification and antimicrobial susceptibility testing should be repeated for any such isolate. If confirmed, the isolate should be 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 reported as resistant.

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

4 The cut-off values apply only to meningitis.

5 Non-species-related breakpoints were derived primarily from pharmacokinetic/pharmacodynamic data and are independent of the MIS 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 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.

6 Beta-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, and it is therefore advisable to take into account local information on resistance patterns, particularly when treating 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 are listed below, 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

Species of Acinetobacter Burkholderia cepacia

Pseudomonas aeruginosa

Inherently resistant microorganisms

Gram-negative aerobes

Stenotrophomonas maltophilia

Legionella species

Other microorganisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetii

Mycoplasma pneumoniae

7 Species that have shown natural intermediate sensitivity.

8 All methicillin-resistant staphylococci are resistant to meropenem.

9 Resistance 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 volunteers, the mean plasma half-life is approximately 1 hour, the mean volume of distribution is approximately 0.25 l/kg (11-27 l), and 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 an infusion over 30 minutes, the mean maximum concentration (Cmax) values are approximately 23 μg/ml, 49 μg/ml and 115 μg/ml, respectively; the corresponding values of the area under the pharmacokinetic curve "concentration-time" (AUC) were 39.3 μg×h/ml, 62.3 μg×h/ml and 153 μg×h/ml. After a 5-minute infusion, Cmax is 52 μg/ml and 112 μg/ml for 500 mg and 1000 mg, respectively. No accumulation of meropenem was observed when multiple doses were administered every 8 hours in patients with normal renal function.

In a study of 12 patients receiving meropenem 1000 mg every 8 hours after surgery for intra-abdominal infections, Cmax and half-life (t1/2) values were found to be similar to those in healthy subjects, but with 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 lungs, bronchial secretions, bile, cerebrospinal fluid, female genital tissues, skin, fascia, muscle, and peritoneal exudates.

Metabolism

Meropenem is metabolised by hydrolysis of the beta-lactam ring to a microbiologically inactive metabolite. In vitro, meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, therefore there is no need for concomitant use of a DHP-I inhibitor.

Breeding

Meropenem is primarily excreted unchanged by the kidneys, with approximately 70% (50-75%) of the dose excreted unchanged within 12 hours, with a further 28% excreted as a microbiologically inactive metabolite. Only approximately 2% of the dose is excreted in the faeces. The measured renal clearance and the effect of probenecid indicate that meropenem is subject to both filtration and tubular secretion.

Kidney failure

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

Liver failure

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 volunteers 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 mg/kg, 20 mg/kg and 40 mg/kg demonstrated Cmax values approaching those observed in adults at doses of 500 mg, 1000 mg and 2000 mg, respectively. The comparison revealed pharmacokinetic characteristics between doses and t1/2 similar to those observed in adults in all but the youngest patients (6 months t1/2 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 metabolite. The concentration of meropenem in the cerebrospinal fluid of children with meningitis is approximately 20% of the simultaneously detected plasma level, 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 dosing regimen of 20 mg/kg every 8 hours achieved a T >MIC 60% against P. aeruginosa in 95% of preterm neonates and 91% of term neonates.

Elderly patients

Pharmacokinetic studies in healthy elderly volunteers (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. 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.

Meropenem can be used to treat patients with neutropenia and fever suspected to be due to 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 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 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 valproic acid levels, 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 it is difficult to assess the contribution of antibacterial agents to the increase in INR (international normalized ratio). Frequent monitoring of INR 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 EU. It is recommended that local penem resistance of these bacteria be taken into account when prescribing the drug.

Hypersensitivity reactions

As with other beta-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 beta-lactam antibiotics may also be sensitive to meropenem. Careful inquiry should be made regarding previous hypersensitivity reactions to beta-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 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. Do not administer medicinal products that inhibit intestinal motility.

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' test)

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).

This medicinal product contains 90.2 mg/dose of sodium. Caution should be exercised when administering this medicinal product 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.

Breastfeeding period

Small amounts of meropenem have been reported to pass into human breast milk. Meropenem should be used during lactation 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 dosing 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.

Meropenem, when used at a dose of up to 2 g 3 times a day in adults and children weighing more than 50 kg and at a dose of up to 40 mg/kg 3 times a day in children, may be particularly useful in the treatment of certain types of infections caused by less susceptible bacterial species (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

Meropenem should be administered as an intravenous infusion over 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

No dose adjustment is required for patients with impaired liver function (see section "Special warnings and precautions for use").

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 renal impairment.

Method of administration and doses.

Meropenem should 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 medicinal product 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 drug 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 closely monitored.

The 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 "Method of administration and dosage" section.

Limited post-marketing experience indicates that if adverse reactions occur following overdose, they are consistent with the profile of these adverse reactions described in the Adverse Reactions section and are usually mild in severity and resolve upon discontinuation of the drug or dose reduction. Symptomatic treatment should be considered.

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

During hemodialysis, meropenem and its metabolites are removed from the body.

Adverse reactions

In a review of 4872 of 5026 patients treated with 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 reactions associated with meropenem 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 ≥ 1/10,000 to

Infections and infestations: uncommon – oral and vaginal candidiasis.

From the blood and lymphatic system: often - thrombocythemia; infrequently - agranulocytosis, hemolytic anemia, eosinophilia, thrombocytopenia, leukopenia, neutropenia.

On the part of the immune system: infrequently - anaphylactic reaction (see sections "Contraindications" and "Special instructions for use"), angioedema.

On the part of the psyche: rarely - delirium.

Nervous system: often - headache; infrequently - paresthesia; rarely - convulsions (see section "Special instructions").

Gastrointestinal: often - diarrhea, vomiting, nausea, abdominal pain; infrequently - colitis associated with the use of antibiotics (see section "Special instructions").

Hepatobiliary disorders: often - increased transaminase levels, increased alkaline phosphatase levels in the blood, increased lactate dehydrogenase levels in the blood; infrequently - increased bilirubin levels in the blood.

Skin and subcutaneous tissue disorders: common: rash, pruritus; uncommon: urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme; frequency unknown: drug allergy with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis (see section "Special warnings and precautions for use").

Renal and urinary disorders: infrequently - 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 suspected adverse reactions after a medicinal product has been authorised is essential. This ensures continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions as required by law.

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.

Each vial is intended for single use only.

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

The solution must be shaken before use.

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

Incompatibility.

Meropenem to be used for bolus intravenous injection 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

Powder for solution for injection or infusion 1000 mg; 1 vial of powder in a 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, Jarmajari, ERIR Phase-1 (Ext.), Batoli Kalan, Baddi, Dist. Solan, Himachal Pradesh, 173205, India.

Applicant

Ananta Medicare Ltd.

Location of the applicant and/or the applicant's representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.