Makpenem 1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Macpenem 1000 (Macpenem 1000)

Composition:

Active ingredient: meropenem;

Each vial contains 1000 mg of meropenem (calculated as meropenem trihydrate);

Excipient: sodium carbonate anhydrous.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystals or crystalline powder, colorless to white or light yellow.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Carbapenems. ATC code J01DH02.

Pharmacological properties.

Pharmacodynamics.

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

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

Bacterial resistance to meropenem may arise due to:

• reduced permeability of the outer membrane of Gram-negative bacteria (due to decreased porin production);
• reduced affinity for target PBPs;
• increased expression of efflux pump components;
• production of β-lactamases capable of hydrolyzing carbapenems.

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

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

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

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

2. Microorganism strains with MIC values exceeding the S/R breakpoint 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 clinical response data are available for verified isolates with MIC values exceeding current resistance breakpoints (indicated in italics), isolates should be reported as resistant.

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

4. The breakpoints apply only to meningitis.

5. Non-species-related breakpoints have been primarily established based on PK/PD data and do not depend on the MIC distribution of individual species. They are intended for use with species not listed in the table and footnotes. Non-species-related breakpoints are based on the following dosing regimens: EUCAST breakpoints apply to meropenem administered at 1000 mg three times daily intravenously over 30 minutes as the lowest dose. Doses of 2 g three times daily were considered for severe infections and for intermediate/resistant breakpoints.

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

«–» Performance of susceptibility testing is not recommended, as the organism is a poor target for treatment with this agent. Isolates may be designated as resistant without prior testing.

The prevalence of acquired resistance may vary geographically and over time among individual species; therefore, local information on microbial resistance should be consulted, especially when treating severe infections. When necessary, if the local prevalence of resistance is such that the benefit of using the medicinal product is questionable, at least for certain types of infections, expert consultation should be sought.

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

Typically 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 for which acquired resistance may be a problem

Gram-positive aerobes

Enterococcus faecium^7,9

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

7. Species exhibiting intrinsic intermediate susceptibility.

8. All methicillin-resistant staphylococci are resistant to meropenem.

9. Resistance 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 human data. 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 following a 250 mg dose, decreasing to 205 mL/min with a 2 g dose. Following administration of 500 mg, 1000 mg, and 2000 mg doses as 30-minute infusions, 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 mg 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 extent of meropenem binding to plasma proteins is approximately 2% and is independent of drug concentration. Following 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 lungs, bronchial secretions, bile, cerebrospinal fluid, female genital tract tissues, skin, fascia, muscle, and peritoneal exudates.

Metabolism

Meropenem is metabolized via hydrolysis of the β-lactam ring, forming a microbiologically inactive metabolite. In vitro, meropenem demonstrates reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, and therefore does not require co-administration with 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 probenecid effects 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 for meropenem. AUC increased by 2.4-fold in patients with moderate renal impairment (creatinine clearance (CrCl) 33–74 mL/min), by 5-fold in patients with severe renal impairment (CrCl 4–23 mL/min), and by 10-fold in patients undergoing hemodialysis (CrCl <2 mL/min), compared to healthy individuals (CrCl >80 mL/min). AUC values for 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 effectively removed by hemodialysis, with a clearance during hemodialysis approximately 4 times higher than in anuric patients.

Hepatic impairment

A study in patients with alcoholic cirrhosis of the liver showed no influence of liver disease on meropenem pharmacokinetics 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 key parameters on body weight, creatinine clearance, and age.

Children

Pharmacokinetic studies in infants and children with infection, using doses of 10, 20, and 40 mg/kg, demonstrated Cmax values approaching those observed in adults after 500, 1000, and 2000 mg doses, respectively. Comparison revealed pharmacokinetic characteristics between drug doses and elimination half-lives similar to those in adults, except in the youngest patients (<6 months, t_1/2 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 as meropenem and an additional 12% as metabolite within 12 hours. Meropenem concentrations in cerebrospinal fluid in children with meningitis are approximately 20% of simultaneous plasma levels, although considerable inter-individual variability exists.

Pharmacokinetics of meropenem in neonates receiving antibacterial therapy demonstrated higher clearance in neonates with greater chronological or gestational age, with an overall mean elimination half-life of 2.9 hours. Monte Carlo simulations based on the population pharmacokinetic model showed that with a dosing regimen of 20 mg/kg every 8 hours, T>MIC of 60% was achieved against P. aeruginosa in 95% of preterm neonates and 91% of term neonates.

Elderly patients

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

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of the following infections in adults and children from 3 months of age:

• 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.

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

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

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

Contraindications.

Hypersensitivity to the active substance 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 β-lactam antibacterial agent (e.g., penicillins or cephalosporins).

Interaction with other medicinal products and other forms of interaction.

Studies on interaction of the medicinal product 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 an increased elimination half-life and elevated plasma concentrations of meropenem. Caution should be exercised when probenecid is administered concomitantly with meropenem.

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

Decreased serum levels of valproic acid have been reported with concomitant administration of carbapenems, resulting in a 60–100% reduction in valproic acid levels within approximately 2 days. Due to the rapid onset and extent of this reduction, concomitant administration of valproic acid/sodium valproate/valpromide and carbapenems is considered non-adjustable and should therefore be avoided (see section «Special precautions for use»).

Oral anticoagulants

Concomitant use of antibiotics with warfarin may enhance 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 contribution of antibacterial agents to the increase in INR (International Normalized Ratio). Frequent monitoring of INR levels is recommended during and immediately after concomitant use of antibiotics with oral anticoagulants.

Children

All drug interaction studies have been conducted in adults only.

Special precautions for use

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

Resistance of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter

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

Hypersensitivity reactions

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

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

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

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

Antibiotic-associated colitis

Cases of antibiotic-associated colitis, including pseudomembranous colitis, have been reported with nearly all antibacterial agents, including meropenem, with severity ranging from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or following treatment with meropenem (see section «Adverse reactions»). Consideration should be given to discontinuing meropenem therapy and initiating specific treatment directed against Clostridium difficile. Medicinal products that inhibit intestinal motility should not be administered.

Seizures

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

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 «Adverse reactions»).

Use in patients with hepatic disease: liver function should be closely monitored in patients with pre-existing liver disease receiving meropenem. Dose adjustment is not required (see section «Dosage and administration»).

Serum conversion in the 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»).

The medicinal product contains approximately 4.0 mEq of sodium per 1 g dose, which should be taken into consideration 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 lacking or limited in number.

Animal studies have not shown direct or indirect effects on reproductive toxicity. As a precautionary measure, it is advisable to avoid the use of meropenem during pregnancy.

Breastfeeding

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 or operate machinery have not been conducted.

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

Dosage and Administration

Dosage

The tables below provide general recommendations for dosing of the medicinal product.

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

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

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

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

Table 1

The drug 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. Safety data supporting administration of a 2 g dose of the drug as an intravenous bolus injection in adults are limited.

Renal impairment

Recommended doses of the drug for adults and children with body weight over 50 kg when patients' creatinine clearance is less than 51 ml/min

Table 2

Data supporting the use of doses of the drug adjusted to the 2 g unit dose as indicated in Table 2 are limited.

Meropenem is eliminated by hemodialysis and hemofiltration; therefore, the required dose of the drug should be administered after completion of the hemodialysis procedure.

There are no recommendations regarding established dosing for patients undergoing peritoneal dialysis.

Hepatic impairment

Dose adjustment of the drug is not required in patients with hepatic impairment (see section «Special warnings and precautions for use»).

Dosing in elderly patients

Dose adjustment is not required in 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. There are limited pharmacokinetic data justifying the use of a meropenem dose of 20 mg/kg every 8 hours (see section «Pharmacokinetics»).

Recommended doses of the drug for children aged

from 3 months to 11 years and with body weight less than 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 drug in children with renal impairment.

Method of administration

The drug is usually administered as an intravenous infusion over 15 to 30 minutes. Additionally, doses of meropenem up to 20 mg/kg may be given as an intravenous bolus injection over approximately 5 minutes. Safety data supporting administration of the drug 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 medicinal product in water for injections to obtain a concentration of 50 mg/ml.

Chemical and physical stability of the prepared bolus injection solution has been demonstrated for 3 hours at temperatures up to 25 °C or for 12 hours under refrigeration (2–8 °C).

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

If the medicinal product is not used immediately, the storage period and conditions of the prepared solution should be strictly controlled.

Administration of intravenous infusion

The infusion solution should be prepared by dissolving the 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 has been demonstrated for 3 hours at 25 °C or for 12 hours under refrigeration (2–8 °C). From a microbiological standpoint, the medicinal product should be used immediately. If the medicinal product is not used immediately, the storage period and conditions of the prepared solution should be strictly controlled.

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

Prepared solutions should not be frozen.

Each vial is intended for single use only.

Standard aseptic techniques should be used during solution preparation and administration.

The solution should be shaken before use.

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

Children.

The drug may be administered to children aged 3 months and older.

Overdose.

Relative overdose is possible in patients with impaired renal function if the dose of the drug is not adjusted as described in the section «Method of administration and dosage». Limited post-marketing experience with the drug suggests that if adverse reactions occur following overdose, they are consistent with the profile of the adverse reactions listed in the section «Adverse reactions» and are generally mild in severity and resolve after discontinuation of the drug or dose reduction. Symptomatic treatment should be considered as necessary.

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

Haemodialysis removes meropenem and its metabolites from the body.

Adverse Reactions

In a review of data from 4872 out of 5026 patients regarding the impact of meropenem treatment, the most commonly reported adverse reactions associated with the use of meropenem were diarrhea (2.3%), rash (1.4%), nausea/vomiting (1.4%), and injection site inflammation (1.1%). The most frequently reported laboratory abnormalities associated with meropenem use 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); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in 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: angioneurotic edema, anaphylactic reaction (see sections «Contraindications» and «Special precautions»).

Psychiatric disorders ‒ rare: delirium.

Nervous system disorders ‒ common: headache; uncommon: paresthesia; rare: seizures (see section «Special precautions»).

Gastrointestinal disorders ‒ common: diarrhea, vomiting, nausea, abdominal pain; uncommon: colitis associated with antibiotic use (see section «Special precautions»).

Hepatobiliary disorders ‒ common: increased transaminase levels, increased alkaline phosphatase levels in blood, increased lactate dehydrogenase levels in blood; uncommon: increased bilirubin levels in blood.

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

Renal and urinary disorders ‒ uncommon: increased creatinine levels in blood, increased urea levels in blood.

General disorders and administration site conditions ‒ common: inflammation, pain; uncommon: thrombophlebitis, injection site pain.

There are no data suggesting an increased risk of adverse events in children based on the limited available data. All reported events corresponded to adverse reactions observed in adult patients.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legislation.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Do not freeze.

Keep out of reach of children.

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

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

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

Packaging. 1 vial per cardboard package.

Prescription status. Prescription only.

Manufacturer.

Brook Sterisciences Limited

Manufacturer's address and place of business.

Unit-II, Village Mangledj, Naresar Road, Off NH-8, Taluka-Karjan, Vadodara, Gujarat, 391210, India.