Macpenem

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MACPENEM

Composition:

Active substance: meropenem;

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

Excipient: anhydrous sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or slightly yellowish powder.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Beta-lactam antibiotics. Carbapenems.

ATC code J01DH02.

Pharmacological properties.

Pharmacodynamics.

Meropenem is a carbapenem antibiotic for parenteral administration, relatively stable to the action of human dihydropeptidase-1 (DHP-1), therefore it does not require the addition of a DHP-1 inhibitor.

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

As with other beta-lactam antibacterial agents, the duration of time during which meropenem concentrations exceeded the minimum inhibitory concentrations (MIC) (T>MC) has been shown to correlate highly with efficacy. In preclinical models, meropenem demonstrated activity at plasma concentrations exceeding the MIC for 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: (1) decreased permeability of the outer membrane of gram-negative bacteria (due to reduced porin production), (2) decreased affinity for target PBPs, (3) increased expression of efflux pump components, and (4) production of beta-lactamases capable of hydrolyzing carbapenems.

In the European Union, cases of infectious diseases caused by carbapenem-resistant bacteria have been reported.

Cross-resistance between meropenem and medicinal products belonging to the classes of quinolones, aminoglycosides, macrolides, and tetracyclines, with respect to target microorganisms, is absent. However, bacteria may exhibit resistance to more than one class of antibacterial agents when the mechanism involved includes membrane impermeability 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 listed below.

1The meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25 mg/L.

2Strains of microorganisms with MIC values exceeding the S/I breakpoint are very rare or have not been reported to date. Testing for identification and antimicrobial susceptibility for 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 MICs above the current resistance breakpoints (indicated in italics), isolates should be reported as resistant.

3Susceptibility of staphylococci to meropenem is predicted based on methicillin susceptibility data.

4Meropenem breakpoints for Neisseria meningitidis apply only to meningitis.

5Non-species-related breakpoints were primarily determined based on PK/PD data and do not depend on the MIC distribution of individual species. They are intended for use with species not listed in the table and footnotes.

"–" Susceptibility testing is not recommended, as the organism is a poor target for treatment with this medicinal product.

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

The following table lists pathogenic microorganisms based on clinical experience and therapeutic treatment guidelines.

Typically susceptible species

Gram-positive aerobes

Enterococcus faecalis 6

Staphylococcus aureus (methicillin-susceptible)7

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 freudii

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 6,8

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

6Species exhibiting natural intermediate susceptibility.

7All methicillin-resistant staphylococci are resistant to meropenem.

8Resistance rate > 50% in one or more EU countries.

Pharmacokinetics.

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

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

Distribution

Mean plasma protein binding of meropenem is approximately 2% and is independent of drug concentration. After rapid administration (5 minutes or less), meropenem 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 tissues, skin, fascia, muscle, and peritoneal exudates.

Metabolism

Meropenem is metabolized by hydrolysis of the beta-lactam ring, forming a microbiologically inactive metabolite. In vitro, meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, and 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 and prolonged elimination half-life for meropenem. AUC increased 2.4-fold in patients with moderate renal impairment (creatinine clearance (CrCl) 33–74 mL/min), 5-fold in patients with severe renal impairment (CrCl 4–23 mL/min), and 10-fold in patients undergoing hemodialysis (CrCl <2 mL/min), compared to healthy subjects (CrCl >80 mL/min). AUC values 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.

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

Hepatic impairment

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

Adult patients

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

Children

Pharmacokinetic studies in infants and children with infection receiving doses of 10, 20, and 40 mg/kg showed Cmax values approaching those observed in adults after 500, 1000, and 2000 mg doses, respectively. Comparative analyses revealed pharmacokinetic characteristics between doses and elimination half-lives similar to those observed in adults, except in the youngest patients (<6 months, t1/2 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 treatment 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 PK model indicated that with a dosing regimen of 20 mg/kg every 8 hours, T>MIC of 60% against P. aeruginosa was achieved in 95% of preterm neonates and 91% of term neonates.

Geriatric patients

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

Clinical characteristics.

Indications.

Meropenem 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;
• 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 may be used for the treatment of patients with neutropenia and fever suspected of having a bacterial infection.

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

Official recommendations regarding 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 forms of interaction.

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

Probenecid competes with meropenem for active tubular secretion and thus 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 or metabolism of other drugs has not been studied. However, since protein binding is so minimal, interactions with other compounds based on this mechanism are not expected.

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

Oral anticoagulants

Concomitant use of antibiotics with warfarin may potentiate its anticoagulant effect. Numerous reports have documented increased anticoagulant effect of oral anticoagulants, including warfarin, in patients receiving antibacterial agents 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 increased INR (International Normalized Ratio). Frequent monitoring of INR is recommended during and immediately after concomitant use of antibiotics with oral anticoagulants.

Paediatric population

All drug interaction studies have been conducted in adults only.

Special precautions for use

When selecting meropenem as a treatment option, 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 suitable antibacterial agents, and the risk of selecting carbapenem-resistant bacterial strains.

Resistance in 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

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

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

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

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

Antibiotic-associated colitis

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

Seizures

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

Liver function monitoring

Due to the risk of hepatotoxicity (liver function abnormalities with cholestasis and cytolysis) during meropenem therapy, liver function should be closely monitored (see section "Side effects").

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

Serum conversion in the direct antiglobulin test (Coombs test)

Meropenem therapy may cause a positive direct 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").

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

Use during pregnancy or breastfeeding

Data on the use of meropenem in pregnant women are lacking or limited in quantity. Animal studies have not shown direct or indirect effects on reproductive toxicity. As a precautionary measure, use of meropenem during pregnancy should be avoided. Meropenem should not be used during pregnancy or breastfeeding except when the expected benefit to the mother outweighs the potential risk to the fetus or infant. In each case, the drug should be administered under direct medical supervision.

It is unknown whether meropenem passes into human breast milk. Meropenem is present at very low concentrations in the milk of animals. Considering the benefit of therapy to the woman, a decision should be made whether to discontinue breastfeeding or to discontinue meropenem therapy.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted.

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

Method of administration and dosage.

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

The dose of meropenem and duration of treatment depend on the type of causative agent of the disease, severity of the condition, and individual patient sensitivity.

Macpenem, when administered at a dose of up to 2 g three times daily in adults and children with body weight over 50 kg, and at a dose of up to 40 mg/kg three times daily in children, may be particularly suitable for the treatment of certain types of infections, such as hospital-acquired infections caused by Pseudomonas aeruginosa or Acinetobacter spp.

Table 1

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

Meropenem is usually administered as an intravenous infusion over 15 to 30 minutes.

Additionally, doses of up to 1 g may be given as an intravenous bolus injection over approximately 5 minutes. Safety data supporting the administration of meropenem 2 g as an intravenous bolus injection in adults are limited.

Renal impairment

Table 2

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

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

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

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

Hepatic impairment

Dose adjustment of the drug is not required for patients with hepatic impairment.

Dosing in elderly patients

Dose adjustment is not required for elderly patients with normal renal function or with creatinine clearance values above 50 ml/min.

Table 3

Recommended doses of the drug for children aged 3 months to 11 years and with body weight less than 50 kg

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

Meropenem is usually administered as an intravenous infusion lasting from 15 to 30 minutes. In addition, doses of meropenem up to 20 mg/kg may be administered as an intravenous bolus injection over approximately 5 minutes. Safety data supporting administration of meropenem at a dose of 40 mg/kg as an intravenous bolus injection in children are limited.

Children with body weight above 50 kg

The dose should be administered as for adult patients.

Administration of intravenous bolus injection

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

Chemical and physical stability of the prepared bolus injection solution was maintained for 3 hours at room temperature (15–25 °C).

From a microbiological standpoint, the medicinal product should be used immediately.

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

Administration of intravenous infusion

The infusion solution should be prepared by dissolving the Macpenem 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 was maintained for 6 hours at room temperature (15–25 °C) or for 24 hours at 2–8 °C. The prepared solution, if cooled, should be used within 2 hours after refrigeration. From a microbiological standpoint, the medicinal product should be used immediately. If the medicinal product is not used immediately, responsibility for the duration and conditions of storage after preparation lies with the physician.

The solution of Macpenem prepared with 5% glucose (dextrose) solution should be used immediately, i.e., within 1 hour after preparation.

Freshly prepared solutions of Macpenem for intravenous injection and infusion are recommended.

When preparing the solution, standard aseptic techniques should be used.

Shake the prepared solution well before use.

All vials are intended for single use only.

Children.

The drug should not be administered to children under 3 months of age or to children with impaired liver or kidney function.

There is no experience with use in children with neutropenia or primary or secondary immunodeficiency.

Overdose.

Relative overdose is possible in patients with impaired kidney function if the dose of the drug is not adjusted. Limited post-marketing experience with the drug suggests that if adverse reactions occur after overdose, they are consistent with the profile of the specified side effects 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 kidney function, the drug is rapidly eliminated by the kidneys.

Hemodialysis removes meropenem and its metabolites from the body.

Adverse reactions.

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

The adverse reactions listed below are categorized 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 from available data). Within each frequency grouping, adverse reactions are listed in decreasing order of severity.

Infections and infestations — uncommon: oral and vaginal candidiasis.

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

Immune system disorders — uncommon: angioedema, anaphylactic reaction (see sections "Contraindications" and "Special precautions").

Nervous system disorders — common: headache; uncommon: paresthesia; rare: seizures (see section "Special precautions"). Delirium.

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

Hepatobiliary and pancreatic disorders — common: increased levels of transaminases, increased alkaline phosphatase levels in blood, increased lactate dehydrogenase levels in blood; uncommon: increased blood bilirubin levels.

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

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 are no data indicating an increased risk of adverse events in children. All reported events corresponded to adverse reactions observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is highly 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.

Incompatibilities

Macpenem must not be mixed or combined with other medicinal products.

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

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

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25 °C, in the original packaging.

Keep out of reach of children.

Packaging

1 or 10 vials with powder in a cardboard pack.

Prescription status

Prescription only.

Manufacturer

Manufacturer responsible for batch release:

A.C.S. Dobfar S.P.A., Italy.

Manufacturer's address and site of manufacturing

Nucleo Industriale S. Atto (loc. S. Nicolo’ A Tordino), 64100 Teramo (TE), Italy.