Diapenem

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIAPEM (DIAPENEM)

Composition:

Active substance: meropenem;

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

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection and infusion.

Main physicochemical properties: powder from white to light yellow color.

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

Pharmacological properties.

Pharmacodynamics.

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 (PBPs).

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

Bacterial resistance to meropenem may arise due to:

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

Cases of infectious diseases caused by bacteria resistant to carbapenems have been reported.

Cross-resistance between meropenem and medicinal products belonging to the quinolone, aminoglycoside, macrolide, and tetracycline classes, with respect to target microorganisms, is absent. However, bacteria may exhibit resistance to more than one class of antibacterial agents when the underlying mechanism involves reduced membrane permeability and/or presence of efflux pump(s).

Table 1

MIC breakpoint values determined during antimicrobial susceptibility testing.

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

2. Microbial strains with MIC values above the S/R breakpoint are very rare or have not been reported to date. Susceptibility testing for any such isolate must 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 the current resistance breakpoints (indicated in italics), such isolates should be reported as resistant.

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

4. The meropenem breakpoint values for Neisseria meningitidis apply only to meningitis.

5. Non-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 Table 1 and footnotes. Non-species-related breakpoints are based on the following dosing regimens: EUCAST breakpoints apply to meropenem 1000 mg administered intravenously three times daily 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. Beta-lactam susceptibility of Groups A, B, C, and G streptococci is predicted based on penicillin susceptibility.

«–» Susceptibility testing is not recommended, as the organism is a poor target for the drug. Isolates may be reported 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 taken into account, especially when treating severe infections. If necessary, when the local prevalence of microbial resistance is such that the benefit of using the drug is questionable, at least for certain types of infections, expert consultation should be sought.

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

Generally 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 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^7,9

Gram-negative aerobes

Acinetobacter species

Burkholderia cepacia

Pseudomonas aeruginosa

Naturally 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 European Union 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 consider national and/or international consensus documents regarding the treatment of glanders and melioidosis.

Pharmacokinetics.

In healthy volunteers, the mean plasma elimination 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 after administration of a 250 mg dose, decreasing to 205 mL/min with a 2 g dose. After administration of 500 mg, 1000 mg, and 2000 mg doses infused over 30 minutes, mean maximum concentration (C_max) values were approximately 23 µg/mL, 49 µg/mL, and 115 µg/mL, respectively, and corresponding area under the concentration-time curve (AUC) values were 39.3 µg×h/mL, 62.3 µg×h/mL, and 153 µg×h/mL. After 5-minute infusions, C_max values were 52 µg/mL 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, C_max and elimination half-life values were consistent with those in healthy volunteers, but the volume of distribution was higher—27 L.

Distribution

The mean plasma protein binding of meropenem is approximately 2% and is independent of drug concentration. After rapid administration (5 minutes or less), pharmacokinetics are biexponential, but this is much less evident after a 30-minute infusion. Meropenem has been shown to penetrate well into certain 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 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, thus eliminating the need for concomitant administration of a DHP-I inhibitor.

Excretion

Meropenem is primarily excreted unchanged by the kidneys, with approximately 70% (50–75%) of the dose excreted unchanged within 12 hours. An additional 28% is excreted as a microbiologically inactive metabolite. Only about 2% of the dose is excreted in feces. Measured renal clearance and the effect of probenecid 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 of meropenem. AUC increased by 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 on hemodialysis (CrCl < 2 mL/min), compared to healthy volunteers (CrCl > 80 mL/min). AUC values of 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

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

Adult patients

Pharmacokinetic studies in patients showed no significant pharmacokinetic differences compared to healthy volunteers 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 receiving doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg demonstrated C_max values approaching those observed in adults after 500 mg, 1000 mg, and 2000 mg doses, respectively. Comparative analyses revealed pharmacokinetic characteristics between doses and elimination half-lives similar to those observed in all adults except 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 within 12 hours, and an additional 12% as metabolite. Meropenem concentrations in cerebrospinal fluid in children with meningitis are approximately 20% of plasma levels, although there is considerable inter-individual variability.

Pharmacokinetics of meropenem in newborns receiving antibacterial treatment demonstrated higher clearance in newborns with greater chronological or gestational age, with a mean elimination half-life of 2.9 hours. Monte Carlo simulation based on the population pharmacokinetic model showed 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 newborns and 91% of term newborns.

Elderly patients

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

Clinical characteristics.

Indications.

Treatment of 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.

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

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

When prescribing the drug, official recommendations regarding the appropriate use of antibacterial agents should be followed.

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 reactions (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 drug 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, leading to 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 of other drugs or metabolism has not been studied. However, since protein binding is so minimal, interactions with other compounds via this mechanism are not expected.

Decreased blood levels of valproic acid have been reported when co-administered with carbapenems, with reductions of approximately 60–100% occurring within about two 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.

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 antibacterial agents concomitantly. The risk may vary depending on the type of underlying infection, age, and general condition of the patient, making it difficult to predict the impact of antibacterial agents on the increase in international normalized ratio (INR). 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 only in adults.

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 bacterial strains.

Resistance of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetob combustor>