Ronem

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RONEM (RONEM)

Composition:

active substance: meropenem;

1 vial contains meropenem trihydrate equivalent to anhydrous meropenem 125 mg or 250 mg or 500 mg or 1,000 mg;

excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or slightly yellowish powder.

Pharmacotherapeutic group. Antimicrobial agents for systemic use.
β-lactam antibiotics. Carbapenems. ATC code J01D H02.

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).

Bacterial resistance to meropenem may occur due to: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to reduced production of porins), (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 is absent with regard to the target microorganisms. However, bacteria may exhibit resistance to more than one class of antibacterial agents when the mechanism involved includes membrane impermeability and/or the presence of efflux pump(s).

The clinical breakpoints for MIC values, as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), are provided below.

Microorganism	Susceptible (S), (mg/l)	Resistant (R), (mg/l)
Enterobacteriaceae	≤ 2	> 8
Pseudomonas	≤ 2	> 8
Acinetobacter	≤ 2	> 8
Streptococcus, groups A, B, C, G	≤ 2	> 2
Streptococcus pneumoniae1	≤ 2	> 2
Other streptococci	2	2
Enterococcus
Staphylococcus2	note 3	note 3
Haemophilus influenzae1 and Moraxella catarrhalis	≤ 2	> 2
Neisseria meningitidis2,4	≤ 0.25	> 0.25
Gram-positive anaerobes	≤ 2	> 8
Gram-negative anaerobes	≤ 2	> 8
Species-unrelated interpretive criteria5	≤ 2	> 8

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 MIC values 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.

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, local information on microbial resistance is desirable, 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.

Usually 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 intrinsic 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); the mean clearance is 287 mL/min at a dose of 250 mg, decreasing to 205 mL/min at a dose of 2 g. 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. After 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.

Distribution

The mean extent of meropenem binding to plasma proteins is approximately 2% and is 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 certain 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 demonstrates reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, and co-administration with a DHP-I inhibitor is not required.

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 a microbiologically inactive metabolite. Fecal excretion accounts for only about 2% of the dose. Measured renal clearance and the effect of probenecid indicate that meropenem undergoes both glomerular filtration and tubular secretion.

Renal impairment

Impaired renal function leads to higher plasma AUC values and a prolonged elimination half-life of meropenem. AUC values 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 of the microbiologically inactive open-ring metabolite were also significantly increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate to 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 influence of liver disease on the pharmacokinetics of meropenem after repeated dosing.

Adult patients

Pharmacokinetic studies in patients have not revealed significant pharmacokinetic differences compared to healthy individuals with similar renal function.

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. Comparative analyses revealed pharmacokinetic characteristics between doses and elimination half-lives similar to those observed in all 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 was 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 concentrations, although considerable inter-individual variability exists.

Pharmacokinetics of meropenem in neonates receiving antibacterial treatment showed 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 population pharmacokinetic modeling 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.

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.

Ronem 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.

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

Consideration should be given to obtaining official guidance on the appropriate use of antibacterial agents.

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 interactions with individual 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 a prolonged elimination half-life and increased plasma concentrations of meropenem. Caution should be exercised when probenecid is administered concomitantly with meropenem.

The potential effect of Ronem on protein binding of other drugs or metabolism has not been studied. However, since protein binding is minimal, interactions with other compounds based on this mechanism are unlikely.

Decreased levels of valproic acid in the blood have been reported when co-administered with carbapenems, resulting in reductions 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 uncorrectable; therefore, such interaction should be avoided.

Concomitant use of antibiotics with warfarin may enhance its anticoagulant effect. Numerous reports have documented increased anticoagulant effects of orally administered anticoagulants, including warfarin, in patients receiving antibacterial agents concomitantly. The risk may vary depending on the underlying infections, age, and general condition of the patient, making it difficult to assess the exact contribution of antibacterial agents to the increase in INR (International Normalized Ratio). Frequent monitoring of INR levels is recommended during and shortly after concomitant use of antibiotics with oral anticoagulants.

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 suitable antibacterial agents, and the risk of selecting for carbapenem-resistant bacteria.

Serious, and occasionally fatal, hypersensitivity reactions have been reported, as with other beta-lactam antibiotics.

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

If a severe allergic reaction occurs, the drug should be discontinued immediately and appropriate measures should be instituted.

When using nearly all antibacterial agents, including meropenem, cases of antibiotic-associated colitis and pseudomembranous colitis have been reported, with severity ranging from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after meropenem therapy. Consideration should be given to discontinuing meropenem and initiating specific therapy directed against Clostridium difficile. Antiperistaltic agents should not be used.

Seizures have been rarely reported during treatment with carbapenems, including meropenem.

Due to the risk of hepatic toxicity (liver function abnormalities with cholestasis and cytolysis) during meropenem therapy, liver function should be closely monitored.

Use in patients with hepatic disease: Liver function should be closely monitored in patients with pre-existing liver disease during meropenem therapy. Dose adjustment is not required.

Meropenem therapy may result in a positive direct or indirect Coombs test.

Concomitant administration of meropenem and valproic acid/sodium valproate is not recommended.

Ronem contains approximately 2.0 mEq or 4.0 mEq of sodium per 500 mg or 1 g dose, respectively, which 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 adverse effects on reproductive toxicity. As a precautionary measure, it is advisable to avoid the use of meropenem during pregnancy.

It is unknown whether meropenem is excreted in human breast milk. Meropenem has been detected in 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 drug on the ability to drive vehicles or operate machinery have not been conducted.

Dosage and Administration.

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.

Ronem, 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

Infection	Single dose administered every 8 hours
Pneumonia, including community-acquired and hospital-acquired pneumonia	500 mg or 1 g
Respiratory tract infections in cystic fibrosis	2 g
Complicated urinary tract infections	500 mg or 1 g
Complicated intra-abdominal infections	500 mg or 1 g
Infections during childbirth and postpartum infections	500 mg or 1 g
Complicated skin and soft tissue infections	500 mg or 1 g
Acute bacterial meningitis	2 g
Treatment of patients with febrile neutropenia	1 g

Ronem is usually 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 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

Creatinine clearance (mL/min)	Single dose (see Table 1)	Frequency
26-50	full single dose	every 12 hours
10-25	half the single dose	every 12 hours
<10	half the single dose	every 24 hours

Data supporting the use of doses of the drug as indicated in Table 2, adjusted to the 2 g unit dose, 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 dosage recommendations established for patients undergoing 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 up to 50 kg

Infection	Single dose to be administered every 8 hours
Pneumonia, including community-acquired and hospital-acquired	10 or 20 mg/kg body weight
Bronechopulmonary infections in cystic fibrosis	40 mg/kg body weight
Complicated urinary tract infections	10 or 20 mg/kg body weight
Complicated intra-abdominal infections	10 or 20 mg/kg body weight
Complicated skin and soft tissue infections	10 or 20 mg/kg body weight
Acute bacterial meningitis	40 mg/kg body weight
Treatment of patients with febrile neutropenia	20 mg/kg body weight

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

Ronem 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 to children at a dose of 40 mg/kg as an intravenous bolus injection are limited.

Children with body weight over 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 Ronem medicinal product in water for injections to obtain 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 storage duration and conditions after preparation lies with the physician.

Administration of intravenous infusion

The infusion solution should be prepared by dissolving the Ronem medicinal product in 0.9% sodium chloride solution for infusions or in 5% glucose (dextrose) solution for infusions 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 refrigerated, should be used within 2 hours after removal from the refrigerator. From a microbiological standpoint, the medicinal product should be used immediately. If the medicinal product is not used immediately, responsibility for the storage duration and conditions after preparation lies with the physician.

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

Children

The drug should not be administered to children under 3 months of age.

Overdose

Relative overdose is possible in patients with impaired renal function if the dose of the drug is not adjusted. Limited post-marketing experience indicates that if adverse reactions occur following overdose, they are consistent with the profile of the specified 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 by the kidneys.

Haemodialysis removes meropenem and its metabolites from the body.

Adverse Reactions

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 grouping, adverse reactions are listed in order of decreasing severity.

System organ class	Frequency	Adverse reaction
Infections and infestations	Uncommon	Oral and vaginal candidiasis.
Blood and lymphatic system disorders	Common Uncommon Frequency unknown	Thrombocytosis. Eosinophilia, thrombocytopenia, leukopenia, neutropenia. Agranulocytosis, hemolytic anemia.
Immune system disorders	Frequency unknown	Angioedema, anaphylactic reaction.
Nervous system disorders	Common Uncommon Rare	Headache. Paresthesia. Seizures.
Gastrointestinal disorders	Common Frequency unknown	Diarrhea, vomiting, nausea, abdominal pain. Antibiotic-associated colitis.
Hepatobiliary disorders	Common Uncommon	Elevated transaminase levels, elevated alkaline phosphatase levels in blood, elevated lactate dehydrogenase levels in blood. Elevated bilirubin levels in blood.
Skin and subcutaneous tissue disorders	Common Uncommon Frequency unknown	Rash, pruritus. Urticaria. Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
Renal and urinary disorders	Uncommon	Elevated creatinine levels in blood, elevated urea levels in blood.
General disorders and administration site conditions	Common Uncommon Frequency unknown	Inflammation, pain. Thrombophlebitis. Injection site pain.

Shelf life.

2 years.

Storage conditions.

Store in a light-protected place at a temperature not exceeding 30°C. Store out of reach of children.

It is recommended that freshly prepared Ronem solutions be used immediately for intravenous injection or intravenous infusion. However, prepared Ronem solutions retain sufficient stability at room temperature (up to 25°C) or under refrigeration (4°C). Data regarding storage conditions and shelf life of meropenem solutions are shown in Table 4:

Table 4

Solvent	Storage time (hours) at temperatures up to
	25 °C	4 °C
Vial reconstituted with water for injections	8	48
Solutions (1–20 mg/mL) prepared with:
0.9 % sodium chloride	8	48
5 % glucose	3	14
5 % glucose and 0.225 % sodium chloride	3	14
5 % glucose and 0.9 % sodium chloride	3	14
5 % glucose and 0.15 % potassium chloride	3	14
2.5 % or 10 % mannitol solution for intravenous infusion	3	14
10 % glucose	2	8
5 % glucose and 0.02 % sodium bicarbonate for intravenous injection	2	8

Roenem solutions must not be frozen. The reconstituted solution should be shaken before administration. All vials are intended for single use only.

Standard aseptic techniques must be applied during preparation and administration.

Incompatibility.

The drug must not be mixed in the same syringe with other medicinal products. Only the diluents specified in the section "Method of administration and dosage" should be used to dissolve Roenem.

Packaging.

Powder in a vial; 1 or 10 vials in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Venus Remedies Limited / Venus Remedies Limited.

Manufacturer's address and location of business operations.

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