Brena 500

INSTRUCTIONS for medical use of the medicinal product BRENAM 500 (BRENUM 500)

Composition:

Active substance: meropenem;

1 vial contains meropenem trihydrate equivalent to 500 mg of meropenem;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

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

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 (PBP).

As with other β-lactam antibacterial agents, the duration of time during which meropenem concentrations exceed the minimum inhibitory concentrations (MIC) (T>MIC) has been shown to correlate highly with efficacy. In preclinical models, meropenem demonstrated 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 β-lactamases capable of hydrolyzing carbapenems.

In the European Union, outbreaks of infection 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 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 breakpoints defined during clinical studies by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are listed below.

Microorganism	Susceptible (S), (mg/l)	Resistant (R), (mg/l)
Enterobacteriaceae	≤ 2	> 8
Pseudomonas species	≤ 2	> 8
Acinetobacter species	≤ 2	> 8
Streptococcus, groups A, B, C, G	note 6	note 6
Streptococcus pneumoniae1	≤ 2	> 2
Other streptococci2	≤ 2	> 2
Enterococcus species
Staphylococcus species	note 3	note 3
Haemophilus influenzae1,2 and Moraxella catarrhalis2	≤ 2	> 2
Neisseria meningitidis2,4	≤ 0.25	> 0.25
Gram-positive anaerobes, excluding Clostridium difficile	≤ 2	> 8
Gram-negative anaerobes	≤ 2	> 8
Listeria monocytogenes	≤ 0.25	> 0.25
Species-independent breakpoint values5	≤ 2	> 8

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

2Strains of microorganisms with MIC values exceeding the S/R breakpoint are very rare or have not been reported so far. 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 exceeding the current resistance breakpoints (indicated in italics), isolates should be reported as resistant.

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

4Breakpoints 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. Non-species-related breakpoints are based on the following dosing regimens: EUCAST breakpoints apply to meropenem administered intravenously at 1000 mg 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.

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

"–" Performance of susceptibility testing is not recommended, as the organism is a poor target for the use of the medicinal product. Isolates may be designated as resistant without prior testing.

The prevalence of acquired resistance may vary geographically and over time for 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 medicinal product is questionable, at least for certain types of infections, consultation with an expert should be sought.

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

Usually 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

7Species exhibiting natural intermediate susceptibility.

8All methicillin-resistant staphylococci are resistant to meropenem.

9Resistance 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 refer to national and/or international consensus documents regarding the treatment of glanders and melioidosis.

Pharmacokinetics.

In healthy individuals, the mean elimination half-life from plasma 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 with 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 as 30-minute infusions, mean peak concentrations (C_max) are approximately 23, 49, and 115 µg/mL, respectively; corresponding values for the area under the concentration-time curve (AUC) are 39.3, 62.3, and 153 µg×h/mL. After 5-minute infusions, C_max values are 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 is 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 (t_1/2) values were consistent with those in healthy individuals, but the volume of distribution was larger (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 lung, bronchial secretions, bile, cerebrospinal fluid, female genital 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 there is no need for concomitant administration of 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, with an additional 28% excreted as the 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 for meropenem. AUC values 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 volunteers (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 removed by hemodialysis, with a clearance during hemodialysis approximately 4 times higher than in anuric patients.

Hepatic impairment

A study in patients with alcoholic liver cirrhosis showed 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 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, using doses of 10, 20, and 40 mg/kg, demonstrated C_max 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 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 the simultaneously measured plasma levels, although there is considerable inter-individual variability.

Pharmacokinetics of meropenem in neonates receiving antibacterial treatment demonstrated higher clearance in neonates with greater chronological or gestational age, with an overall mean t_1/2 of 2.9 hours. Monte Carlo simulations based on the population PK 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 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 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.

The medicinal product 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.

The medicinal product can 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 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 β-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 thereby inhibits renal excretion of meropenem, resulting in prolonged elimination half-life and increased meropenem plasma concentrations. Caution should be exercised when probenecid is administered concomitantly with meropenem.

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

Decreased serum levels of valproic acid have been reported when co-administered with carbapenems, with reductions of approximately 60–100% occurring within 2 days. Due to the rapid onset and extent of this reduction, concomitant administration of valproic acid/sodium valproate/valpromide with carbapenems is considered non-adjustable; therefore, such interaction should be avoided (see section "Special warnings and precautions for use").

Oral anticoagulants

Concomitant administration of antibiotics with warfarin may potentiate 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 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 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 suitable antibacterial agents, and the risk of promoting resistance in 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 occasionally 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 be at increased risk of hypersensitivity to meropenem. A thorough 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 have been reported in patients receiving meropenem treatment, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, and acute generalized exanthematous pustulosis (see section "Adverse reactions"). If signs or symptoms suggestive of these reactions occur, meropenem should be discontinued immediately and alternative therapy considered.

Antibiotic-associated colitis

Cases of colitis, including pseudomembranous colitis, associated with antibiotic use 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 after meropenem therapy (see section "Adverse reactions"). Discontinuation of meropenem and initiation of specific therapy directed against Clostridium difficile should be considered. Medicinal products that suppress 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 "Method of administration and dosage").

Serum conversion in the direct antiglobulin test (Coombs test)

Treatment with meropenem may result in a positive direct or indirect Coombs test.

Concomitant administration 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 account 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 vehicles or operating machinery.

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

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

Administration and Dosage

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 disease, and response to therapy.

The use of the drug 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 appropriate for the treatment of certain infections caused by less susceptible bacterial species (e.g., Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter), or in cases of severe infections.

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

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	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 febrile neutropenic patients	1 g

The drug 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 of the drug 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 patients' 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 the doses of the drug 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 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 precautions").

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 supporting the use of a meropenem dose of 20 mg/kg every 8 hours (see section "Pharmacokinetics").

Table 3. Recommended doses of the drug for children aged from 3 months to 11 years and with body weight up to 50 kg

Infection	Single dose administered every 8 hours
Pneumonia, including community-acquired and hospital-acquired	10 or 20 mg/kg body weight
Bronehopulmonary 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

Children with body weight more than 50 kg

The dose for adults should be used.

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

Method of administration

The drug is usually administered as an intravenous infusion lasting from 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 at a dose of 40 mg/kg as an intravenous bolus injection 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.

Administration of intravenous infusion

The infusion solution should be prepared by dissolving the medicinal product in 0.9% sodium chloride infusion solution or 5% glucose (dextrose) infusion solution to obtain a concentration of 1–20 mg/ml.

The prepared solutions should be used immediately.

Children.

The drug may be used in children aged from 3 months.

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 "Dosage and administration". Limited post-marketing experience suggests that if adverse reactions occur after overdose, they are consistent with the profile of the specified adverse reactions described in the section "Adverse reactions", are usually 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 review of data from 4872 out of 5026 patients regarding the impact of meropenem treatment, the most commonly reported adverse reactions associated with meropenem use were diarrhea (2.3%), rash (1.4%), nausea/vomiting (1.4%), and injection site inflammation (1.1%). The most frequently reported laboratory-related adverse events 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 (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are listed in order of decreasing 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 warnings and precautions for use”).

Psychiatric disorders: rare – delirium.

Nervous system disorders: common – headache; uncommon – paresthesia; rare – seizures (see section “Special warnings and precautions for use”).

Gastrointestinal disorders: common – diarrhea, vomiting, nausea, abdominal pain; uncommon – antibiotic-associated colitis (see section “Special warnings and precautions for use”).

Hepatobiliary disorders: common – increased transaminase levels, 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 (see section “Special warnings and precautions for use”); frequency not known – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (see section “Special warnings and precautions for use”).

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 suggesting an increased risk of adverse events in children based on the limited available data. All reported cases corresponded to adverse reactions observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of importance. 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 in the original packaging at a temperature not exceeding 30 °C. Do not freeze the reconstituted solution. Keep out of the reach of children.

Each vial is for single use only.

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

The solution should be shaken before use.

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

Incompatibilities.

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

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

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

Packaging. 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Brook Laboratories Limited.

Manufacturer's address and place of business.

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