RONEM is indicated for treatment of the following infections in adults and children over 3 month of
age (see section 4.4 and 5.1) :

• Pneumonia, including community acquired pneumonia and nosocomial pneumonias
• Broncho-pulnonary infections in cystic fibrosis
• Complicated urinary tract infections
• Complicated intra-abdominal infections
• Intra- and post-partum infections
• Complicated skin and soft tissue infections
• Acute bacterial meningitis

RONEM may be used in management of neutropenic patients with fever that is suspected to be due to a
bacterial infection.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

The table below provide general recommendations for dosing.

The dose of meropenem administered and the duration of treatment should take into account the type of
infection to be treated, including its severity, and the clinical response.

A dose of up to 2 g three times daily in adults and adolescents and a dose of up to 40 mg/kg three times
daily in children may be particularly appropriate when treating some types of infections, such as
nosocomial infections due to Pseudomonas aeruginosa or Acinetobacacter spp.

Additional consideration for dosing are needed when treating patients with renal insufficiency (see
further below).

Adults and adolescent

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes (see section
6.2, 6.3 and 6.6)

Alternatively, doses up to 1 g can be given as an intravenous bolus injection over approximately 5
minutes. There are limited safety data available to support the administration of a 2 g dose in adults as an
intravenous bolus injection.

Renal Impairment
The dose of adult and adolescents should be adjusted when creatinine clearance is less than 51 ml/min, as
shown below. There are limited data to support the application of these dose adjustment for a unit dose of 2g.

Meropenem is cleared by haemodialysis and hemofilteration. The required dose should be administered
after completion of the hemodialysis cycle.

There are no established dose recommendations for patients receiving peritoneal dialysis.

Hepatic Impairment
No dosage adjustment is necessary in patients with hepatic insufficiency (see Section 4.4).

Dose in elderly Patients
No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 ml/min.

Pediatric population
Children under 3 months of age
The safety and efficacy of meropenem in children under 3 months of age have not been established and
the optimal dose regimen has not been identified. However, limited pharmacokinetic data suggest that 20 mg/kg every 8 hours may be an appropriate regimen (see section 5.2)

Children from 3 months to 11 years of age and up to 50 kg body weight
The recommended dosage regimens are shown in the table below:

Children over 50 kg body weight
The adult dose should be administered

There is no experience in children with renal impairment.

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes (see section
6.2, 6.3 and 6.6). Alternatively, meropenem doses of up to 20 mg/kg may be given as an intravenous
bolus over approximately 5 minutes. There are limited safety data available to support the administration
of 40 mg/kg dose in children as an intravenous bolus injection.

Appearance of Reconstituted Solution
The reconstituted solution should be clear to slight yellow transparent and should be free of any visible
particles.

Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to any other carbapenem antibacterial agents. Severe hypersensitivity (e.g anaphylatic reactions, severe skin reactions) to any other type of betalactam antibacterial agents (e.g. penicillins or cephalosporins).

sing a carbapenem antibacterial agent based on factors such as severity of the infection, the prevalence
of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant
bacteria.

As with all beta-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions have been
reported (see sections 4.3 and 4.8).

Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam
antibiotics may also be hypersensitive to meropenem. Before initiating therapy with meropenem, careful
inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics.

If a severe allergic reaction occurs, the medicinal product should be discontinued and appropriate
measures taken.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial
agents, including meropenem, and may range in severity from mild to life threatening.
Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or
subsequent to the administration of meropenem (see section 4.8). Discontinuation of therapy with
meropenem and the administration of specific treatment for Clostridium difficile should be considered.
Medicinal products that inhibit peristalsis should not be given.

Seizures have infrequently been reported during treatment with carbapenems, including meropenem (see
section 4.8).

Hepatic functions should be closely monitored during treatment with meropenem due to the risk of
hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis) (see section 4.8).

Use in patients with liver disease: patients with pre-existing liver disorders should have liver function
monitored during treatment with meropenem. There is no dose adjustment necessary (see section 4.2).

A positive direct or indirect Coombs test may develop during treatment with meropenem.
The concomitant use of meropenem and valproic acid/sodium valproate is not recommended (see section4.5).

Ronem contains sodium.

This medicinal product contains approximately 2.0 mEq of sodium per 500 mg dose which should be
taken into consideration by patients on a controlled sodium diet.

No specific medicinal product interaction studies other than probenecid were conducted.
Probenecid competes with meropenem for active tubular secretions and thus inhibits the renal excretion
of meropenem with the effect of increasing the elimination half- life and plasma concentration of
meropenem. Caution is required if probenecid is co-administered with meropenem.

The potential effect of meropenem on the protein binding of other medicinal products or metabolism has
not been studied. However, the protein binding is so low that no interactions with other compounds would
be expected on the basis of this mechanism.

Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem
agents resulting in a 60-100 % decrease in valproic acid levels in about two days. Due to the rapid onset
and the extent of the decrease, co-administration of valproic acid with carbapenem agents is not
considered to be manageable and therefore should be avoided (see section 4.4).

Oral anti-coagulants

Simultaneous administration of antibiotics with warfarin may augment its anti-coagulant effects.
There have been many reports of increases in the anti-coagulant effects of orally administered anticoagulant
agents, including warfarin in patients who are concomitantly receiving antibacterial agents.
The risk may vary with the underlying infection, age and general status of the patient so that the
contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to
assess. It is recommended that the INR should be monitored frequently during and shortly after coadministration
of antibiotics with an oral anti-coagulant agent.

Fertility
No Information is available about the effects of meropenem on fertility. Please consult the doctor or
pharmacist to clear any doubts.
 

Pregnancy
There are no or limited amount of data from the use of meropenem in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see
section 5.3)
As a precautionary measure, it is preferable to avoid the use of meropenem during pregnancy.
 

Lactation
It is unknown whether meropenem is excreted in human milk. Meropenem is detectable at very low
concentrations in animal breast milk. A decision must be made whether to discontinue breast-feeding
or to discontinue/abstain from meropenem therapy taking into account the benefit of therapy for the
woman.

No studies on the effect on the ability to drive and use machines have been performed.

In a review of 4,872 patients with 5,026 meropenem treatment exposures, meropenem-related adverse
reactions most frequently reported were diarrhoea (2.3 %), rash (1.4 %), nausea/vomiting (1.4 %) and
injection site inflammation (1.1 %). The most commonly reported meropenem-related laboratory
adverse events were thrombocytosis (1.6 %) and increased hepatic enzymes (1.5-4.3 %).

Adverse reactions listed in the table with a frequency of “not known” were not observed in the 2,367
patients who were included in pre-authorisation clinical studies with intravenous and intramuscular
meropenem but have been reported during the post-marketing period.

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 (≥ 1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very
rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency
grouping, undesirable effects are presented in order of decreasing seriousness.

 

Relative overdose may be possible in patients with renal impairment if the dose is not adjusted as
described in section 4.2. Limited post-marketing experience indicates that if adverse reactions occur
following overdose, they are consistent with the adverse reaction profile described in section 4.8, are
generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should
be considered.

In individuals with normal renal function, rapid renal elimination will occur.

Haemodialysis will remove meropenem and its metabolite.

Pharmacotherapeutic group: antibacterials for systemic use, carbapenems, ATC code: J01DH02

Mode of action

Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive
and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

Pharmacokinetic/Pharmacodynamic (PK/PD) relationship

Similar to other beta-lactam antibacterial agents, the time that meropenem concentrations exceed the
MIC (T>MIC) has been shown to best correlate with efficacy. In preclinical models meropenem
demonstrated activity when plasma concentrations exceeded the MIC of the infecting organisms for
approximately 40 % of the dosing interval. This target has not been established clinically.

Mechanism of resistance

Bacterial resistance to meropenem may result from: (1) decreased permeability of the outer membrane of
Gram-negative bacteria (due to diminished production of porins) (2) reduced affinity of the target PBPs
(3) increased expression of efflux pump components, and (4) production of beta-lactamases that can
hydrolyse carbapenems.

Localised clusters of infections due to carbapenem-resistant bacteria have been reported in the European
Union.

There is no target-based cross-resistance between meropenem and agents of the quinolone,
aminoglycoside, macrolide and tetracycline classes. However, bacteria may exhibit resistance to more
than one class of antibacterials agents when the mechanism involved include impermeability and/or an
efflux pump(s).

Breakpoints
European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC
testing are presented below.
EUCAST clinical MIC breakpoints for meropenem (2009-06-05, v 3.1)

¹Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are
0.25/1 mg/L.
²Strains with MIC values above the S/I breakpoint are rare or not yet reported. The identification and
antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the
isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed
isolates with MIC above the current resistant breakpoint (in italics) they should be reported as resistant.
³Susceptibility of staphylococci to meropenem is inferred from the methicillin susceptibility.
⁴Meropenem breakpoints in Neisseria meningitidis relates to meningitis only.
⁵Non-species related breakpoints have been determined mainly from PK/PD data and are independent
of the MIC distributions of specific species. They are for use for species not mentioned in the table and
footnotes.
-- = Susceptibility testing not recommended as the species is a poor target for therapy with the
medicinal product.

The prevalence of acquired resistance may vary geographically and with time for selected species and
local information on resistance is desirable, particularly when treating severe infections. As necessary,
expert advice should be sought when the local prevalence of resistance is such that the utility of the agent
in at least some types of infections is questionable.

1Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are
0.25/1 mg/L.
2Strains with MIC values above the S/I breakpoint are rare or not yet reported. The identification and
antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the
isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed
isolates with MIC above the current resistant breakpoint (in italics) they should be reported as resistant.
3Susceptibility of staphylococci to meropenem is inferred from the methicillin susceptibility.
4Meropenem breakpoints in Neisseria meningitidis relates to meningitis only.
5Non-species related breakpoints have been determined mainly from PK/PD data and are independent
of the MIC distributions of specific species. They are for use for species not mentioned in the table and
footnotes.
-- = Susceptibility testing not recommended as the species is a poor target for therapy with the
medicinal product.
The prevalence of acquired resistance may vary geographically and with time for selected species and
local information on resistance is desirable, particularly when treating severe infections. As necessary,
expert advice should be sought when the local prevalence of resistance is such that the utility of the agent
in at least some types of infections is questionable.

The following table of pathogens listed is derived from clinical experience and therapeutic guidelines.
Commonly susceptible species
Gram-positive aerobes
Enterococcus faecalis$
Staphylococcus aureus (methicillin-susceptible) £
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^$†
Gram-negative aerobes
Acinetobacter species
Burkholderia cepacia
Pseudomonas aeruginosa

Inherently resistant organisms
Gram-negative aerobes
Stenotrophomonas maltophilia
Legionella species

Other micro-organisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetii

Mycoplasma pneumoniae

^$ Species that show natural intermediate susceptibility
^£All methicillin-resistant staphylococci are resistant to meropenem
^†Resistance rate ≥ 50% in one or more EU countries.

In healthy subjects the mean plasma 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 at 250 mg falling to 205 ml/min
at 2 g. Doses of 500, 1000 and 2000 mg doses infused over 30 minutes give mean Cmax values of
approximately 23, 49 and 115 μg/ml respectively, corresponding AUC values were 39.3, 62.3 and 153
μg.h/ml. After infusion over 5 minutes Cmax values are 52 and 112 μg/ml after 500 and 1000 mg doses
respectively. When multiple doses are administered 8-hourly to subjects with normal renal function,
accumulation of meropenem does not occur.

A study of 12 patients administered meropenem 1000 mg 8 hourly post-surgically for intra-abdominal
infections showed a comparable Cmax and half-life to normal subjects but a greater volume of
distribution 27 l.

Distribution
The average plasma protein binding of meropenem was approximately 2 % and was independent of
concentration. After rapid administration (5 minutes or less) the pharmacokinetics are biexponential but
this is much less evident after 30 minutes infusion. Meropenem has been shown to penetrate well into
several body fluids and tissues: including lung, bronchial secretions, bile, cerebrospinal fluid,
gynaecological tissues, skin, fascia, muscle, and peritoneal exudates.
 

Metabolism
Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive
metabolite. In vitro meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I
(DHP-I) compared to imipenem and there is no requirement to co-administer a DHP-I inhibitor.
 

Elimination
Meropenem is primarily excreted unchanged by the kidneys; approximately 70 % (50 –75 %) of the dose
is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive
metabolite. Faecal elimination represents only approximately 2% of the dose. The measured renal
clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular
secretion.

Renal insufficiency
Renal impairment results in higher plasma AUC and longer half-life for meropenem. There were AUC
increases of 2.4 fold in patients with moderate impairment (CrCL 33-74 ml/min), 5 fold in severe
impairment (CrCL 4-23 ml/min) and 10 fold in haemodialysis patients (CrCL <2 ml/min) when compared
to healthy subjects (CrCL >80 ml/min). The AUC of the microbiologically inactive ring opened
metabolite was also considerably increased in patients with renal impairment. Dose adjustment is
recommended for patients with moderate and severe renal impairment (see section 4.2).

Meropenem is cleared by haemodialysis with clearance during haemodialysis being approximately 4
meropenem after repeated doses.

Adult patients
Pharmacokinetic studies performed in patients have not shown significant pharmacokinetic differences
versus healthy subjects with equivalent renal function. A population model developed from data in 79
patients with intra-abdominal infection or pneumonia, showed a dependence of the central volume on
weight and the clearance on creatinine clearance and age.

Paediatrics
The pharmacokinetics in infants and children with infection at doses of 10, 20 and 40 mg/kg showed
Cmax values approximating to those in adults following 500, 1000 and 2000 mg doses, respectively.
Comparison showed consistent pharmacokinetics between the doses and half-lives similar to those
observed in adults in all but the youngest subjects (<6 months t1/2 1.6 hours). The 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 over 12
hours as meropenem with a further 12 % as metabolite. Meropenem concentrations in the CSF of children
with meningitis are approximately 20 % of concurrent plasma levels although there is significant interindividual
variability.

The pharmacokinetics of meropenem in neonates requiring anti-infective treatment showed greater
clearance in neonates with higher chronological or gestational age with an overall average half-life of 2.9
hours. Monte Carlo simulation based on a population PK model showed that a dose regimen of 20 mg/kg
8 hourly achieved 60 %T>MIC for P. aeruginosa in 95 % of pre-term and 91 % of full term neonates.

Elderly
Pharmacokinetic studies in healthy elderly subjects (65-80 years) have shown a reduction in plasma
clearance, which correlated with age-associated reduction in creatinine clearance, and a smaller reduction
in non-renal clearance. No dose adjustment is required in elderly patients, except in cases of moderate to
severe renal impairment (see section 4.2).

Animal studies indicate that meropenem is well tolerated by the kidney. Histological evidence of renal
tubular damage was seen in mice and dogs only at doses of 2000 mg/kg and above after a single
administration and above and in monkeys at 500 mg/kg in a 7-day study.

Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity
studies in rodent at doses exceeding 1000 mg/kg.
The IV LD₅₀ of meropenem in rodents is greater that 2000 mg/kg.

In repeat dose studies of up to 6 months duration only minor effects were seen including a decrease in red
cell parameters in dogs.

There was no evidence of mutagenic potential in a conventional test battery and no evidence of
reproductive toxicity including teratogenic potential in studies in rats up to 750 mg/kg and in monkeys up
to 360 mg/kg.

There was increased evidence of abortions at 500 mg/kg in a preliminary study in monkeys.

There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals.

The intravenous formulation was well tolerated in animal studies.

The sole metabolite of meropenem had a similar profile of toxicity in animal studies.

Anhydrous sodium carbonate.

This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.

2 years. After reconstitution: The reconstituted solutions for intravenous injection or infusion should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous injection or infusion should not exceed one hour.

Store below 30°C.
Do not freeze the reconstituted solution.

674 mg powder in a 10 ml Type 1 glass vial with stopper (grey butyl rubber with an aluminium caps)
The medicinal product is supplied in pack sizes of 10 vials.
Not all pack sizes may be marketed.

How to prepare this medicine
i. Wash your hands and dry them very well. Prepare a clean working area.
ii. Remove the Ronem bottle (vial) from the packaging. Check the vial and the expiry date
printed on the box and the vial label. Check that the vial is intact and has not been damaged.
iii. Remove the coloured cap and clean the grey rubber stopper with an alcohol wipe. Allow the
rubber stopper to dry.
iv. Connect a new sterile needle to a new sterile syringe, without touching the ends.
v. Draw up the recommended amount of sterile ‘Water for Injections’ into the syringe. The
amount of liquid that you need is shown in the table below:

Ronem-500mg vial has a size of 10ml and can be reconstituted with 10 ml Water for Injection

Please note: If your prescribed dose of Ronem is more than 1g, you will need to use more than 1vial
of Ronem. You can then draw the liquid in the vials into the one syringe.

vi. Put the needle of the syringe through the center of the grey rubber stopper and inject the
recommended amount of Water for Injections into the vial or vials of Ronem.
vii. Remove the needle from the vial and shake the vial well until all the powder has dissolved.
Clean the grey rubber stopper once more with a new alcohol wipe and allow the rubber
stopper to dry.
viii.With the plunger of the syringe pushed fully into the syringe, put the needle back through the
grey rubber stopper. You must then hold both the syringe and the vial and turn the vial upside
down.
ix. Keeping the end of the needle in the liquid, pull back the plunger and draw all the liquid in
the vial into the syringe.
x. Remove the needle and syringe from the vial and throw the empty vial away in a safe place.
xi. Hold the syringe upright, with the needle pointing upwards. Tap the syringe so that any
bubbles in the liquid rise to the top of the syringe.
xii. Remove any air in the syringe by gently pushing the plunger until all the air has gone.
xiii. If you are using Ronem at home, dispose of any needles and infusion lines that you have
used in an appropriate way. If your doctor decides to stop your treatment, dispose of any
unused Ronem in an appropriate way.

Please note:
An Intravenous infusion of meropenem may be prepared by directly constituting the contents of the
vials with 0.9 % sodium chloride or 5% glucose solutions for infusion. Please follow the instructions
that stated below:
To Ronem-500mg add 10 ml of the infusion Diluent, then shake well to reconstitute and then add this
to the Dilution infusion bag.

Appearance of Reconstituted Solution
The reconstituted solution should be free of any visible particles.
The re-constituted solution in the vial should be shaken to dissolve the entire contents of the vial.

Injection
Meropenem to be used for bolus intravenous injection should be constituted with sterile water for
injection as mentioned above.

Infusion
For intravenous infusion, meropenem vials may be directly constituted with 0.9 % sodium chloride or 5%
glucose solutions for infusion as described above.

Each vial is for single use only.
Standard aseptic techniques should be used for solution preparation and administration.
Any unused product or waste material should be disposed of in accordance with local requirements.