MERONEM 1 G.

Israel - English - Ministry of Health

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Active ingredient:
MEROPENEM AS TRIHYDRATE
Available from:
PFIZER PFE PHARMACEUTICALS ISRAEL LTD
ATC code:
J01DH02
Pharmaceutical form:
POWDER FOR SOLUTION FOR INJECTION
Composition:
MEROPENEM AS TRIHYDRATE 1000 MG/VIAL
Administration route:
I.V
Prescription type:
Required
Manufactured by:
ASTRA ZENECA UK LIMITED
Therapeutic group:
MEROPENEM
Therapeutic area:
MEROPENEM
Therapeutic indications:
Meronem is indicated for treatment in adults and children of the following severe infections caused by single or multiple susceptible bacteria sensitive to meropenem: - Pneumonias and nosocomial pneumonias. - Pulmonary infections in patients with cystic fibrosis. - Urinary tract infections. - Intra-abdominal infections. - Gynecological infections such as endometritis and pelvic inflammatory disease. - Skin and skin structure infections. - Meningitis. - Septicemia. Meronem has proved efficacious alone or in combination with other antimicrobial agents in the treatment of polymicrobial infections. There is no experience in pediatric patients with neutropenia or primary or secondary immunodeficiency.
Authorization number:
104 11 28624 01
Authorization date:
2012-01-31

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

:ךיראת

29.12.2013

םש

רישכת

:תילגנאב

Meronem 500mg

Meronem 1g

רפסמ

םושיר

1041128624

1040828622

םש

לעב

םושירה

:

הקינזהרטסא

מ"עב )לארשי(

אפורל ןולע

םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ ןולעב טסקט

יחכונ טסקט

שדח

Contrain

dication

Hypersensitivity to any other carbapenem antibacterial

agent

Severe hypersensitivity

(e.g.

anaphylactic

reaction,

severe skin reaction) to any other type of betalactam

antibacterial agent (e.g. penicillins or cephalosporins

Special

warnings

special

precautio

ns for

Seizures have infrequently been reported during treatment

with carbapenems, including meropenem (see section 4.8)

Hepatic function should be closely monitored during

treatment with meropenem due to the risk of hepatic toxicity

(hepatic dysfunction with cholestasis and cytolysis)

lactation

Meropenem has been reported to be excreted in human milk

Undesir

able

Effects

Frequency adverse reaction

Renal and urinary disorders Uncommon Blood creatinine

increased, blood urea increased

Reporting Rate of Adverse Reactions (data derived from a

combination of post-marketing clinical trial and spontaneous

sources)

General disorders and administration site conditions Not known

Pain at the injection site

Incomp

atibilitie

Meronem

should not be

mixed with or

added to other

drugs

Meronem is

compatible with

the following

infusion fluids:

0.9% Sodium

Chloride

solution

5% or 10%

Glucose

solution

5% Glucose

solution with

0.02% Sodium

Bicarbonate

5% Glucose and

0.9% Sodium

Chloride

solution

5% Glucose

with 0.225%

Sodium

Chloride

solution

5% Glucose

with 0.15%

Potassium

Chloride

solution

Mannitol 2.5%

or 10%

solution.

Meronem should not be mixed with or added to other drugs

Meronem is compatible with the following infusion fluids:

0.9% Sodium Chloride solution

5% or 10% Glucose solution

5% Glucose solution with 0.02% Sodium Bicarbonate

5% Glucose and 0.9% Sodium Chloride solution

5% Glucose with 0.225% Sodium Chloride solution

5% Glucose with 0.15% Potassium Chloride solution

Mannitol 2.5% or 10% solution.

Chemical and physical in-use stability for a prepared solution

for infusion using 0.9% sodium chloride solution has been

demonstrated for 6 3 hours

at up to 25°C

at controlled room

temperature (15-25°C) or 24 hours

under refrigerated

conditions

at (2-8°C)

Constituted solutions of Meronem IV in 5% glucose (dextrose)

solution should be used immediately.

The prepared solution

should, if refrigerated, be used within 2 hours after it has left

the refrigerator

The constituted solutions should not be frozen.

ל ןולע ןכרצ םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח ינפל

תליטנ שי ,הפורתה

עדיל תא

אפורה

:םא םא

התא

חקול תופורת

תורחא ןוירה

הקנהו

Meronem LPD CC 12032020

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MERONEM 500MG

MERONEM 1G

1.

NAME OF THE MEDICINAL PRODUCT

Meronem 500mg

Meronem 1g

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Meronem 500mg

Each vial contains meropenem trihydrate equivalent to 500 mg anhydrous meropenem.

Excipients with known effect:

Each 500 mg vial contains 104 mg sodium carbonate which equates to approximately 2 mEq

of sodium (approximately 45 mg).

Meronem 1 g

Each vial contains meropenem trihydrate equivalent to 1 g anhydrous meropenem.

Excipients with known effect:

Each 1 g vial contains 208 mg sodium carbonate which equates to approximately 4 mEq of

sodium (approximately 90 mg).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for solution for injection or infusion.

A white to light yellow powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Meronem IV is indicated for treatment, in adults and children, of the following infections

caused by single or multiple bacteria sensitive to meropenem.

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Pneumonias and Nosocomial Pneumonias

Pulmonary infections in patients with cystic fibrosis

Urinary Tract Infections

Intra abdominal Infections

Gynaecological Infections, such as endometritis and pelvic inflammatory disease

Skin and Skin Structure Infections

Meningitis

Septicaemia

Meronem has proved efficacious alone or in combination with other antimicrobial agents in

the treatment of polymicrobial infections.

There is no experience in paediatric patients with neutropenia or primary or secondary

immunodeficiency.

4.2

Posology and method of administration

Adults

The dosage and duration of therapy shall be established depending on type and severity of

infection and the condition of the patient.

The recommended daily dosage is as follows:

500 mg IV every 8 hours in the treatment of pneumonia, UTI, gynaecological infections such

as endometritis, pelvic inflammatory disease, skin and skin structure infections.

1 g IV every 8 hours in the treatment of nosocomial pneumonias, peritonitis, presumed

infections in neutropenic patients, septicaemia.

In cystic fibrosis, doses up to 2 g every 8 hours have been used; most patients have been

treated with 2 g every 8 hours.

In meningitis the recommended dosage is 2 g every 8 hours.

When treating infections known or suspected to be caused by Pseudomonas aeruginosa,

a dose of at least 1g every 8 hours in adults (maximum approved dose is 6g daily given

in 3 divided doses) and a dose of at least 20mg/kg every 8 hours in children (maximum

approved dose is 120mg/kg/ daily given in 3 divided doses) are recommended.

Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infection.

There are limited safety data available to support the administration of a 2g bolus dose in

adults as an intravenous bolus injection

Dosage Schedule for Adults with Impaired Renal Function

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Dosage should be reduced in patients with creatinine clearance less than 51 mL/min, as

scheduled below.

Table 1

Creatinine Clearance

(mL/min)

Dose (based on “unit” dose range

of 500 mg, 1 g, 2 g)

Frequency

26-50

one unit dose

every 12 hours

10-25

one-half unit dose

every 12 hours

<10

one-half unit dose

every 24 hours

Meropenem is cleared by haemodialysis and haemofiltration; if continued treatment with

Meronem is necessary, it is recommended that the unit dose (based on the type and severity of

infection)

administered

completion

haemodialysis

procedure

restore

therapeutically effective plasma concentrations.

There is no experience with the use of Meronem in patients under peritoneal dialysis.

Dosage in Adults with Hepatic Insufficiency

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

Elderly Patients

No dosage adjustment is required for the elderly with normal renal function or creatinine

clearance values above 50 mL/min.

Children

For children over 3 months and up to 12 years of age the recommended dose is 10 to 20 mg/kg

every 8 hours depending on type and severity of infection, susceptibility of the pathogen and

the condition of the patient. In children over 50 kg weight, adult dosage should be used. In

meningitis and cystic fibrosis the recommended dose is 40 mg/kg every 8 hours.

There is no experience in children with renal impairment.

Method of Administration

Meronem IV can be given as an intravenous bolus injection over approximately 5 minutes or

by intravenous infusion over approximately 15 to 30 minutes using the specific available

presentations. There is limited safety data available to support the administration of a 40

mg/kg

bolus

dose

children).

There

limited

safety

data

available

support

administration of a 2g bolus dose (in adults).

Meronem IV to be used for bolus intravenous injection should be constituted with sterile

Water

Injections

meropenem).

This

provides

approximate

concentration of 50 mg/mL. Constituted solutions are clear, and colourless or pale yellow.

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Meronem IV for intravenous infusion may be constituted with compatible infusion fluids (50

to 200 ml) (see Sections 6.2 and 6.3 6.6).

Meronem should not be mixed with or physically added to solutions containing other drugs.

Solutions of meronem should not be frozen.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to any other carbapenem antibacterial agent.

Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of

beta-lactam antibacterial agent (e.g. penicillins or cephalosporins).

4.4

Special warnings and precautions for use

The selection of meropenem to treat an individual patient should take into account the

appropriateness of using 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.

Enterobacteriaceae

Pseudomonas aeruginosa

Acinetobacter

spp. resistance

Resistance to penems of

Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter

spp. varies across the European Union. Prescribers are advised to take into account the local

prevalence of resistance in these bacteria to penems.

Hypersensitivity reactions

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.

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic

epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms

(DRESS), erythema multiforme (EM) and acute generalised exanthematous pustulosis

(AGEP) have been reported in patients receiving meropenem (see section 4.8). If signs and

symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately

and an alternative treatment should be considered.

Antibiotic

-

associated colitis

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all

anti-bacterial agents, including meropenem, and may range in severity from mild to life

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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 4.84.8).

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

Seizures have infrequently been reported during treatment with carbapenems, including

meropenem (see section 4.8).

Hepatic function monitoring

Hepatic function 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).

Direct antiglobulin test (Coombs test) seroconversion

A positive direct or indirect Coombs test may develop during treatment with meropenem.

Concomitant use with valproic acid/sodium valproate/valpromide

The concomitant use of meropenem and valproic acid/sodium valproate/valpromide is not

recommended (see section 4.5).

Meronem contains sodium.

Meronem 500 mg: This medicinal product contains 45 mg sodium per 500 mg vial, equivalent

to 2.25% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Meronem 1 g: This medicinal product contains 90 mg sodium per 1 g vial, equivalent to 4.5%

of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5

Interaction with other medicinal products and other forms of

interaction

No specific medicinal product interaction studies other than probenecid were conducted.

Probenecid competes with meropenem for active tubular secretion 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.

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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/sodium valproate/valpromide 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 anti-coagulant 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 co-administration of antibiotics with an oral

anti-coagulant agent.

Paediatric population

Interaction studies have only been performed in adults.

4.6

Pregnancy and lactation

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.

Breast-feeding

Small amounts of meropenem have been reported to be excreted in human milk. Meropenem

should not be used in breast-feeding women unless the potential benefit for the mother

justifies the potential risk to the baby.

4.7

Effects on ability to drive and use machines

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

However, when driving or operating machines, it should be taken into account that headache,

paraesthesia and convulsions have been reported for meropenem.

4.8

Undesirable effects

Summary of the safety profile

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

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meropenem-related laboratory adverse events were thrombocytosis (1.6%) and increased

hepatic enzymes (1.5-4.3%).

Tabulated risk of 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 (≥ 1/1,000 to <1/100); rare

(≥ 1/10,000 to <1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the

available data). Within each frequency grouping, undesirable effects are presented in order of

decreasing seriousness.

Table 1

System Organ Class

Frequency

Event

Infections and infestations

Uncommon

oral and vaginal candidiasis

Blood and lymphatic system

disorders

Common

thrombocythaemia

Uncommon

agranulocytosis, haemolytic

anaemia, thrombocytopenia,

neutropenia, leukopenia,

eosinophilia

Immune system disorders

Psychiatric disorders

Uncommon

Rare

, anaphylaxis (see sections 4.3 and

4.4), angioedema

delirium

Nervous system disorders

Common

headache

Uncommon

paraesthesia

Rare

convulsions (see section 4.4)

Gastrointestinal disorders

Common

diarrhoea, abdominal pain

vomiting, nausea

Uncommon

antibiotic-associated colitis (see

section 4.4)

Hepatobiliary disorders

Common

transaminases increased, blood

alkaline phosphatase increased,

blood lactate dehydrogenase

increased.

Uncommon

blood bilirubin increased

Skin and subcutaneous tissue

disorders

Common

rash, pruritus

Uncommon

toxic epidermal necrolysis, Stevens

Johnson syndrome, erythema

multiforme. (see section 4.4),

urticaria

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Table 1

System Organ Class

Frequency

Event

Not known

drug reaction with eosinophilia and

systemic symptoms , acute

generalised exanthematous

pustulosis (see section 4.4)

Renal and urinary disorders

Uncommon

blood creatinine increased, blood

urea increased

General disorders and

administration site conditions

Common

inflammation, pain

Uncommon

thrombophlebitis, pain at the

injection site

Paediatric population

Meronem is licensed for children over 3 months of age. There is no evidence of an increased

risk of any adverse drug reaction in children based on the limited available data. All reports

received were consistent with events observed in the adult population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse event should be reported to the Ministry of Health according to the

National Regulation by using an online form https://sideeffects.health.gov.il/

4.9

Overdose

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.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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

J01DH02

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Mechanism 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 antibacterial 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 (2013-02-11, v 3.1)

Organism

Susceptible (S)

(mg/l)

Resistant (R)

(mg/l)

Enterobacteriaceae

≤ 2

> 8

Pseudomonas

spp.

≤ 2

> 8

Acinetobacter

spp.

≤ 2

> 8

Streptococcus groups

A, B, C and G

note 6

note 6

Streptococcus pneumoniae

1

≤ 2

> 2

Viridans

group

streptococci

2

≤ 2

> 2

Enterococcus

spp.

Staphylococcus

spp.

note 3

note 3

Haemophilus influenzae

1, 2

and Moraxella

catarrhalis

2

≤ 2

> 2

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Organism

Susceptible (S)

(mg/l)

Resistant (R)

(mg/l)

Neisseria meningitidis

2,4

≤ 0.25

> 0.25

Gram-positive anaerobes except

Clostridium

difficile

≤ 2

> 8

Gram-negative anaerobes

≤ 2

> 8

Listeria monocytogenes

≤ 0.25

> 0.25

Non-species related breakpoints

≤ 2

> 8

Meropenem breakpoints for

Streptococcus pneumoniae

Haemophilus influenzae

in meningitis are

0.25 mg/l (Susceptible) and 1 mg/l (Resistant).

Isolates with MIC values above the susceptible breakpoint are very 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 values above the current resistant breakpoint they should be reported resistant.

Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.

Breakpoints relate to meningitis only.

Non-species related breakpoints have been determined using PK/PD data and are independent of MIC

distributions of specific species. They are for use only for organisms that do not have specific breakpoints. Non

species related breakpoints are based on the following dosages: EUCAST breakpoints apply to meropenem

1000 mg x 3 daily administered intravenously over 30 minutes as the lowest dose. 2 g x 3 daily was taken into

consideration for severe infections and in setting the I/R breakpoint.

6 The beta-lactam susceptibility of streptococcus groups A, B, C and G is inferred from the penicillin

susceptibility.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug. Isolates may

be reported as R without prior testing.

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)

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

)תוחיטב )תוחיטב

:ךיראת

18

רבמטפסל

2011

םש

רישכת

:תילגנאב

Meronem 500 mg

Meronem 1g

ירפסמ

:םושיר

Meronem 500 mg: 104 08 28622 00

Meronem 1g : 104 11 28624 00

םש

לעב

םושירה

:

הקינזהרטסא

מ"עב )לארשי(

םייונישה

ןולעב

םינמוסמ

עקרב

בוהצ אפורל ןולע םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Posology

Method of

administrat

ion

with

other

antibiotics, particular

caution

recommended

using meropenem as

monotherapy

critically ill

patients

with

known

suspected

Pseudomonas

aeruginosa

lower

respiratory

tract

infection

When treating infections known or suspected to be

caused by Pseudomonas aeruginosa and/or

Acinetobacter spp and the susceptibility of the pathogen

is unknown, a dose of 1g three times

daily or higher in adults and a dose of up to 40mg/kg

three times daily in children is recommended

There is limited safety data available to support the

administration of a 2g bolus dose

Meropenem is cleared by haemodialysis and

hemofiltration; if continued treatment with Meronem is

necessary, it is recommended that the unit dose (based

on the type and severity of infection) is administered at

the completion of the haemodialysis procedure to restore

therapeutically effective plasma concentrations

Method of

administrat

ion

There is limited safety data available to support the

administration of a 40 mg/kg bolus dose. There is limited

safety data available to support the administration of a 2g

Special

warnings

There is some clinical and laboratory evidence of partial

cross-allergenicity between other carbapenems and

beta-lactam antibiotics, penicillins and cephalosporins

As with all beta-lactam antibiotics, (serious and

and

precautions

for use

occasionally fatal) rare hypersensitivity reactions have

been reported (see Section 4.8). Before initiating

therapy with meropenem, careful inquiry should be made

concerning previous hypersensitivity reactions to beta-

lactam antibiotics. Meronem should be used with caution

in patients with such a history. If an allergic reaction to

meropenem occurs, the drug should be discontinued and

The concomitant use of valproic acid/sodium valproate

and Meronem is not recommended (see

section Interactions with other medicinal products and

Meronem 500 mg: 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

Meronem 1.0 g: This medicinal product contains

approximately 4.0 mEq of sodium per 1.0 g dose

which should be taken into consideration by patients on a

Interactio

ns with

other

medicinal

products

and other

forms of

interaction

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 Meronem in patients stabilised on

valproic acid is not considered to be manageable and

see Special Warnings and Precautions for use

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-

Effects on

Ability to

Drive and

Use

Machines

No data are available, but it

is not anticipated that

Meronem will affect the

ability to drive and use

machines.

No studies on the ability to drive and use machines have

driving or operating machines, it should be taken into

account that headache, paraesthesia

and convulsions have been reported for Meronem

Undesirable

Effects

Meronem is generally well

tolerated. Adverse events

rarely lead to cessation of

treatment. Serious adverse

events are rare

Frequency

Common (≥1% and < 10%)

Uncommon (≥0.1% and <1 %)

Rare (≥0.01% and <0.1%)

Not known

Meronem is generally well tolerated. Adverse reactions rarely

lead to cessation of treatment. Serious adverse reactions are

The following adverse reactions have been identified following

clinical studies with Meronem. Their frequency is presented in

Table 1 Frequency of Adverse Reactions (data derived from

clinical

trial

data

sources)

using

CIOMS

frequency

classification and then listed by MedDRA SOC and at the

preferred level. Frequencies of occurrence of undesirable effects

are defined as: very common (≥1/10; ≥10%); common (≥1/100 to

<1/10; ≥1% to <10%); uncommon (≥1/1,000 to <1/100; ≥0.1% to

<1%); rare (≥1/10,000 to <1/1,000; ≥0.01% to <0.1%); very rare

Frequency of Adverse Reactions (data derived from clinical trial data sources)

Frequency

Uncommon

Common

Uncommon

Common

Uncommon

Rare

Common

Common

Uncommon

Skin and subcutaneous tissue

Common

Uncommon

Common

Uncommon

The following adverse reactions have been identified from post-

marketing clinical trials and spontaneous reports. Their

frequency is presented in Table 2:

Reporting Rate of Adverse

Reactions (data derived from a combination of post-marketing clinical

trial and spontaneous sources) using CIOMS III frequency classification

and then listed by MedDRA SOC and at the preferred level.

Frequencies of occurrence of undesirable effects are defined as: very

common (≥1/10; ≥10%); common (≥1/100 to <1/10; ≥1% to <10%);

uncommon (≥1/1,000 to <1/100; ≥0.1% to <1%); rare (≥1/10,000 to

<1/1,000; ≥0.01% to <0.1%); very rare (<1/10,000; <0.01%).

Reporting Rate of Adverse Reactions (data derived from a combination of post-

marketing clinical trial and spontaneous sources)

Frequency

Rare

Very rare

Very rare

Very rare

Skin and subcutaneous tissue

Very rare

Pharmacod

ynamic

Properties

Gram-positive

aerobes

Bacillus spp.,

Corynebacterium

diphtheriae,

Enterococcus faecalis,

Enterococcus

liquifaciens,

Enterococcus avium,

Listeria

monocytogenes,

Lactobacillus spp.,

Nocardia asteroides,

Staphylococcus

aureus (penicillinase

negative and positive),

Staphylococci- coagula

se-negative; including,

Staphylococcus

epidermidis,

Staphylococcus

saprophyticus,

Staphylococcus

capitis,

Staphylococcus cohnii,

Staphylococcus

xylosus,

Staphylococcus

warneri,

Staphylococcus

hominis,

Staphylococcus

simulans,

Staphylococcus

intermedius,

Staphylococcus sciuri,

Staphylococcus

lugdunensis,

Streptococcus

Bacterial resistance to meropenem may result from: (1)

decreased permeability of the outer

membrane of Gram-negative bacteria (due to diminished

affinity of the target PBPs (3) increased expression of

production of β-lactamases that can hydrolyse

Localised clusters of infections due to carbapenem-

resistant bacteria have been reported in some

The susceptibility to meropenem of a given clinical

isolate should be determined by standard

methods. Interpretations of test results should be made

in accordance with local infectious

diseases and clinical microbiology guidelines

The antibacterial spectrum of meropenem includes the

following species, based on clinical

experience and therapeutic guidelines

Enterococcus faecalis (note that E. faecalis can

naturally display intermediate susceptibility),

Staphylococcus aureus (methicillin-susceptible

strains only: methicillin-resistant staphylococci

including MRSA are resistant to meropenem),

Staphylococcus species including Staphylococcus

epidermidis (methicillin-susceptible strains only:

methicillin-resistant staphylococci including MRSE

are resistant to meropenem), Streptococcus

agalactiae (Group B streptococcus), Streptococcus

milleri group (S. anginosus, S. constellatus, and S.

intermedius), Streptococcus pneumoniae,

Streptococcus pyogenes (Group A streptococcus)

pneumoniae (penicillin

susceptible and

resistant),

Streptococcus

agalactiae,

Streptococcus

pyogenes,

Streptococcus equi,

Streptococcus bovis,

Streptococcus mitis,

Streptococcus mitior,

Streptococcus milleri,

Streptococcus

sanguis,

Streptococcus

viridans,

Streptococcus

salivarius,

Streptococcus

morbillorum,

Streptococcus Group

G, Streptococcus

Group F, Rhodococcus

equi

Gram-negative

aerobes

Achromobacter

xylosoxidans,

Acinetobacter

anitratus,

Acinetobacter lwoffii,

Acinetobacter

baumannii, Aeromonas

hydrophila, Aeromonas

sorbria, Aeromonas

caviae, Alcaligenes

faecalis, Bordetella

bronchiseptica,

Brucella melitensis,

Campylobacter coli,

Campylobacter jejuni,

Citrobacter freundii,

Citrobacter diversus,

Citrobacter koseri,

Citrobacter

amalonaticus,

Enterobacter

aerogenes,

Enterobacter

(Pantoea)

agglomerans,

Enterobacter cloacae,

Enterobacter

sakazakii, Escherichia

coli, Escherichia

hermannii, Gardnerella

vaginalis, Haemophilus

influenzae (including

beta-lactamase

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

Anaerobic bacteria

Clostridium

perfringens,

Peptoniphilus

asaccharolyticus,

Peptostreptococcus

species

(including P. micros, P anaerobius, P. magnus)

Bacteroides caccae, Bacteroides fragilis group,

Prevotella bivia, Prevotella disiens

Species for which acquired resistance may be a

problem: Gram-positive aerobes

Enterococcus faecium

(E. faecium

can naturally

display intermediate susceptibility even without

acquired resistance mechanisms; note that in some

European countries the frequency of resistance

among E. faecium is greater than 50 % of isolates)

Species for which acquired resistance may be a

problem: Gram-negative aerobes

Acinetobacter species, Burkholderia cepacia,

Pseudomonas aeruginosa

Inherently resistant organisms: Gram-negative

aerobes

Stenotrophomonas maltophilia, Legionella species

Other inherently resistant organisms

Chlamydophila pneumoniae, Chlamydophila

psittaci, Coxiella burnetii, Mycoplasma pneumonia

The published medical microbiology literature describes in-

vitro meropenem-susceptibilities of many other bacterial

species. However the clinical significance of such in-vitro

findings is uncertain. Advice on the clinical significance of in-

vitro findings should be obtained from local infectious diseases

and clinical microbiology experts and local professional

positive and ampicillin

resistant strains),

Haemophilus

parainfluenzae,

Haemophilus ducreyi,

Helicobacter pylori,

Neisseria meningitidis,

Neisseria gonorrhoeae

(including

beta-lactamase

positive, penicillin

resistant and

spectinomycin resistant

strains), Hafnia alvei,

Klebsiella

pneumoniae,

Klebsiella aerogenes,

Klebsiella ozaenae,

Klebsiella oxytoca,

Moraxella

(Branhamella)

catarrhalis, Morganella

morganii, Proteus

mirabilis, Proteus

vulgaris, Proteus

penneri, Providencia

rettgeri, Providencia

stuartii, Providencia

alcalifaciens,

Pasteurella multocida,

Plesiomonas

shigelloides,

Pseudomonas

aeruginosa,

Pseudomonas putida,

Pseudomonas

alcaligenes,

Burkholderia

(Pseudomonas)

cepacia,

Pseudomonas

fluorescens,

Pseudomonas stutzeri,

Pseudomonas

pseudomallei,

Pseudomonas

acidovorans,

Salmonella spp.,

including Salmonella

enteritidis/typhi,

Serratia marcescens,

Serratia liquefaciens

Serratia rubidaea,

Shigella sonnei,

Shigella flexneri,

Shigella boydii,

Shigella dysenteriae,

Vibrio cholerae, Vibrio

parahaemolyticus,

Vibrio vulnificus,

Meropenem and imipenem have a similar profile of clinical

utility and activity against multi-resistant bacteria. However,

meropenem is intrinsically more potent against Pseudomonas

aeruginosa and may be active in vitro against imipenem-

Meropenem is active in vitro against many strains resistant to

-lactam antibiotics. This is explained in part by

-lactamases. Activity in vitro against

strains resistant to unrelated classes of antibiotics such as

aminoglycosides or quinolones is common.

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

Yersinia enterocolitica

Anaerobic bacteria

Actinomyces

odontolyticus,

Actinomyces meyeri,

Bacteroides-

Prevotella-

Porphyromonas spp.,

Bacteroides fragilis,

Bacteroides vulgatus,

Bacteroides variabilis,

Bacteroides

pneumosintes,

Bacteroides

coagulans,

Bacteroides uniformis,

Bacteroides distasonis,

Bacteroides ovatus,

Bacteroides

thetaiotaomicron,

Bacteroides eggerthii,

Bacteroides

capsillosis, Prevotella

buccalis, Prevotella

corporis, Bacteroides

gracilis, Prevotella

melaninogenica,

Prevotella intermedia,

Prevotella bivia,

Prevotella

splanchnicus,

Prevotella oralis,

Prevotella disiens,

Prevotella rumenicola,

Bacteroides

ureolyticus, Prevotella

oris, Prevotella

buccae, Prevotella

denticola, Bacteroides

levii, Porphyromonas

asaccharolytica,

Bifidobacterium spp.,

Bilophila wadsworthia,

Clostridium

perfringens,

Clostridium

bifermentans,

Clostridium ramosum,

Clostridium

sporogenes,

Clostridium cadaveris,

Clostridium sordellii,

Clostridium butyricum,

Clostridium

clostridiiformis,

Clostridium innocuum,

Clostridium

subterminale,

Clostridium tertium,

Eubacterium lentum,

Eubacterium

aerofaciens,

Fusobacterium

mortiferum,

Fusobacterium

necrophorum,

Fusobacterium

nucleatum,

Fusobacterium varium,

Mobiluncus curtisii,

Mobiluncus mulieris,

Peptostreptococcus

anaerobius,

Peptostreptococcus

micros,

Peptostreptococcus

saccharolyticus,

Peptococcus

saccharolyticus,

Peptostreptococcus

asaccharolyticus,

Peptostreptococcus

magnus,

Peptostreptococcus

prevotii,

Propionibacterium

acnes,

Propionibacterium

avidum,

Propionibacterium

granulosum

Stenotrophomonas

maltophilia,

Enterococcus faecium

methicillin-resistant

staphylococci have

been found to be

resistant to

meropenem

Pharmacok

inetic

Properties

Studies in children

have shown that the

pharmacokinetics of

Meronem in children

are similar to those

adults.

elimination

half-life

for meropenem was

approximately 1.5 to

2.3 hours in children

under the age of 2

years

pharmacokinetics

are linear over the

dose range of 10 to

40 mg/kg

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

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

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

Special

Precaution

s for

Storage

However,

reconstituted

solutions

Meronem

maintain

satisfactory potency

at room temperature

(at 15

C - 25

C) or

under

refrigeration

C) as shown in

the following table

Reconstituted

product,

constituted

as described above,

should

used

immediately

must be stored for no

longer than 24 hours

under

refrigeration,

only if necessary

Reconstituted product, constituted as described above,

should be used immediately and must be stored for no

longer than 24 hours under refrigeration, only if

necessary

Diluent

--------------------------------------------------------------

Vials reconstituted with Water for Injection for bolus injection

Solutions (1 to 20 mg/ml) prepared with

Hours

At 15 – 25

---------------------

_____________

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