MERONEM 1 G.

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)