FRAXIPARINE 5700 IU AXa/0.6 ML

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Ï¢Ó 0.3 /2850 IU AXa

™ ÔȯÙÈÒ˜¯Ù

Ï¢Ó 0.4 /3800 IU AXa ™ ÔȯÙÈÒ˜¯Ù

Ï¢Ó 0.6 /5700 IU AXa ™ ÔȯÙÈÒ˜¯Ù

Ï¢Ó 0.8 /7600 IU AXa ™ ÔȯÙÈÒ˜¯Ù

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Nadroparin Calcium 2850 IU AXa/ 0.3 ml

Nadroparin Calcium 3800 IU AXa/ 0.4 ml

Nadroparin Calcium 5700 IU AXa/ 0.6 ml

Nadroparin Calcium 7600 IU AXa/ 0.8 ml

∫ÌÈÏÈÚÙ†È˙Ï·†ÌȯÓÂÁ

Water for injection, calcium hydroxide solution or dilute hydrochloride acid.

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∫Ï¢Ó†∞Æ¥ /3800 IU AXa ÔȯÙÈÒ˜¯Ù ±≤±≠±∑≠≥∞∞μμ≠∞∞

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†∫Ï¢Ó†∞Æ∏ /7600 IU AXa ÔȯÙÈÒ˜¯Ù ±≥≥≠≤∏≠≤π∑π∂≠∞∞

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PATIENT PACKAGE INSERT IN ACCORDANCEWITH

THEPHARMACISTS'REGULATIONS(PREPARATIONS)-1986

The dispensing of this medicine requires a physician's prescription

Read this package insert carefully in its entirety before using this medicine

The format of this leaflet was determined by the Ministry of Health

and its content was checked and approved by it in July 2010

FRAXIPARINE ™ 2850 IU AXa/ 0.3 ml

FRAXIPARINE ™ 3800 IU AXa/ 0.4 ml

FRAXIPARINE ™ 5700 IU AXa/ 0.6 ml

FRAXIPARINE ™ 7600 IU AXa/ 0.8 ml

Subcutaneous Injections

Composition:

Active ingredient and quantity:

Each syringe contains:

Nadroparin Calcium 2850 IU AXa/ 0.3 ml

Nadroparin Calcium 3800 IU AXa/ 0.4 ml

Nadroparin Calcium 5700 IU AXa/ 0.6 ml

Nadroparin Calcium 7600 IU AXa/ 0.8 ml

Inactive ingredients:

Water for injection, calcium hydroxide solution or dilute hydrochloride acid.

Therapeutic activity:

Preventive treatment of venous thromboembolism in moderate to high risk

surgery.

Treatment of deep vein thrombosis (DVT).

Prevention of blood clotting during hemodialysis.

Preventive treatment of coagulation disorders in high risk patients with

respiratory failure, respiratory infections and/or cardiac failure, hospitalized

in intensive care units.

When should the preparation not be used?

Do not use this medicine if you havea known sensitivity to any of its

ingredients, heparin and its derivatives.

In patients suffering from hemorrhage or patients at high risk for uncontrolled

bleeding.

In patients who havesuffered in the past from a decrease in number of

platelets following treatment with heparin or its derivatives.

In patients suffering from a gastric or duodenal ulcer.

In patients suffering from acute infective inflammation of the heart.

Do not use this medicine in case of hemorrhagic stroke.

In patients suffering from severe renal insufficiency, except during the course

of dialysis.

Spinal or epidural anesthesia.

Do not take this medicine without consulting a physician before starting

treatment:

If you are pregnant or breastfeeding.

If you are suffering, or havesuffered in the past, from impaired function of:

the kidney/urinary tract, the liver, the digestive system (e.g.ulcer), the heart

and/or vascular system, from uncontrolled hypertension, if you haverecently

undergone brain, spinal column or eyesurgery.

In preventive treatment - do not take this medicine without consulting a

physician before starting treatment in case of:

Severe renal insufficiency.

24 hours following an intracerebral hemorrhage.

Warnings:

During treatment with this medicine, blood tests should be performed.

If there is a marked decrease in platelet count and/or increase in potassium

levels, inform the attending physician immediately.

If you are sensitive to any type of food or medicine, including this medicine,

inform your physician before taking this medicine.

indications in which the treatment is intravenous, the medicine will be

administered by a healthcare professional.

Patients over 65, when treatment lasts more than 10 days, or patients with

renal insufficiency - should be under medical supervision.

Drug interactions:

If you are taking another drug, or if you havejust finished treatment with

another medicine, including non-prescription medicines,inform the attending

physician, in order to prevent hazards or lack of efficacy arising from drug

interactions, especially for medicines from the following groups:salicylates,

non-steroidal anti-inflammatories and antipyretics (NSAIDs), dextran 40,

anticoagulants such as:aspirin, ticlopidine.

Side effects:

In addition to the desired effect of the medicine, adverse reactions may occur

during the course of treatment with this medicine, such as:bruising at the

injection site.

Bleeding, refer to the physician immediately.

Allergic reactions such as:rash, irritation, reddening of the skin, swelling of

the face or difficulty breathing, refer to the physician immediately.

Thrombocytopenia - decrease in number of blood platelets, refer to the

physician immediately.

Risk of osteoporosis (in prolonged treatment over a number of months), refer

to the physician immediately.

Increase in blood liver enzyme level (transaminases), refer to the physician

immediately.

Increase in blood potassium level, refer to the physician immediately.

In the event that you experience side effects not mentioned in this leaflet, or

if the side effects get worse, or if there is a change in your general health,

consult your physician immediately.

Dosage:

Dosage is according to physician's instructions only.

Do not exceed the recommended dosage.

Attention: This medicine is intended for subcutaneous injection with the

exception of hemodialysis treatment in which the treatment is intravenous -

and then will be administered bya healthcare professional.

Directions for use:

Before use, please read the instructions that appear below carefully.

How can you contribute to the success of the treatment?

Complete the full course of treatment as instructed bythe physician.

Even if there is an improvement in your health, do not discontinue use of this

medicine without consulting your physician.

Avoidpoisoning! This medicine, and all other medicines, must be stored in

a safe place out of the reach of children and/or infants, to avoid poisoning.

If you havetaken an overdose, or if a child has accidentally swallowed the

medicine, proceed immediately to a hospital emergency room and bring the

package of the medicine with you.

Donotinducevomiting unless explicitly instructed to do so bya physician!

This medicine has been prescribed for the treatment of your ailment;in another

patient it may cause harm.Do not give this medicine to your relatives,

neighbors or acquaintances.

Donottakemedicinesinthedark! Check the label and the doseeachtime

you take your medicine.Wear glasses if you need them.

Storage: Store below 30 o C.

Keep the medicine in its package until it is to be used.

Even if kept in their original container and stored as recommended, medicines

may be kept for a limited period only.Please note the expiry date of the

medicine! In case of doubt, consult the pharmacist who dispensed the medicine

to you.Do not store different medications in the same package.

License numbers:

FRAXIPARINE 2850 IU AXa/ 0.3 ml: 133-26-29794-00

FRAXIPARINE 3800 IU AXa/ 0.4 ml: 121-17-30055-00

FRAXIPARINE 5700 IU AXa/ 0.6 ml: 133-27-29795-00

FRAXIPARINE 7600 IU AXa/ 0.8 ml: 133-28-29796-00

Manufacturer: GlaxoWellcome Production, Notre Dame De Bondeville, France.

License Holder and Importer: GlaxoSmithKline (Israel) Ltd.,

25 Basel St., Petach-Tikva.

Directions for use:

This medicine is intended for subcutaneous

injection with the exception of hemodialysis

treatment in which the treatment is intravenous

- and then will be administeredbya healthcare

professional.

Technique of subcutaneous injection

Subcutaneous injection should be administered

to the subcutaneous tissue of the abdomen or

the sides of the abdomen.Change the injection

site between the two sides of the abdomen

alternating.It is preferable to administer the

injection in a lying position.

Pinch a fold of skin between the thumb and

the forefinger, and insert the entire length of

the needle perpendicularly into the fold of skin.

Hold the fold of skin throughout the entire

The package contains a new syringe for use with Fraxiparine

with a simple safety system to protect the needle after injection After injection, install the safety system on theFraxiparinesyringe.

Hold the syringe well bythe safety shaft with one hand and pull firmly with

the other hand on the finger hold to unlock the shaft.Slide until you hear a

“click”sound for locking it in place.

BEFORE injection AFTER injection

safety shaft safety shaft

grasp

to unlock

safety shaft

finger

hold grasp

to lock

safety shaft

After the safety system

Click!

to unlock

The used needle is now completely protected.

The syringe can be discarded in accordance with the regular procedure for

disposing of medical waste. Click!

to lock Pull firmly on

finger hold

For improved safety, the system

has normal resistance during

unlocking and locking

Theformat of thisleaflet wasdeterminedbytheMinistryof HealthanditscontentwascheckedandapprovedinJuly2010

FRAXIPARINE

ForSubcutaneous injection(apart from the kidneydialysisindication)

PRESCRIBINGINFORMATION

1. NAMEOFTHEMEDICINALPRODUCT

FRAXIPARINE 2850 anti-factorXa IU/0.3ml,solutionforinjection inpre-filled syringes

FRAXIPARINE 3800 anti-factorXa IU/0.4ml,solutionforinjection inpre-filled syringes

FRAXIPARINE 5700 anti-factorXa IU/0.6ml,solutionforinjection inpre-filled syringes

FRAXIPARINE 7600 anti-factorXa IU/0.8ml,solutionforinjection inpre-filled syringes

2. QUALITATIVEAND QUANTITATIVECOMPOSITION

Nadroparin Calcium.

2850I.U AXa/0.3ml

3800I.U AXa/0.4ml

5700I.U AXa/0.6ml

7600I.U AXa/0.8ml

Listof Excipients

Calcium Hydroxide solution or dilute

Hydrochloricacid, waterforinjection

3. PHARMACEUTICALFORM

Solution forInjection

4. CLINICAL PARTICULARS

4.1Therapeuticindications

This heparin is a low molecularweight heparin (LMWH).

Its indications areasfollows:

Prophylactictreatmentofvenousthromboembolicdiseaseduringsurgeryforpatientspresentingwith

moderateorhighrisk.Treatmentofconstituteddeepveinthrombosis.Preventionofcoagulationin

theextracorporealcircuitduringhaemodialysis.Theprophylaxisofthromboembolicdisordersin

highriskmedicalpatients(respiratoryfailureand/orrespiratoryinfectionand/orcardiacfailure)

hospitalised in intensive careunit.

4.2Posologyand methodof administration

SUBCUTANEOUS ROUTE (apart from the kidneydialysisindication)

This dosageform is suitableforadults.

Do not inject bythe intramuscular route.

1 mlof FRAXIPARINEis equivalent to approximately9500anti-factor XaIU nadroparin.

-Subcutaneousinjection technique

Do not purgethe air bubble.

Subcutaneousinjectionofnadroparinshouldpreferablybegivenwiththepatientinthedecubitus

position,inthesubcutaneouscellulartissueoftheanterolateralandposterolateralabdominalgirdle,

onthe right and left sidealternately.

Theneedlemustbefullyinsertedperpendicularlyandnottangentiallyintothethicknessofaskin

foldmadebetweenthethumbandtheindexfingerofthepersonadministeringit.Thisskinfold

mustbemaintained throughout theinjection.

-General recommendation

Regularmonitoringofplateletcountisessentialthroughouttreatmentduetotheriskofheparin-

induced thrombopenia(HIT)(cf. chapter4.4 Warnings andprecautions for use).

Prevention ofvenous thrombo-embolicdiseaseinsurgery

Theserecommendationsgenerallyapplyto surgical procedures performedundergeneral anaesthetic.

Forspinalandepiduralanaesthesiatechniques,thevalueofinjectionbeforesurgerymustbeassessed

dueto theincreased theoretical risk of intraspinal haematoma (cf. Chapter4.4. Precautions foruse).

*Frequencyof administration

1 injection per day.

*Doseadministered

This depends on theindividual level of risk, related to the patient and thetypeof surgery.

-Situationofmoderate thrombogenicrisk:

Intheeventofsurgerywithamoderatethrombogenicriskandwhenthepatientsdonotpresenta

highthrombo-embolicrisk,effectivepreventionofthrombo-embolicdiseaseisobtainedbydaily

injection ofadoseof 2850 anti-factorXaIU(0.3ml).

Thetreatment regimen studied includes an initial injection conducted 2 hours beforesurgery.

-Situation ofhigh thrombogenicrisk:

.Hip and kneesurgery:

Thenadroparin dosagedepends on theweight of thepatient, at adosageof1 dailyinjection of:

38 anti-factorXaIU/kg

beforesurgery, i.e. 12 hours beforethe procedure,

after surgery, i.e.from the12 th

hourafter theendofthe procedure,

then dailyup to the3 rd

dayafter surgeryinclusive.

57 anti-factorXaIU/kgfrom the4 th

dayafter surgery.

Bywayofindication,thedosagestobeadministeredasafunctionofpatients’weightsareas

follows:

Bodyweight

(kg) FRAXIPARINE volume

Per injection and per day

Before surgeryand

up to the3 rd

day FRAXIPARINE volume

Per injection and per day

From the4 th

day

<51 0.2 ml 0.3 ml

51–70 0.3 ml 0.4 ml

>70 0.4 ml 0.6 ml

.Other situations:

Whenthethrombo-embolicriskrelatedtothetypeofsurgery(inparticular,oncological)and/or

thepatient(inparticular,historyofthrombo-embolicdisease)appearstobeincreased,a

nadroparin dosageof 2850IU (0.3 ml) appears tobesufficient.

*Treatment duration:

TreatmentwithaLMWH,accompaniedbytheusualelasticlowerlimbcompression

techniques, mustbemaintained until complete activedeambulation ofthe patient.

Ingeneralsurgery,thedurationofLMWHtreatmentmustbelessthan10days,intheabsence

ofanyspecificvenousthrombo-embolicriskrelatedtothepatient(Cf.Chapter4.4

Precautions foruse, platelet monitoring).

Ifthevenousthrombo-embolicriskpersistsbeyondtherecommendedtreatmentduration,itis

necessaryto considercontinuingpreventivetreatment, notablyusingoralanticoagulants.

However,theclinicalbenefitoflong-termtreatmentwithlowmolecularweightheparinor

anti-vitamin K has notbeen evaluated at thecurrent time.

. Prevention ofcoagulationoftheextra-corporalcirculationloop/kidneydialysis

INJECTIONBY THEINTRAVASCULAR ROUTE (into the arterial line ofthe dialysisloop).

Inpatientsgivenrepeatedkidneydialysissessions,preventionofcoagulationintheextra-renal

purificationloopisobtainedbyinjectinganinitialdoseof65IU/kgintothearteriallineofthe

dialysisloop at the startofthe session.

This dose, administeredas a singleintravascularbolus,is onlysuitablefordialysissessions lasting

4hoursorless.Itmaysubsequentlybeadjustedduetothehighlevelofintra-andinter-individual

variability.

Bywayofindication,thedosagestobeadministeredasafunctionofpatients’weightsareas

follows:

Bodyweight FRAXIPARINE volumeper session

<51 kg

51–70 kg

>70 kg 0.3 ml

0.4 ml

0.6 ml

Ifnecessary,thedoseisadjustedtothespecificcaseofeachpatientandthetechnicaldialysis

conditions.Insubjectswithahaemorrhagicrisk,thedialysissessionsmaybeconductedusinga

halved dose.

. Curative treatment ofdeep-veinthrombosis(DVT)

Anysuspicion of deep-vein thrombosis must be rapidlyconfirmed bymeans of appropriatetests.

*Frequencyof administration

2 injections per day,given 12 hours apart.

*Doseadministered:

Thedoseper injection is85 anti-factorXaIU/kg.

ThedosageofLMWHhasnotbeenevaluatedasafunctionofbodyweightinpatientswitha

bodyweightofmorethan100kgorlessthan40kg.TheefficacyofLMWHmaybereducedfor

patientsweighingmorethan100kg,ortheremaybeanincreasedhaemorrhagicriskforpatients

weighingless than 40 kg.Specific clinical monitoringis required.

Bywayofindication,thedosagestobeadministeredasafunctionofpatients’weightsare0.1

ml/10 kgevery12 hours,as indicated in the tablebelow:

Bodyweight FRAXIPARINE volumeper injection

40–49 kg

50–59 kg

60–69 kg

70–79 kg

80–89 kg

90–99 kg

100 kg 0.4 ml

0.5 ml

0.6 ml

0.7 ml

0.8 ml

0.9 ml

1.0 ml

Adjustthevolumetobeadministeredbymovingthepistontothedesiredgraduation,holdingthe

syringeupright.

*Treatment duration forDVT:

TreatmentwithLMWHmustbequicklyswitchedtooralanticoagulants,unlesscontraindicated.

TheLMWHtreatmentdurationmustnotexceed10days,includingthestabilisingperiodwith

AVKs,unlesstherearestabilisingdifficulties(Cf.Chapter4.4.Precautionsforuse:platelet

monitoring). Oral anticoagulant treatment should thereforebeinstigatedassoon as possible.

Theprophylaxisofthromboembolicdisordersinhighriskmedicalpatients(respiratory

failureand/orrespiratoryinfectionand/orcardiacfailure)hospitalisedinintensivecare

unit

Nadroparinisadministeredsubcutaneouslyoncedaily.Thedoseshouldbeadjustedforbody

weightaccordingtothetablebelow.Treatmentshouldbecontinuedthroughouttheriskperiodof

thromboembolism.

Bodyweight

(kg) Oncedaily

Volumeinjected(ml) Anti-Xa IU

≤70 0.4 3,800

>70 0.6 5,700

RenalImpairment

Prophylaxis ofthromboembolicdisorders

Dosereduction isnot required in patients with mildrenal impairment (creatinine clearancegreater

than orequal to 50ml/min). Moderateand severerenalimpairment is associated with increased

exposureto nadroparin. Thesepatients areat increased risk ofthromboembolismand

haemorrhage.

Ifadosereduction isconsidered appropriatebytheprescribingphysician, takinginto account the

individual risk factors forhaemorrhageand thromboembolismin patientswith moderate renal

impairment (creatinine clearancegreater than orequal to 30 ml/min and less than 50ml/min) the

doseshould bereduced by25 to 33% (seeWarnings andPrecautions and Pharmacokinetics).

Thedoseshouldbereducedby25%to33%inpatientswithsevererenalimpairment(creatinine

clearanceless than30ml/min)(seeWarnings andPrecautions and Pharmacokinetics).

Treatment ofthromboembolicdisorders

Dosereductionisnotrequiredinpatientswithmildrenalimpairment(creatinineclearancegreater

than orequal to 50ml/min).

Moderateandsevererenalimpairmentisassociatedwithincreasedexposuretonadroparin.These

patients areat increased risk of thromboembolismand haemorrhage.

Ifadosereductionisconsideredappropriatebytheprescribingphysician,takingintoaccountthe

individualriskfactorsforhaemorrhageandthromboembolisminpatientswithmoderaterenal

impairment(creatinineclearancegreaterthanorequalto30ml/minandlessthan50ml/min)the

doseshould bereduced by25 to 33% (seeWarnings andPrecautions and Pharmacokinetics).

Nadropariniscontraindicatedinpatientswithsevererenalimpairment(seeWarningsand

Precautions and Pharmacokinetics).

4.3Contraindications

Irrespectiveofthedoses(curativeorpreventive),thisdrugMUSTNOTBEUSEDinthefollowing

situations:

-hypersensitivityto nadroparinoranyof theexcipients of nadroparin injections;

-historyofseveretype-IIheparin-inducedthrombopenia(orHIT)inducedunderunfractionated

heparin orunder lowmolecularweight heparin (Cf. Chapter4.4 Precautions foruse);

-haemorrhagicsignsortendencieslinkedtohaemostasisdisorders(disseminatedintravascular

coagulationsmaybeanexceptiontothisruleifthesearenotrelatedtoheparintreatment–Cf.

Chapter4.4 Precautions foruse);

-organic lesion liableto bleed.

At curativedoses, this drugMUST NOTBE USED in the followingsituations:

-intracerebral haemorrhage;

-intheabsenceofdata,severekidneyfailure(definedbycreatinineclearanceofapproximately30

ml/minaccordingtocalculationusingtheCockroftformula),apartfromthespecificsituationof

dialysis.In severekidneyfailure, useunfractionated heparin.

ForcalculationoftheCockroftformula,itisnecessarytohavearecentweightofthepatient(Cf.

Chapter4.4 Precautions foruse).

-Inaddition,anepiduralorspinalanaestheticmustneverbegivenintheeventofcurative

treatment withLMWH.

At curativedoses, this drugis NOT GENERALLYRECOMMENDED in the followingsituations:

-extensiveischemiccerebrovascularaccidentintheacutephase,withorwithoutimpaired

consciousness.Whenthestrokeisofembolicorigin,theperiodtobecompliedwithis72hours.

EvidenceoftheefficacyofLMWHatcurativedoseshasnot,however,beenestablishedtodate,

irrespectiveof thecause,extent and clinical severityof thecerebral infarction;

-acute infectious endocarditis (apart from certain emboligenic cardiopathies);

mild to moderate kidneyfailure(creatinine clearance>30 and<50ml/min)(Cf. Chapter 4.2Posology

and method ofadministration).

Inaddition,thisdrugatcurativedosesisNOTGENERALLYRECOMMENDEDinsubjectsofany

ageincombinationwith(Cf.Chapter4.5Interactionswithothermedicinalproductsandotherforms

ofinteractions)

+ acetylsalicylicacidatanalgesic, antipyreticandanti-inflammatory doses,

+ NSAIDs(systemic route),

+ dextran40(parenteralroute).

At preventivedoses, thisdrugis NOT GENERALLY RECOMMENDED in the followingsituations:

severekidneyfailure(creatinineclearanceofapproximately30ml/minaccordingtocalculationusing

theCockroftformula,Cf.Chapter4.4PrecautionsforuseandChapter4.2Posologyandmethodof

administration).

-within the first 24 hours followingan intracerebralhaemorrhage.

Inaddition,atpreventivedoses,thisdrugisNOTGENERALLYRECOMMENDEDinelderly

subjectsovertheageof65,incombinationwith(Cf.Chapter4.5Interactionswithothermedicinal

products and otherformsof interactions):

+ acetylsalicylicacidatanalgesic, antipyreticandanti-inflammatory doses,

+ NSAIDs(systemic route),

+ dextran40(parenteralroute).

4.4Special warnings andspecial precautions foruse

Althoughthevariousproprietarylowmolecularweightheparinproductsallhavetheirconcentrations

expressedinanti-factorXainternationalunits,theirefficacyisnotlimitedtothisanti-factorXa

activity.ItwouldbedangeroustosubstitutethedosageregimenofoneLMWHforanother,since

eachregimenhasbeenvalidatedbyspecificclinicaltrials.Particularcautionisthereforerequiredand

the specific instructions foruse foreach proprietarymedicinal product must be complied with.

Warnings

. Haemorrhagic risk

Itisessentialtofollowtherecommendedtreatmentregimens(dosagesandtreatmentdurations).

Otherwise,haemorrhagicaccidentscouldoccur,particularlyinpatientsatrisk(elderlysubjects,

patients with kidneyfailure, etc.).

Serious haemorrhagic accidents havenotablybeen observed:

- in theelderly, in particular dueto thedeterioration in kidneyfunction related to age,

- in theevent of kidneyfailure,

- in theevent of abodyweight under40 kg

- in theevent of treatment prolonged beyond the recommended mean duration of10days,

- intheeventofnon-compliancewiththerecommendedtreatmentconditions(inparticular

treatment duration and dosageadjustment on thebasisof weight forcurativetreatments),

- in the event of combination with drugs increasing the haemorrhagic risk

(Cf. Chapter4.5Interactions with othermedicinalproducts and otherformsof interactions).

Cautionshouldbeexercisedwhennadroparinisadministeredinthefollowingsituationsastheymaybe

associated with an increased risk ofbleeding:

hepaticfailure

severearterial hypertension

historyof pepticulceration orotherorganic lesion likelyto bleed

vasculardisorder ofthechorio-retina

duringthe post-operativeperiod followingsurgeryof thebrain, spinal cordoreye.

RenalImpairment

Nadroparin is known to be mainlyexcreted bythekidney, which results in increased nadroparin

exposurein patients with renal impairment(seePharmacokinetics–RenalImpairment). Patients

with impaired renal function areat increased riskofbleedingand should betreatedwith caution.

Thedecision on whetheradosereduction isappropriate forpatients with creatinineclearance30

to 50 ml/min should be based on the physician’s assessment of an individualpatient's risk of

bleedingversus the risk of thromboembolism.

Inallcases,specificmonitoringisessentialintheelderlyand/orsubjectswithkidneyfailure,and

alsointheeventoflong-termtreatmentformorethan10days.Inordertodetectany

accumulation,measurementofanti-factorXaactivitycanbeusefulincertaincases(Cf.Chapter

4.4 Precautions foruse/Laboratorymonitoring).

. Risk of heparin-induced thrombopenia(HIT)

IntheeventofapatienttreatedwithLMWH(atcurativeorpreventivedoses)presentinga

thrombotic event, such as:

- an exacerbation ofthe thrombosis forwhich he/sheis beingtreated,

- phlebitis,

- pulmonaryembolism,

- acute ischemiaof thelower limbs,

- oreven myocardial infarction orischemiccerebrovascularaccident,

onemustsystematicallyconsiderheparin-inducedthrombopenia(HIT)andurgentlyperforma

platelet count (Cf. Chapter 4.4Precautions foruse).

. Usein children

In theabsenceof data, theuse ofLMWHs in children is not recommended.

Precautions foruse

. Kidneyfunction

BeforestartingtreatmentwithLMWH,itisessentialtoassesskidneyfunction,particularlyinthe

elderlyover theageof75years, calculatingcreatinine clearance(Clcr)usingtheCockroft formula

and on the basisof arecent weight for thepatient:

Inmen,Clcr=(140–age)xweight/(0.814xserumcreatinine)withageexpressedinyears,

weight in kgand serum creatinine in µmol/l.

This formulamustbecorrectedforwomen bymultiplyingtheresultby0.85.

When creatinine is expressed in mg/ml, multiplybyafactor of8.8.

Detectionofseverekidneyfailure(Clcrofapproximately30ml/min)contraindicatesthe

prescription ofLMWH in curativeindications (Cf. Chapter 4.3Contraindications).

. Laboratorymonitoring

*Platelet monitoring

Heparin-induced thrombopenia (orHIT)

Thereisariskofseverethrombopenia,sometimescausingthrombosis,inducedbyheparin

(unfractionatedheparinand,lesscommonly,lowmolecularweightheparins),ofimmunological

origin, calledtypeIIthrombopenia(seealsoChapter4.8 Undesirable effects).

DuetotheriskofHIT,monitoringofplateletcountisnecessary,irrespectiveoftheindicationfor

treatmentandthedosageadministered.Performaplateletcountbeforetreatmentor,atthelatest,

within24hoursaftertreatmentinstigation,thentwiceweeklythroughouttheusualdurationofthe

treatment.

HITmustbesuspectediftheplateletcountis<100,000/mm 3

and/orthereisarelativefallin

plateletsof30to50%in2successivecounts.Itmainlydevelopsbetweenthe5 th

and21 st

day

followingthe start of heparin treatment (with a peak in frequencyataroundthe 10 th

day).

Butitcanoccurmuchearlierwhenthereisahistoryofthrombopeniaunderheparintreatmentand

isolatedcaseshavebeenreportedbeyond21days.Thistypeofhistorymustbesystematically

investigatedduringanin-depthinterviewpriortotreatment.Inaddition,theriskofrecurrencein

theeventofthereintroductionofheparincouldpersistforseveralyearsorevenindefinitely(Cf.

Chapter4.3 Contraindications).

Inallcases, the onset ofHIT isan emergencysituationand requires specialistadvice.

Anysignificantfall(30to50%oftheinitialvalue)inplateletcountmustbeseenasanalert,

beforethevaluereachesacriticallevel.Observationofafallinthenumberofplateletsalways

demands:

1)-an immediate platelet count;

2)–thesuspensionofheparintreatmentifthefallisconfirmedorevenaccentuatedatthiscount,

in theabsenceof anyother obvious cause.

Asamplemustbetakeninacitratetubetoperformplateletaggregationtestsinvitroand

immunologicaltests.But,undertheseconditions,theimmediatemeasurestobetakendonot

dependontheresultsoftheseinvitroorimmunologicalplateletaggregationtestsbecauseonlya

fewspecialisedlaboratoriesconductthemroutinelyandtheresultsareobtained,atbest,onlyafter

severalhours.Thesetestsmustnonethelessbeperformedtoassistthediagnosisofthis

complication sinceif heparin treatment is continued, thereis a majorrisk ofthrombosis.

3)–prevention ortreatment of thromboticcomplications of HIT.

Ifitappearstobeessentialtocontinueanticoagulation,heparinmustbereplacedwithanother

classofantithrombotic:danaparoidsodiumorhirudin,prescribedatpreventiveorcurativedoses

dependingonthecase.SubstitutionwithAVKsshouldonlytakeplaceoncetheplateletcounthas

normalised, dueto therisk of exacerbation ofthe thrombotic phenomenonbyAVKs.

*Substitutionof heparinwithAVKs

Inthiscase,reinforceclinicalandlaboratorymonitoring(QuicktimeexpressedinINR)to

monitor theeffect of AVKs.

DuetothelatencytimepriortothefulleffectoftheantivitaminKused,heparinmustbe

maintainedatanequivalentdoseforaslongasnecessarytoensurethattheINRiswithinthe

desired therapeuticzoneofthe indication at two successivecontrols.

*Controlof anti-factor Xa activity

SincethemajorityofclinicaltrialsdemonstratingtheefficacyofLMWHhavebeen conductedat

adosetailoredtobodyweightandwithoutanyspecificlaboratorymonitoring,thevalueofthis

typeoflaboratorymonitoringhasnotbeenestablishedtoassesstheefficacyofLMWH.However,

laboratorymonitoringbydeterminationofanti-factorXaactivitymaybeusefultomanagethe

haemorrhagic risk in someclinical situationsfrequentlyassociated with a risk of overdose.

ThesesituationsmainlyconcernthecurativeindicationsofLMWH,duetothedoses

administered, when thereis:

-mildtomoderatekidneyfailure(clearancecalculatedusingtheCockroftformulaofaround30

to50ml/min):infact,incontrastwithunfractionatedstandardheparin,LMWHsarelargely

eliminatedbythekidneysandanyimpairedkidneyfunctioncanleadtorelativeoverdose.As

forseverekidneyfailure,thisisacontraindicationtotheuseofLMWHsatcurativedoses(Cf.

Chapter4.3 Contraindications);

-an extreme weight (underweight or even cachexia, obesity);

-unexplained haemorrhage.

Conversely,laboratorymonitoringisnotrecommendedatpreventivedosesiftreatmentwith

LMWHcomplieswiththerecommendedtreatmentconditions(particularlyfortreatmentduration)

and duringkidneydialysis.

Inordertodetectapossibleaccumulationafterseveraladministrations,itisrecommendedthata

bloodsamplebetakenfromthepatientifnecessaryatthepeakactivity(accordingtothedata

available), i.e.:

- approximately4hoursafterthe3 rd

administration,whenthedrugisgivenas

2 SCinjections per day,

- approximately4hoursafterthe2 nd administration,whenthedrugisgivenas

1 SCinjection per day.

Repetitionofassayofanti-factorXaactivitytomeasureserumheparinlevels–every2to3days,

forexample–shouldbediscussedonacase-by-casebasis,dependingontheresultsofthe

previousassayandadjustment oftheLMWH doseshould beconsidered ifnecessary.

ForeachLMWH andeach treatment regimen, theanti-factorXaactivitygenerated is different.

Bywayofindicationandaccordingtothedataavailable,themeanobserved(

standard

deviation) at the4 th

hourfornadroparin, administered:

- at a doseof83 IU/kgbyinjection, as 2 injections per 24 hours, was1.01

0.18IU.

- at a doseof166 IU/kgas1 injection per24 hours,was1.34

0.15 IU.

Thismeanvaluewasobservedduringclinicaltrialsforassaysofanti-factorXaactivityconducted

usingthe chromogenic method (amidolytic).

*Activated partial thromboplastintime(APTT)

CertainLMWHsmoderatelyprolongAPTT.Intheabsenceofanyestablishedclinicalrelevance,

anytreatment monitoring based on this test is pointless.

Hyperkalaemia

Heparincansuppressadrenalsecretionofaldosteroneleadingtohyperkalaemia,particularlyin

patientswithraisedplasmapotassium,oratriskofincreasedplasmapotassiumlevels,suchas

patientswithdiabetesmellitus,chronicrenalfailure,pre-existingmetabolicacidosisorthose

takingdrugs that maycause hyperkalaemia(e.g.ACE inhibitors, NSAIDs).

Therisk of hyperkalaemiaappears to increasewith duration oftherapybutis usuallyreversible.

Plasmapotassiumshouldbemonitored in patients at risk.

. Administration ofspinal/epidural anaestheticin theevent of preventivetreatment withLMWH

- Aswithotheranticoagulants,rarecasesofintraspinalhaematomaleadingtolong-termor

permanentparalysishavebeenreportedduringtheadministrationofLMWHduringspinalor

epidural anaesthetic.

Theriskofintraspinalhaematomaappearstobehigherwithanepiduralusingacatheterthan

with a spinal anaesthetic.

Theriskoftheserareeventsmaybeincreasedbytheprolongeduseofepiduralcathetersafter

surgery.

- Ifpre-surgicaltreatmentwithLMWHisnecessary(prolongedbedrest,injury)andthebenefit

ofaloco-regionalspinalanaesthetichasbeencarefullyevaluated,thistechniquemaybeused

inapatienthavingreceivedaninjectionofLMWHbeforesurgery,aslongasaperiodofat

least 12hoursis left between theheparin injection andadministration of thespinal anaesthetic.

Careful neurological monitoringis recommendeddueto therisk of intraspinal haematoma.

Inalmostallcases,preventivetreatmentwithLMWHcanbestartedwithin6to8hours

followingthe techniqueorremoval ofthecatheter, under neurological monitoring.

Particularcautionisrequiredintheeventofcombinationwithotherdrugsinterferingwith

haemostasis(notablynonsteroidal anti-inflammatories, aspirin).

. Situations at risk

Monitoringof treatmentshould bereinforced in thefollowingcases:

. liver failure,

. historyofgastrointestinal ulcers oranyother organic lesionsliable to bleed,

. vasculardiseases of thechorioretina,

.inthepost-operativeperiodfollowingbrainandspinalbonemarrowsurgery,the

performanceofalumbarpuncturemustbediscussed,takingintoaccounttheriskof

intraspinal bleeding.It must be deferred whereverpossible.

. LatexAllergy

Theneedleguardofthepre-filledsyringecontainsdrynaturallatexrubberthathasthe

potential to cause allergicreactions in latexsensitive individuals.

4.5Interactions with othermedicinal products andotherforms of interaction

Certaindrugsortherapeuticclassesareliabletopromotetheonsetofhyperkalaemia:potassiumsalts,

hyperkalaemicdiuretics,conversionenzymeinhibitors,angiotensinIIinhibitors,nonsteroidalanti-

inflammatories,heparins(lowmolecularweightorunfractionated),ciclosporinandtacrolimus,

trimethoprim.

Theonset of hyperkalaemiamaydepend on theexistenceofconcomitant risk factors.

This risk is increased in theevent ofcombination with theabovementioned drugs.

1. Insubjects under theageof 65at curativeLMWHdoses,

andintheelderly(> 65years) irrespectiveof theLMWHdose

Inadvisablecombinations

+Acetylsalicylicacidatanalgesic,antipyreticandanti-inflammatorydoses(and,by

extrapolation, other salicylates)

Increaseinhaemorrhagicrisk(inhibitionofplateletfunctionandaggressionofthegastro-

duodenal mucosa bysalicylates),

Useanon-salicylate antipyreticanalgesic (suchas paracetamol).

+NSAIDs(systemicroute)

Increaseinhaemorrhagicrisk(inhibitionofplateletfunctionandaggressionofthegastro-

duodenal mucosa bynonsteroidal anti-inflammatories),

Ifthe combinationcannot be avoided, closeclinical monitoring.

+Dextran40(parenteral route)

Increasein haemorrhagicrisk (inhibition of platelet function byDextran 40).

Combinations requiringprecautions for use

+Oral anticoagulants

Potentiation of anticoagulant action

When switchingfrom heparin to an oralanticoagulant, reinforceclinical monitoring.

Combinations to betaken into account

+Plateletanti-aggregants(otherthanacetylsalicylicacidatanalgesic,antipyreticandanti-

inflammatorydoses;NSAIDs):abciximab,acetylsalicylicacidatanti-aggregantdosesin

cardiologicalandneurologicalindications,beraprost,clopidogrel,eptifibatide,iloprost,

ticlopidine, tirofiban

Increasein haemorrhagicrisk.

2. Insubjects under theageof 65at preventiveLMWHdoses

Combinations to betaken into account

Theconcomitantuseofdrugsactingatvariouslevelsonhaemostasisincreasestheriskofbleeding.

Thus,irrespectiveofage,combinationofLMWHsatpreventivedoseswithoralanticoagulants,

plateletanti-aggregants(abciximab,NSAIDs,acetylsalicylicacidirrespectiveofdose,clopidogrel,

eptifibatide,iloprost,ticlopidine,tirofiban)andthrombolyticsmustbetakenintoaccount,maintaining

clinical and, ifnecessary,laboratorymonitoring.

4.6Pregnancyand lactation

Pregnancy

Studies conducted in animals havenot revealedanyteratogeniceffect of nadroparin.

Intheabsenceofanyteratogeniceffectinanimals,nomalformativeeffectisexpectedinhumans.In

fact,todate,substancesresponsibleformalformationsinhumanshavebeenshowntobeteratogenic

in animals duringproperlyconducted studies in two species.

Preventivetreatment in the 1 st trimesterand curativetreatment

Inaclinicalcontext,therearenotyetenoughrelevantdatainordertoevaluateapossibleteratogenic

orfoetotoxiceffectofnadroparinwhenadministeredatapreventivedoseduringthefirsttrimesterof

pregnancyor at acurativedosethroughout pregnancy.

Consequently,asaprecautionarymeasure,itispreferabletoavoiduseofnadroparinatapreventive

doseduringthefirst trimester ofpregnancyor at acurativedosethroughoutpregnancy.

Preventivetreatment in the 2 nd and 3 rd trimesters

Inaclinicalcontext,theuseofnadroparinduringthe2 nd and3 rd trimestersofalimitednumberof

pregnanciesdoesnotappeartohaveevidencedanyteratogenicorfoetotoxiceffectstodate.However,

furtherstudies arenecessaryin order toevaluatetheconsequences of exposureunder theseconditions.

Consequently,theuseofnadroparinatapreventivedoseduringthe2 nd and3 rd trimestersof

pregnancymustonlybeenvisaged duringpregnancyif necessary.

Ifepiduralanaesthesiaisenvisaged,itisadvisabletosuspendheparintreatmentatthelatestwithin12

hours priorto anaesthesia, insofar as possible,forpreventivetreatment.

Lactation

Thereislimitedinformationontheexcretionofnadroparininbreastmilk.Therefore,theuseof

nadroparin duringbreastfeedingis not advised.

4.7Effects onabilitytodriveand usemachines

Not applicable.

4.8AdverseReactions

Adversereactions arelisted below bysystem organ class and frequency.

Thefollowingconventionhasbeenusedfortheclassificationofadversereactionsintermsoffrequency:

Verycommon≥1/10,common≥1/100and<1/10,uncommon≥1/1000and<1/100,rare≥1/10,000and

<1/1000, veryrare<1/10,000.

Blood& lymphatic systemdisorders

Verycommon: Haemorrhagicmanifestationsatvarioussites,morefrequent

inpatientswithotherriskfactors(seeContraindicationsand

Interactions).

Rare: Thrombocytopenia,sometimesthrombogenic(seeWarnings

and Precautions), thrombocytosis.

Veryrare: Eosinophilia, reversiblefollowingtreatment discontinuation.

Immunesystemdisorders

Veryrare: Hypersensitivityreactions(includingangioedemaand

cutaneous reactions),anaphylactoid reaction.

Metabolism& nutritiondisorders

Veryrare: Reversiblehyperkalaemiarelatedtoheparin-induced

aldosteronesuppression,particularlyinpatientsatrisk(see

Warnings andPrecautions).

Hepato-biliary disorders

Common: Raised transaminases, usuallytransient.

Reproductivesystem&breast disorders

Veryrare: Priapism.

General disorders andadministrationsiteconditions

Verycommon: Small haematoma at theinjection site.

Insomecases,theemergenceoffirmnodules,whichdonotindicatean

encystmentoftheheparinmaybenoted.Thesenodulesusuallydisappearafter

afewdays.

Common: Injection site reaction.

Rare: Calcinosis at theinjection site.

Calcinosisismorefrequentinpatientswithabnormalcalciumphosphate

product, such as in somecases ofchronic renal failure.

Veryrare: Cutaneous necrosis, usuallyoccurringat theinjection site.

Cutaneousnecrosisisprecededbypurpuraorinfiltratedorpainful

erythematousblotches,withorwithoutgeneralsigns.Insuchcases,treatment

should beimmediatelydiscontinued.

4.9Overdose

-Accidentaloverdosefollowingthesubcutaneousadministrationofmassivedosesoflowmolecular

weight heparin couldcausehaemorrhagic complications.

Intheeventofhaemorrhage,treatmentwithprotaminesulphatemaybeindicatedincertaincases,

takinginto account thefollowingfacts:

.itsefficacyissignificantlylessthanthatreportedintheeventofoverdosewithunfractionated

heparin;

.duetoitsadverseevents(inparticular,anaphylacticshock),thebenefit/riskratioofprotamine

sulphate mustbecarefullyassessed beforeitis prescribed.

Inthisevent,neutralisationisconductedbyslowintravenousinjectionofprotamine(sulphateor

hydrochloride).

Theeffectiveprotaminedosedepends on:

.the heparin doseinjected(100anti-heparin units of protamine can beusedto neutralisethe activity

of100 anti-factor XaIUoflow molecularweight heparin),

.the timeelapsed sinceinjection ofthe heparin, with possible reduction oftheantidote doses.

Nevertheless, it is notpossible to totallyneutralisethe anti-factor Xaactivity.

Moreover,theabsorptionkineticsoflowmolecularweightheparinmaymakethisneutralisation

transientandrequirefragmentationofthetotalcalculatedprotaminedoseintoseveralinjections(2

to 4) divided over 24 hours.

-Intheeventofingestion–evenmassive–oflowmolecularweightheparin(nocasesreported),no

seriousconsequencesare,inprinciple,expected,giventheverylowgastrointestinalabsorptionof

the product.

5. PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

B01 AB 06: ANTI-THROMBOTICS

- Nadroparinisalowmolecularweightheparininwhichtheantithromboticandanticoagulant

properties ofstandard heparin havebeen split.

It ischaracterised byahigher anti-factorXaactivitythananti-factorIIaor thromboticactivity.For

nadroparin, theratio between thesetwo activitiesisbetween2.5 and4.

-Atprophylactic doses, nadroparin doesnotcauseanymarked changesin APTT.

Atcurativedoses,atthepeakactivity,APTTmaybeprolongedto1.4timesthereferencetime.

This prolongation isareflection ofthe residualantithrombotic effect of nadroparin.

5.2Pharmacokinetic properties

Thepharmacokineticparametersarestudiedonthebasisoftheevolutioninplasmaanti-factorXa

activities.

- Bioavailability

Aftersubcutaneousinjection,almost100%oftheproductisrapidlyabsorbed.Peakplasma

activityisreachedbetweenthe3 rd

andthe4 th

hourifnadroparinisadministeredas2injectionsper

day.

Thispeakisshiftedtobetweenthe4 th

andthe6 th

hourifnadroparinisadministered

as 1 injection per day.

- Metabolism

This mainlyoccurs in theliver (desulfatation, depolymerisation).

- Distribution

Aftersubcutaneousinjection,thehalf-lifeofanti-factorXaactivityishigherforlowmolecular

weight heparins than forunfractionated heparins.

This half-lifeis around 3to 4 hours.

Asfortheanti-factorIIaactivity,thisdisappearsmorerapidlyfromtheplasmathantheanti-factor

Xaactivitywith low molecularweight heparins.

- Elimination

Elimination is primarilybythe renal routein littleor non-metabolised form.

- Populationsat risk

*Theelderly:

Intheelderly,sincekidneyfunctionisphysiologicallyreduced,eliminationissloweddown.This

modificationdoesnotaffectthedosesandrhythmofinjectionsforpreventivetreatmentaslongas

the kidneyfunction ofthesepatients remains within acceptable limits, i.e. onlyslightlyimpaired.

Itisessentialtosystematicallyassessthekidneyfunctionofelderlysubjectsovertheageof75

usingtheCockroftformula,beforeinstigatingLMWHtreatment(Cf.4.2Posologyandmethodof

administration,Chapter4.4 Precautions foruse).

RenalImpairment

Inaclinicalstudyinvestigatingthepharmacokineticsofnadroparinadministeredintravenouslyin

patientswithvaryingdegreesofrenalimpairment,acorrelationwasfoundbetweennadroparin

clearanceandthecreatinineclearance.Inpatientswithmoderaterenalimpairment(creatinine

clearance36-43ml/min)bothmeanAUCandhalf-lifewereincreasedby52and39%respectively

comparedwithhealthyvolunteers.Inthesepatients,meanplasmaclearanceofnadroparinwas

decreasedto63%ofnormal.Wideinter-individualvariabilitywasobservedinthestudy.Insubjects

withsevererenalimpairment(creatinineclearance10-20ml/min)bothmeanAUCandhalf-lifewere

increasedby95and112%respectivelycomparedwithhealthyvolunteers.Plasmaclearancein

patientswithsevererenalimpairmentwasdecreasedto50%ofthatobservedinpatientswithnormal

renalfunction.Insubjectswithsevererenalimpairment(creatinineclearance3-6ml/min)on

haemodialysis,bothmeanAUCandhalf-lifewereincreasedby62and65%respectivelycompared

withhealthyvolunteers.Plasmaclearanceinhaemodialysispatientswithsevererenalimpairmentwas

decreasedto67%ofthatobservedinpatientswithnormalrenalfunction(seeWarningsand

Precautions).

*Mild to moderate kidneyfailure (creatinine clearance>30ml/min):

Itmaybeusefulincertaincasestomonitorcirculatinganti-factorXaactivitytoeliminatethe

possibilityof overdoseincurativeindications (Cf.Chapter4.4. Precautions foruse).

*Kidneydialysis:

Lowmolecularweightheparinisinjectedintothearteriallineofthedialysisloopathighenough

doses to prevent coagulation of theloop.

Inprinciple,thepharmacokineticparametersarenotmodified,exceptforintheeventofoverdose,

whenpassageintothesystemiccirculationcanleadtoanincreasedanti-factorXaactivity,related

to theterminal kidneyfailure.

5.3Preclinical safetydata

Not applicable.

6. PHARMACEUTICALPARTICULARS

6.1Incompatibilities

Not applicable.

6.2Shelf life

3years.

6.3Special precautions forstorage

Storebelow 30°C.

Storein original packaginguntil timeof use.

6.4Natureand contentsofcontainer

0.3mlor0.4mlor0.6mlor0.8mlofinjectablesolutioninapre-filledsyringe(glass)withsecurity

device; transparent plasticsleeve;boxof 2or10

MANUFACTURED BY:

GlaxoWellcomeProduction,NotreDameDeBondeville,France

LICENSEHOLDER:

GlaxoSmithKline(Israel)Ltd.

25 Basel St., Petach Tikva49002

LICENSENUMBER:

FRAXIPARINE 2850IUAXa/ 0.3 ML 311-64-67572

FRAXIPARINE 3800IUAXa/ 0.4 ML 363-35-10033

FRAXIPARINE 5700IUAXa/ 0.6 ML 311-65-67573

FRAXIPARINE 7600IUAXa/ 0.8 ML 311-66-67574