Clexane Forte

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Enoxaparin sodium 150 mg/mL;  
Available from:
sanofi-aventis new zealand limited
INN (International Name):
Enoxaparin sodium 150 mg/mL
Dosage:
150 mg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Enoxaparin sodium 150 mg/mL   Excipient: Water for injection
Units in package:
Syringe, glass, Type 1 glass 0.8mL, 1.0mL, 8, 15 syringes (not marketed),
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Aventis Pharma Manufacturing Pte Ltd
Therapeutic indications:
- Treatment of venous thromboembolic disease. - Prevention of thrombus formation in the extra-corporeal circulation during haemodialysis.
Product summary:
Package - Contents - Shelf Life: Syringe, glass, Type 1 glass 0.8mL, 1.0mL, 8, 15 syringes -   - 24 months from date of manufacture stored at or below 25°C - Syringe, glass, Type 1 glass 0.8mL syringes with automatic safety lock system - 10 dose units - 24 months from date of manufacture stored at or below 25°C - Syringe, glass, Type 1 glass 1.0mL syringes with automatic safety lock system - 10 dose units - 24 months from date of manufacture stored at or below 25°C - Syringe, glass, Type 1 glass 0.8mL syringes - 10 dose units - 24 months from date of manufacture stored at or below 25°C - Syringe, glass, Type 1 glass 1.0mL syringes - 10 dose units - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-4648/4
Authorization date:
1999-05-10

Clexane

®

and Clexane

®

Forte*

enoxaparin sodium

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about Clexane.

It does not contain all the available

information.

It does not take the place of talking to

your doctor or pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you using Clexane

against the benefits they expect it

will have for you.

If you have any concerns about

using this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Clexane is used

for

Clexane is used in a number of

medical conditions. It is used to:

treat blood clots

treat certain types of heart disease

(eg. angina and heart attacks),

when used with aspirin

prevent blood clots forming after

an operation, during

hospitalisation or extended bed

rest or during purification of the

blood by an artificial kidney

(haemodialysis).

Clexane is one of a group of

medicines called low molecular

weight heparins (LMWH). These

medicines work by reducing blood

clotting activity.

Your doctor may have prescribed

Clexane for another reason.

Ask your doctor if you have any

questions about why Clexane has

been prescribed for you.

There is no evidence that Clexane is

addictive.

This medicine is only available with

a doctor's prescription.

Before you are given it

When you must not use it

Do not use Clexane if you have an

allergy to Clexane (enoxaparin

sodium), heparin or its derivatives

including other LMWHs. Some

signs and symptoms of an allergic

reaction can include swelling of the

face, lips or tongue, wheezing or

troubled breathing, skin rash,

itching hives, blisters or peeling

skin.

Do not use Clexane if you have, or

have ever had any of the following

medical conditions:

major blood disorders

certain types of stroke

stomach or bowel problems such

as ulcers or ulcerative colitis

bacterial infections in your heart.

Do not give Clexane to a child.

The safety and effectiveness of

Clexane has not been established in

children.

Do not use Clexane after the expiry

date printed on the syringe.

Do not use Clexane if the

packaging is torn or shows signs of

tampering.

If you are not sure whether you

should start using Clexane, talk to

your doctor or pharmacist.

Before you are given it

Tell your doctor or pharmacist if

you have allergies to:

heparin or its derivatives,

including other LMWHs

any other medicines

any other substances, such as

foods, preservatives or dyes.

Tell your doctor or pharmacist if

you have or have had any of the

following medical conditions:

major bleeding disorder or blood

clotting problem, including a

recent stroke or hereditary blood

disorders

bacterial endocarditis,

inflammation of the lining of the

heart caused by bacteria

stomach or bowel problems such

as ulcers or ulcerative colitis

kidney or liver disease

uncontrolled high blood pressure

diabetic related eye disease

recently undergone brain, spinal

or eye surgery

history of spinal surgery or spinal

deformity

an artificial heart valve

obesity

high level of potassium in your

blood

CLEXANE

AND CLEXANE

FORTE*

If you have not told your doctor or

pharmacist about any of the above,

tell them before you start using

Clexane.

Tell your doctor or pharmacist if

you are pregnant or intend to

become pregnant.

Like most LMWHs, Clexane is not

recommended to be used during

pregnancy. If there is a need to

consider Clexane during your

pregnancy, your doctor or pharmacist

will discuss with you the benefits and

risks of using it.

Tell your doctor or pharmacist if

you are breastfeeding or plan to

breastfeed.

Like most LMWHs, Clexane is not

recommended while you are

breastfeeding. If there is a need to

consider Clexane while you are

breastfeeding, your doctor or

pharmacist will discuss with you the

benefits and risks of using it.

Tell your doctor that you are using

Clexane if your doctor is planning

for you to have an anaesthetic

injection in your back (spinal or

epidural injection).

If you have not told your doctor or

pharmacist about any of the above,

tell them before you start using

Clexane.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including any that you

buy without a prescription from

your pharmacy, supermarket or

health food shop.

Some medicines and Clexane may

interfere with each other. These

include:

medicines or substances used to

prevent and treat blood clots

medicines containing aspirin or

salicylates

Dextran 40, a medicine use to

treat shock

medicines used to treat

inflammatory disease, such as

oral non-steroidal anti-

inflammatory medicines or

corticosteroids.

medicines which increase

potassium levels in your blood

such as potassium salts, fluid

tablets and some medicines for

heart problems

If any of these medicines are used

while using Clexane, careful

monitoring of your blood clotting

factors and/or potassium levels is

required by your doctor.

These medicines may be affected by

Clexane or may affect how well it

works. You may need to use different

amounts of your medicine or you

may need to use different medicines.

Your doctor or pharmacist will

advise you.

Your doctor and pharmacist may

have more information on medicines

to be careful with or avoid while

using Clexane.

How to use it

How much to use

Your doctor will decide what dose

you will receive. This depends on

your condition and other factors,

such as your weight.

For the prevention of blood clots, the

following are the usual doses, which

are administered by injection under

the skin once a day:

moderate risk patients: 20mg

high risk patients: 40mg

For the treatment of blood clots

which have formed in the leg/deep

vein,

the usual dose is 1mg/kg body weight

twice a day or 1.5mg/kg body weight

once a day injected under the skin.

Warfarin sodium therapy is usually

started within 72 hours of Clexane by

your doctor.

For patients that require dialysis,

the usual dose is 1mg/kg into the

tubing of the dialysis machine at the

start of the session. Additional doses

may be given if required.

For treatment of severe heart

attacks,

the usual dose is 30mg injected into a

vein plus 1mg/kg injected under the

skin, followed by 1mg/kg injected

under the skin twice a day.

For treatment of certain other

types of heart disease,

the usual dose is 1 mg/kg injected

under the skin twice a day.

These doses of Clexane may be

changed by your doctor. Your doctor

will decide when and how much

Clexane you will be given.

How to use it

Clexane is usually given by an

injection under the skin or into the

tubing of the dialysis machine. The

recommended site for injection is the

stomach area. A different injection

site should be used for each injection.

Do not rub the injection site after

administration.

It may be given by your doctor, nurse

or yourself. Your doctor will tell you

how you will be given your injection.

Clexane can also be given by an

injection into a vein. This will be

done in hospital by your doctor or

nurse.

Prefilled Syringes

The prefilled syringes are ready for

use. The air bubble in the syringe

should not be expelled.

Graduated Prefilled Syringes

When using the 60mg, 80mg, 100mg,

120mg and 150mg graduated

syringes, the volume to be injected

should be measured precisely

according to the dosage

recommended by your doctor.

Injection Technique

The whole length of the syringe

needle should be introduced

vertically into the thickness of a skin

fold gently held between the

operator's thumb and finger. This

skin fold should be held throughout

the duration of the injection.

CLEXANE

AND CLEXANE

FORTE*

Clexane does not contain any

antimicrobial agents, so must be used

once only and any residue discarded.

How long to use it

Your doctor will tell you how long

you will be using Clexane.

If you use too much

(overdose)

As Clexane is often given to you

under the supervision of your

doctor, it is very unlikely that you

will receive too much. However,

some patients may self-inject

Clexane.

Tell your doctor or nurse or

telephone the Poisons Information

Centre in Australia (13 11 26) or

the National Poisons Information

Centre in NZ (0800 POISON or

0800 764 766), or go to Accident

and Emergency at your nearest

hospital, if you think that you or

anyone else may have injected too

much Clexane.

Do this even if there are no signs of

discomfort or poisoning.

You may need urgent medical

attention.

While you are using it

Things you must do

Use Clexane exactly as your doctor

has prescribed.

If you become pregnant while

using Clexane tell your doctor

immediately.

Tell your doctor if you have an

artificial heart valve.

If you are about to be started on

any new medicine tell your doctor,

dentist or pharmacist that you are

using Clexane.

Tell any other doctors, dentists or

pharmacists who are treating you

that you are using Clexane.

If you plan to have surgery, tell

your doctor or dentist that you are

using Clexane.

Tell your doctor that you are using

Clexane if your doctor is planning

for you to have an anaesthetic

injection in your back (spinal or

epidural injection).

Things you must not do

Do not give Clexane to anyone else,

even if they have the same

condition as you.

Do not use Clexane to treat any

other complaints, unless your

doctor tells you to.

Do not stop using Clexane, or

lower the dosage, without checking

with your doctor or pharmacist.

Do not mix Clexane with other

injections or infusion fluids.

Certain medicines or solutions

contain ingredients that can interact

with Clexane. If you need an

injection of Clexane into a vein, your

doctor or nurse will make sure it is

not mixed with any medicines or

solutions with which it can interact.

Do not inject Clexane into a

muscle.

Things to be careful of

Clexane is not interchangeable

with other low molecular weight

heparins (LMWH) products.

Ask your doctor whether there are

any activities you should avoid

while using Clexane, for example

certain sports.

Sometimes after an injury bleeding

may occur inside your body without

you knowing about it.

Be sure to keep all of your doctor

appointments. Your doctor will

check your progress and may want to

take some blood tests from time to

time.

Side Effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are using Clexane.

All medicines can have side effects.

Sometimes they are serious, most of

the time they are not. You may need

medical treatment if you get some of

the side effects.

Ask your doctor or pharmacist to

answer any questions you may

have.

Tell your doctor if you notice any

of the following and they worry

you:

pain, bruising or irritation at the

injection site after Clexane has

been given

hard inflamed nodules at the

injection site

itchy red rash at the injection site

bleeding at the injection site

itchy skin

If any of the following happen, stop

using Clexane and tell your doctor

immediately or go to the

Emergency Department at your

nearest hospital:

painful itchy red/purple rash at

the injection site

difficulty in breathing, symptoms

of hayfever, feeling faint, itching

hives, blisters or other symptoms

of allergy

bleeding (including nose bleeds

or prolonged bleeding from cuts),

bruising more easily than normal,

red or dark brown urine, red or

black bowel motions

numbness (paralysis), problems

with coordination, dizziness,

tiredness, light-headedness,

blurred vision, confusion or

difficulty speaking

severe abdominal, chest pain and

headache

nausea, diarrhoea, fever

swelling of the hands, ankles or

feet

a fine widespread rash, especially

noticeable on your mouth or eyes

or sudden onset of white or blue

colour in fingers or toes

suggesting poor blood supply.

If you need to have had an

anaesthetic injection in your back

CLEXANE

AND CLEXANE

FORTE*

(spinal or epidural injection) while

taking Clexane, this should be done

in a hospital. Tell your doctor

immediately if any of the following

happen after an anaesthetic

injection in your back:

pain in the middle of your back

(midline back pain)

numbness and weakness in your

legs (sensory and motor deficits)

intestinal problems and problems

in passing urine

These are very serious side effects.

You may need urgent medical

attention or hospitalisation. These

side effects are rare.

Other side effects not listed above

may occur in some patients. Tell

your doctor or pharmacist if you

notice anything else that is making

you feel unwell.

Do not be alarmed by this list of

possible side effects. You may not

experience any of them.

After using it

If you have any queries about any

aspect of your medicine, or any

questions regarding the

information in this leaflet, discuss

them with your doctor or

pharmacist.

Storage

Keep Clexane in a cool dry place

where the temperature stays below

25°C.

Keep the syringes in the pack until

it is time to use them.

Do not freeze Clexane.

Do not leave Clexane in the car.

Keep Clexane away from direct

sunlight.

Do not store Clexane or any other

medicine in the bathroom, near a

sink or stove or on a windowsill.

Heat, light and dampness can destroy

some medicines.

Keep Clexane where children

cannot reach it.

A locked cupboard at least one and a

half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

using Clexane or you find that the

syringes have passed their expiry

date, ask your doctor or

pharmacist what to do with any

that are left over.

Return any unused medicine to

your pharmacist.

Product description

What it looks like

Clexane is available in the following

range of presentations:

Ready to use Prefilled Syringes:

20mg/0.2mL (pack of 10)

40mg/0.4mL (pack of 10)

Ready to use Prefilled Syringes

with graduated markings:

60mg/0.6mL (pack of 10)

80mg/0.8mL (pack of 10)

100mg/1.0mL (pack of 10)

120mg/0.8mL (pack of 10)

150mg/1.0mL (pack of 10)

Ingredients

Active Ingredient:

Clexane contains enoxaparin sodium.

Inactive Ingredients:

Clexane also contains water for

injections.

Sponsor

Clexane is distributed in Australia

sanofi-aventis australia pty ltd

12-24 Talavera Road

Macquarie Park NSW 2113

Clexane is distributed in New

Zealand by:

sanofi-aventis new zealand limited

Level 8, 56 Cawley Street

Ellerslie, Auckland

This leaflet was prepared in May

2018

Australian Register Numbers:

Pre-filled Syringes

20mg-AUST R 42965

40mg-AUST R 42962

60mg-AUST R 56709

80mg-AUST R 56710

100mg-AUST R 56711

120mg-AUST R 74173

150mg-AUST R 74175

Pre-filled syringes with automatic

safety lock system

20mg-AUST R 221717

40mg-AUST R 221718

60mg-AUST R 221719

80mg-AUST R 221720

100mg-AUST R 221721

120mg-AUST R 221722

150mg-AUST R 221723

Not marketed in New Zealand

Registered Trademark

* Subsequent references to

"CLEXANE" refer to both

CLEXANE and CLEXANE FORTE.

clexane-ccdsv12-cmiv21-may18

CLEXANE

AND CLEXANE

FORTE*

New Zealand Data Sheet

June 2017

clexane-clexane-forte-ccdsv13-dsv18-16jun17

Page 1

DATA SHEET

1

CLEXANE

®

AND CLEXANE

®

FORTE

*

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

CLEXANE

Pre-filled syringes, ready-to-use:

20 mg injection

enoxaparin sodium 20mg (equivalent to 2,000 IU anti-Xa activity) in 0.2 mL

40 mg injection

enoxaparin sodium 40mg (equivalent to 4,000 IU anti-Xa activity) in 0.4 mL

Ampoules

40 mg injection

enoxaparin sodium 40mg (equivalent to 4,000 IU anti-Xa activity) ampoules

Pre-filled graduated syringes with graduated markings, ready-to-use:

60 mg injection

enoxaparin sodium 60mg (equivalent to 6,000 IU anti-Xa activity) in 0.6 mL

80 mg injection

enoxaparin sodium 80mg (equivalent to 8,000 IU anti-Xa activity) in 0.8 mL

100 mg injection

enoxaparin sodium 100mg (equivalent to 10,000 IU anti-Xa activity) in 1.0

CLEXANE

(with automatic safety lock system)

Pre-filled syringes, ready-to-use:

20 mg injection

enoxaparin sodium 20mg (equivalent to 2,000 IU anti-Xa activity) in 0.2 mL

40 mg injection

enoxaparin sodium 40mg (equivalent to 4,000 IU anti-Xa activity) in 0.4 mL

Pre-filled graduated syringes with graduated markings, ready-to-use:

60 mg injection

enoxaparin sodium 60mg (equivalent to 6,000 IU anti-Xa activity) in 0.6 mL

80 mg injection

enoxaparin sodium 80mg (equivalent to 8,000 IU anti-Xa activity) in 0.8 mL

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June 2017

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Page 2

100 mg injection

enoxaparin sodium 100mg (equivalent to 10,000 IU anti-Xa activity) in 1.0

CLEXANE

FORTE SYRINGES

Pre-filled graduated syringes with the double graduated markings, ready-to-use:

120 mg injection

enoxaparin sodium 120mg (equivalent to 12,000 IU anti-Xa activity) in 0.8

150 mg injection

enoxaparin sodium 150mg (equivalent to 15,000 IU anti-Xa activity) in 1.0

CLEXANE

FORTE SYRINGES (with automatic safety lock system)

Pre-filled graduated syringes with the double graduated markings, ready-to-use:

120 mg injection

enoxaparin sodium 120mg (equivalent to 12,000 IU anti-Xa activity) in 0.8

150 mg injection

enoxaparin sodium 150mg (equivalent to 15,000 IU anti-Xa activity) in 1.0

Not marketed

*

Subsequent references to “CLEXANE” refer to both CLEXANE and CLEXANE FORTE

For full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless to pale yellow solution.

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

CLEXANE is indicated for:

Prophylaxis of venous thromboembolic disease, in particular those which may be associated with

orthopaedic, general, major colorectal or cancer surgery.

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Page 3

Prophylaxis of venous thromboembolism in general medical patients bedridden due to acute

illnesses including acute heart failure, respiratory failure, severe infections, rheumatic disease.

Treatment of venous thromboembolic disease.

Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently

with aspirin.

Prevention of thrombus formation in the extra-corporeal circulation during haemodialysis.

Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) including patients to be

managed medically or with subsequent Percutaneous Coronary Intervention (PCI).

4.2

DOSE AND METHOD OF ADMINISTRATION

LMWH products are not clinically interchangeable.

They differ in their manufacturing process, molecular weights, specific anti-Xa activities, units

and dosage. The biological activity of different LMWH’s cannot be expressed in a test allowing

for a simple dose comparison. Different low molecular weight heparins may not be bioequivalent

in terms of their labelled anti-Xa activities and alternative products should not be introduced nor

interchanged during a course of treatment.

Not to be administered by the intramuscular route.

For subcutaneous use: do not mix CLEXANE with other injections or solutions.

For intravenous use: see section 4.2: Treatment of Acute ST-segment Elevation Myocardial

Infarction.

Prophylaxis of Venous Thrombosis in Surgical Patients

Prophylaxis against thromboembolism should be tailored according to the patient's risk. Risk

factors include age over 40 years, history of deep vein thrombosis or pulmonary embolism,

surgery and other trauma, prolonged immobilisation, cardiac disease, obesity, malignancy,

varicose veins, hypercoagulable states, pregnancy and the puerperium, oral contraceptives, severe

infection, inflammatory bowel disease.

a) High Risk Patients

In patients with high risk of thromboembolism, a CLEXANE dosage of 40 mg (0.4 mL; anti-Xa:

4000 IU) should be administered subcutaneously once daily. In high risk patients undergoing

surgery, the initial dose should be given approximately 12 hours preoperatively or 12 hours

postoperatively. The timing of the first dose may need to be modified if spinal/epidural

anaesthesia is to be performed (see section 4.4 – Spinal/Epidural Anaesthesia).

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Page 4

Prophylaxis should be continued at 40 mg once daily for 7 to 10 days or until the risk of

thromboembolism has diminished.

b) Moderate Risk Patients

In patients with a moderate risk of thromboembolism, the recommended CLEXANE dosage is 20

mg (0.2 mL; anti-Xa: 2000 IU) subcutaneously once daily. In moderate risk patients undergoing

surgery, the initial dose should be given approximately 2 hours preoperatively. The timing of the

first dose may need to be modified if spinal/epidural anaesthesia is to be performed (see section

4.4 – Spinal/Epidural Anaesthesia).

Duration of therapy

High to Moderate Risk: Prophylaxis should be continued at 20 mg once daily for 7 to 10 days or

until the risk of thromboembolism has diminished.

Prolonged Thromboprophylaxis

Therapy with 40 mg once daily for 30 post-operative days has been proven to be beneficial in

total hip replacement surgery.

Under normal conditions of use, CLEXANE does not modify global clotting tests and therefore

there is no need to perform these tests in order to monitor therapy.

Prophylaxis of Venous Thromboembolism in Medical Patients

The recommended dose of CLEXANE is 40 mg once daily by subcutaneous injection.

Treatment with CLEXANE is prescribed for a minimum of 6 days and continued until the return

to full ambulation, for a maximum of 14 days.

Treatment of Venous Thrombosis

The initial clinical trials which established the efficacy of CLEXANE in the treatment of deep

venous thrombosis were conducted on patients who were initially treated with heparin and then

changed to CLEXANE when a definitive diagnosis was established. However, the use of heparin

prior to CLEXANE is not currently recommended. The average duration of therapy in the clinical

trials was 10 days. No data are available on the safety of long term treatment. Data on use in

patients over 65 years of age in these trials were limited.

The recommended dosage for treatment of established deep vein thrombosis with CLEXANE is

1.5 mg/kg body weight once daily (150 IU anti-Xa activity/kg body weight) or 1 mg/kg body

weight (100 IU anti-Xa activity/kg bodyweight) twice daily subcutaneously. In high risk patients,

eg, the obese or patients with baseline iliac vein thrombosis or cancer, a dose of 1 mg/kg body

weight administered twice daily may be more beneficial.

Warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of

commencing CLEXANE initiation). CLEXANE should be continued for a minimum of 5 days

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Page 5

and until a therapeutic anticoagulant effect has been achieved (International Normalisation Ratio

2.0 to 3.0).

Treatment of Unstable Angina and Non-Q-Wave Myocardial Infarction

The recommended dose of CLEXANE is 1 mg/kg (100 IU anti-Xa activity/kg) every 12 hours by

subcutaneous injection, administered concurrently with oral aspirin (100 to 300 mg once daily).

Treatment with CLEXANE in these patients should be prescribed for a minimum of 2 days and

continued until clinical stabilisation. The usual duration of treatment is 2 to 8 days.

Treatment of Acute ST-segment Elevation Myocardial Infarction

In patients with acute ST-segment elevation myocardial infarction, administered in conjunction

with a fibrinolytic (fibrin-specific or non-fibrin specific), the recommended dose of CLEXANE is

a single IV bolus of 30 mg plus a 1 mg/kg SC dose, followed by 1 mg/kg administered SC every

12 hours (maximum 100 mg for each of the first two SC doses only, followed by 1 mg/kg dosing

for the remaining doses). For dosage in patients ≥75 years of age, see section 4.2: Renal

Impairment and Elderly.

When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific),

CLEXANE should be given between 15 minutes before and 30 minutes after the start of

fibrinolytic therapy. All patients should receive aspirin as soon as they are identified as having

STEMI (100 to 300 mg once daily, unless contraindicated). The recommended duration of

CLEXANE treatment is 8 days or until hospital discharge, whichever comes first.

For patients managed with Percutaneous Coronary Intervention (PCI): If the last CLEXANE SC

administration was given less than 8 hours before balloon inflation, no additional dosing is

needed. If the last CLEXANE SC administration was given more than 8 hours before balloon

inflation, an IV bolus of 0.3 mg/kg of CLEXANE should be administered (see section 4.4:

Percutaneous Coronary Revascularisation Procedures).

Haemodialysis

In patients undergoing repeated sessions of haemodialysis, the prevention of thrombosis in the

extracorporeal blood circuit is obtained by injection of a dose of 1 mg/kg (100 IU anti-Xa

activity/kg) into the arterial line of the dialysis circuit at the start of the session. The dose is

usually sufficient for a 4 hour haemodialysis session. If fibrin rings are formed, a further dose of

0.5 to 1 mg/kg (50 to 100 IU anti-Xa activity/kg) should be made depending on the time before

the end of the dialysis.

In haemodialysed patients with a high risk of haemorrhage, (in particular, in pre or post-operative

dialysed patients) or with a progressive haemorrhagic disorder, the dialysis sessions may be

carried out by using a dose of 0.5 mg/kg (50 IU anti-Xa activity/kg) (double vascular access) or

0.75 mg/kg (75 IU anti-Xa activity/kg) (single vascular access).

Renal Impairment

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Severe Renal Impairment

A dosage adjustment is required for patients with severe renal impairment (creatinine clearance

<30 mL/min), according to the following tables.

The following dosage adjustments are recommended for therapeutic dosage ranges:

Standard Dosing

Severe renal impairment

1 mg/kg SC twice daily

1 mg/kg SC once daily

1.5 mg/kg SC once daily

1 mg/kg SC once daily

Acute STEMI patients < 75 years of age

30 mg single IV bolus plus a 1 mg/kg SC

dose followed by 1 mg/kg SC twice daily

(Max 100mg for each of the first two SC

doses)

30 mg single IV bolus plus a 1 mg/kg SC dose

followed by 1 mg/kg SC once daily

(Max 100mg for first SC dose only)

Acute STEMI patients > 75 years of age

0.75 mg/kg SC twice daily without initial

bolus

(Max 75mg for each of the first two SC

doses)

1 mg/kg SC once daily without initial bolus

(Max 75mg for first SC dose only)

The following dosage adjustments are recommended for prophylactic dosage ranges:

Standard Dosing

Severe renal impairment

40 mg SC once daily

20 mg SC once daily

20 mg SC once daily

20 mg SC once daily

The recommended dosage adjustments do not apply to the haemodialysis indication.

Moderate & Mild Renal Impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30-

50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical

monitoring is advised.

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Hepatic Impairment

In the absence of clinical studies, caution should be used in hepatically impaired patients.

Elderly

For treatment of acute ST-segment Elevation Myocardial Infarction in elderly patients ≥75 years

of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours

(maximum 75 mg for each of the first two SC doses only, followed by 0.75 mg/kg dosing for the

remaining doses).

No dose reduction is necessary in the elderly for other indications, unless kidney function is

impaired; however clinical observation is advised (see section 4.4: Elderly and Renal

impairment).

Children

The safety and efficacy of CLEXANE in children has not been established.

Subcutaneous Injection Technique

Injection should be made preferably when the patient is reclining. CLEXANE is administered by

deep subcutaneous injection. Injection of CLEXANE should be alternated between the left and

right anterolateral abdominal wall using a different site for each injection. Do not expel the air

bubble from the syringe before the injection to avoid the loss of drug. CLEXANE contains no

antimicrobial agent and should be used only once and then discarded.

The needles on the pre-filled syringes of CLEXANE are covered in a silicon coating, to enable

ease of penetration. Do not wipe the needle or allow CLEXANE solution to crystallise on the

needle prior to use, as this will damage the silicon coating. A “dart” injection technique should be

used to administer CLEXANE. Do not rub the injection site after administration.

Intravenous (Bolus) Injection Technique (for the treatment of acute STEMI)

For intravenous injection, the graduated pre-filled syringes should be used, see subsection below.

CLEXANE should be administered through an intravenous line and should not be co-administered

with other medications. To avoid the possible mixture of CLEXANE with other drugs, the

intravenous access chosen should be flushed with a sufficient amount of saline or dextrose

solution prior to and following the intravenous bolus administration of CLEXANE to clear the

port of drug. CLEXANE may be safely administered with normal saline solution (0.9%) or 5%

dextrose in water.

Pre-filled Syringes

The pre-filled disposable syringe is ready for immediate use. The whole length of the needle

should be introduced vertically (at a 90° angle to the skin) into a skin fold gently held between the

thumb and forefinger. The skin fold should be held throughout the duration of the injection.

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Graduated Pre-filled Syringes

When using the 60 mg, 80 mg, 100 mg, 120 mg and 150 mg graduated prefilled syringes, the

volume to be injected should be measured precisely according to the dosage recommended,

without expelling the air bubble while adjusting dosage. If the dose required is exactly 60, 80,

100, 120 or 150 mg inject the full contents of the syringe. The whole length of the needle should

be introduced vertically (at a 90° angle to the skin) into a skin fold gently held between the thumb

and forefinger. The skin fold should be held throughout the duration of the injection.

Ampoules

#

When using the ampoules of enoxaparin, the volume should be measured precisely with a

graduated syringe fitted with an appropriate needle for the intravenous or subcutaneous injection.

4.3

CONTRAINDICATION

Allergy to CLEXANE or its derivatives including other LMWH’s.

Acute bacterial endocarditis.

Conditions with a high risk of uncontrolled haemorrhage including major bleeding

disorders, focal lesions, haemorrhagic stroke, active ulcerative conditions showing a

tendency to haemorrhage (e.g. peptic ulcer, ulcerative colitis).

History of immune mediated heparin induced thrombocytopaenia (HIT) within the past

100 days or in the presence of circulating antibodies (see section 4.4).

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

LMWH products are not clinically interchangeable.

They differ in their manufacturing process, molecular weights, specific anti-Xa activities, units

and dosage. The biological activity of different LMWH’s cannot be expressed in a test allowing

for a simple dose comparison. Different low molecular weight heparins may not be bioequivalent

in terms of their labelled anti-Xa activities and alternative products should not be introduced nor

interchanged during a course of treatment.

Not to be administered by the intramuscular route.

Risk of Haemorrhage

CLEXANE should be used with extreme caution in conditions with increased risk of

haemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active

ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain,

spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.

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Major haemorrhages including retroperitoneal and intracranial bleeding have been reported. Some

of these cases have been fatal. As with other anticoagulants, bleeding can occur at any site during

therapy with CLEXANE (see section 4.8). If bleeding occurs, the origin of the haemorrhage

should be investigated and appropriate treatment instigated. An unexplained fall in hematocrit or

blood pressure should lead to a search for a bleeding site and appropriate treatment instituted.

Concomitant Medical Conditions

CLEXANE should be used with caution in patients with the following conditions: hepatic

insufficiency, a bleeding diathesis, uncontrolled arterial hypertension, a history of gastrointestinal

ulceration, impaired haemostasis, recent ischaemic stroke, diabetic retinopathy, recent neuro- or

ophthalmologic surgery and haemorrhage.

Heparin-Induced Thrombocytopenia

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100

days or in the presence of circulating antibodies is contraindicated (see section 4.3). Circulating

antibodies may persist for several years.

CLEXANE is to be used with extreme caution in patients with a history (more than 100 days) of

heparin-induced (including low molecular weight heparins) thrombocytopenia without circulating

antibodies.

The decision to use CLEXANE in such a case must be made only after a careful benefit risk

assessment and after non-heparin alternative treatments are considered.

Spinal/Epidural Anaesthesia

There have been rare cases of neuraxial haematomas reported with the concurrent use of

CLEXANE and spinal/epidural anaesthesia resulting in long-term or permanent paralysis. These

events are rare with CLEXANE dosage regimens 40 mg once daily or lower. The risk is greater

with higher CLEXANE dosage regimens, use of post-operative indwelling catheters or the

concomitant use of additional drugs affecting haemostasis such as non-steroidal anti-inflammatory

drugs (NSAIDs) (See section 4.4 and 4.5). The risk also appears to be increased by traumatic or

repeated neuraxial puncture or in patients with a history of spinal surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of CLEXANE and

epidural or spinal anaesthesia/analgesia, the pharmacokinetic profile of the drug should be

considered (see section 5.2). Placement and removal of the needle/catheter is best performed

when the anticoagulant effect of enoxaparin is low.

Placement or removal of an epidural or spinal needle or catheter should be delayed for at least 12

hours after administration of lower doses (20mg once daily, 30mg once or twice daily or 40mg

once daily) of enoxaparin, and at least 24 hours after the administration of higher doses

(0.75mg/kg twice daily, 1 mg/kg twice daily, or 1.5mg/kg once daily) of enoxaparin. Anti-Xa

levels are still detectable at these time points, and these delays are not a guarantee that neuraxial

haematoma will be avoided. Patients receiving the 0.75mg/kg twice-daily dose or the 1mg/kg

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twice-daily dose should not receive the second enoxaparin dose in the twice-daily regimen to

allow a longer delay before catheter placement or removal. Likewise, although a specific

recommendation for timing of a subsequent enoxaparin dose after catheter removal cannot be

made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment

considering both the risk for thrombosis and the risk for bleeding in the context of the procedure

and patient risk factors. For patients with creatinine clearance <30ml/minute, additional

considerations are necessary because elimination of enoxaparin is more prolonged; consider

doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of

enoxaparin (30mg once daily) and at least 48 hours for the higher dose (1mg/kg/day).The

patient’s regular CLEXANE dose may need to be delayed to ensure this. If blood is present

during needle/catheter placement, the subsequent dose of CLEXANE should be delayed for 24

hours after placement.

Should the physician decide to administer anticoagulation in the context of epidural/spinal

anaesthesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and

symptoms of spinal haematoma such as midline back pain, sensory and motor deficits (numbness

or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to

inform their physician immediately if they experience any of the above signs or symptoms. If

signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment including

spinal cord decompression should be initiated.

Thrombocytopenia

Thrombocytopenia can occur with the administration of CLEXANE. Moderate thrombocytopenia

(platelet counts between 100,000/mm

and 50,000/mm

) occurred at a rate of 1.3% in patients

given CLEXANE, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical

trials. Platelet counts less than 50,000/mm

occurred at a rate of 0.1% in patients given

CLEXANE, in 0.2% of patients given heparin, and 0.4% of patients given placebo in the same

trials. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls

below 100,000/mm

, CLEXANE should be discontinued. Cases of heparin-induced

thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these

cases were complicated by organ infarction, limb ischemia, or death.

Prosthetic Heart Valves

There have been no adequate studies to assess the safe and effective use of CLEXANE in

preventing thromboembolism in patients with prosthetic heart valves. Cases of prosthetic heart

valve thrombosis have been reported in patients with prosthetic heart valves who have received

enoxaparin for thromboprophylaxis. Confounding factors, including underlying disease and

insufficient clinical data, limit the evaluation of these cases. Some of these cases were pregnant

women in whom thrombosis led to maternal and foetal death. Pregnant women with mechanical

prosthetic heart valves may be at a higher risk for thromboembolism. The use of CLEXANE

cannot be recommended for this purpose (see section 4.6).

Percutaneous Coronary Revascularisation Procedures

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To minimise the risk of bleeding following the vascular instrumentation during the treatment of

unstable angina, non Q-wave myocardial infarction and ST-segment elevation acute myocardial

infarction, adhere precisely to the intervals recommended between CLEXANE doses. It is

important to achieve haemostasis at the puncture site after PCI. In case a closure device is used,

the sheath can be removed immediately. If a manual compression method is used, the sheath

should be removed 6 hours after the last IV/SC CLEXANE injection. If the treatment with

enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6

to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding

or haematoma formation.

Renal Impairment

In patients with renal impairment, there is an increase in exposure of CLEXANE which increases

the risk of bleeding. Since exposure of CLEXANE is significantly increased in patients with

severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended

for therapeutic and prophylactic dosage ranges. Although no dose adjustment is recommended in

patients with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80

mL/min) renal impairment, careful clinical observation is advised (see section 4.2: Renal

Impairment).

Pharmacokinetics of enoxaparin are altered in renal impairment. The extent to which a defect in

platelet function in severe renal failure might further contribute to bleeding risk is unknown.

Hepatic Impairment

See section 4.2

Low Weight

An increase in exposure of CLEXANE with prophylactic dosages (non-weight adjusted) has been

observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a

higher risk of bleeding. Therefore, careful clinical observation is advised in these patients.

Obese Patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic

doses in obese patients (BMI >30 kg/m

) has not been fully determined and there is no consensus

for dose adjustment. These patients should be observed carefully for signs and symptoms of

thromboembolism.

Paediatric Use

The safety and efficacy of CLEXANE in children has not been established.

Use in the Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dosage ranges.

Elderly patients (especially patients eighty years of age and older) may be at an increased risk for

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bleeding complications with the therapeutic dosage ranges. Careful clinical observation is

advised. A dosage adjustment may be necessary in elderly patients due to age-related impairment

of renal function (see section 4.2: Renal Impairment).

In the clinical study for treatment of acute STEMI, in patients ≥75 years of age (n = 2532) the rate

of death or myocardial re-infarction was higher than in the global population but lower in the

enoxaparin group (24.8%) than in the UFH group (26.3%, relative risk 0.94, p = 0.38). Patients

≥75 years of age did not receive a 30-mg IV bolus prior to the normal dosage regimen and had

their SC dose adjusted to 0.75 mg/kg every 12 hours (see section 4.2).

In patients ≥75 years of age, the rate of TIMI major bleeding was higher than in the global

population and was higher in the enoxaparin group (3.3%) for patients ≥75 years of age compared

with the UFH group (2.9%, RR 1.15, p=0.57).

Compared to younger patients (<65 years), the rate of TIMI major bleeding was higher in patients

>65 years of age (respectively 1.2% and 2.5%) and was higher in the enoxaparin group as

compared to the UFH group (see Clinical Trials).

Effect on Laboratory Tests

At doses used for prophylaxis of venous thromboembolism, CLEXANE does not influence

bleeding time and global blood coagulation tests significantly, nor does it affect platelet

aggregation or binding of fibrinogen to platelets.

At higher doses, increases in aPTT and ACT (activated clotting time) may occur. Increases in

aPTT and ACT are not linearly correlated with increasing CLEXANE antithrombotic activity and

therefore are unsuitable and unreliable for monitoring CLEXANE activity.

Periodic complete blood counts, including platelet count, and stool occult blood tests are

recommended during the course of treatment with CLEXANE. When administered at

recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and

Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of CLEXANE

activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the

anticoagulant effect of CLEXANE in patients with significant renal impairment. If during

CLEXANE therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa

levels may be used to monitor the anticoagulant effects of CLEXANE.

Monitoring of Platelet Counts

The risk of antibody-mediated heparin-induced thrombocytopenia also exists with LMWH’s.

Should thrombocytopenia occur, it usually appears between the 5th and 21st day following the

beginning of CLEXANE treatment. Therefore, it is recommended that the platelet counts be

measured before the initiation of therapy with CLEXANE and then regularly thereafter during the

treatment. In practice, if a confirmed significant decrease of the platelet count is observed (30 to

50% of the initial value), CLEXANE treatment must be immediately discontinued and the patient

switched to another therapy.

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4.5

INTERACTION WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTION

Clinical trials revealed no adverse effects that could be caused by drug interactions including no

pharmacokinetic interactions between enoxaparin and thrombolytics when administered

concurrently.

It is recommended that agents which affect haemostasis should be discontinued prior to

CLEXANE therapy unless strictly indicated. These agents include medications such as: anti-

coagulants, thrombolytics, non-steroidal anti-inflammatory agents (including ketorolac),

preparations containing aspirin, systemic salicylates, ticlopidine, dextran 40, clopidogrel, other

anti platelet agents including glycoprotein IIb/IIIa antagonists or systemic glucocorticoids.

If the combination is indicated, CLEXANE should be used with careful clinical and laboratory

monitoring of the haemostatic factors, when appropriate.

4.6

FERTILITY, PREGNANCY AND LACTATION

Fertility

Enoxaparin was found to have no effect on fertility or reproductive performance of male and

female rats at subcutaneous doses up to 20 mg/kg/day.

Pregnancy

Category C.

In embryo-foetal development studies of enoxaparin there was no evidence of teratogenicity at 30

mg/kg/day SC or 160 mg/kg/day IV in either rats or rabbits. A reduction in rat pup weights

occurred at 20 mg/kg/day enoxaparin SC only when administered during the late phase of

gestation. An increase in post-implantation loss was noted at 160 mg/kg/day enoxaparin IV in

rabbits, but not at 40 mg/kg/day IV, nor in rats at up to 160 mg/kg/day IV. Post-natal

development in rats was not affected by doses tested up to a maximum of 20 mg/kg/day

enoxaparin IV.

In humans, there is no evidence that enoxaparin sodium crosses the placental barrier during the

second trimester of pregnancy. There is no information available concerning the use of

CLEXANE during the first and the third trimesters. As there are no adequate and well-controlled

studies in pregnant women and because animal studies are not always predictive of human

response, this medicine should be used during pregnancy only if the physician has established a

clear need.

There have been reports of congenital anomalies in infants born to women who received

enoxaparin during pregnancy including cerebral anomalies, limb anomalies, hypospadias,

peripheral vascular malformation, fibrotic dysplasia and cardiac defect. A cause and effect

relationship has not been established nor has the incidence been shown to be higher than in the

general population.

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There have been post-marketing reports of foetal death when pregnant women received

CLEXANE. Causality for these cases has not been determined. Pregnant women receiving anti-

coagulants, including enoxaparin, are at increased risk of bleeding. Haemorrhage can occur at any

site and may lead to death of mother and/or foetus. Pregnant women receiving enoxaparin should

be carefully monitored. Pregnant women and women of child-bearing potential should be apprised

of the potential hazard to the foetus and the mother if enoxaparin is administered during

pregnancy.

The use of enoxaparin for thromboprophylaxis in pregnant women with mechanical prosthetic

heart valves has not been adequately studied. In a clinical study of pregnant women with

mechanical prosthetic heart valves given CLEXANE (1 mg/kg twice daily) to reduce the risk of

thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to

maternal and foetal death. There have been isolated post-marketing reports of valve thrombosis in

pregnant women with mechanical prosthetic heart valves while receiving enoxaparin for

thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves may be at a higher

risk for thromboembolism. In the absence of additional dosing, efficacy and safety information in

this circumstance, CLEXANE is not recommended for use in pregnant women with mechanical

prosthetic heart valves (see section 4.4: Prosthetic Heart Valves).

Lactation

It is unknown whether enoxaparin is excreted into the breast milk of humans. In lactating rats, the

concentration of

S-enoxaparin sodium or its labelled metabolites in milk was similar to that in

maternal plasma. Apart from lower birth weights and slightly delayed physical development,

there were no significant adverse effects of 20 mg/kg/day enoxaparin SC in a peri- and post- natal

study in rats. Effects of CLEXANE on lactating women have not been studied. As a precaution,

women should be advised not to breast feed while using CLEXANE.

4.7

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

CLEXANE has no effect on the ability to drive and operate machines.

4.8

UNDESIRABLE EFFECTS

Clinical Trial Data

Enoxaparin sodium has been evaluated in more than 15,000 patients. The following information

relates to adverse events observed in controlled clinical trials with patients given CLEXANE

prophylaxis of deep vein thrombosis following orthopaedic or abdominal surgery in patients at

risk for thromboembolic complications (n = 1176), prophylaxis of deep vein thrombosis in acutely

ill medical patients with severely restricted mobility (n = 1169) , treatment of deep vein

thrombosis with or without pulmonary embolism (n = 669) or with patients given CLEXANE for

the treatment of unstable angina or non-Q-wave myocardial infarction, administered concurrently

with aspirin (n = 1578) or with patients given CLEXANE for the treatment of acute ST-segment

elevation myocardial infarction (n = 10176).

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Reported adverse events are presented at frequencies of:

Very common

> 1/10 (10%)

common

≥ 1/100 (1%) and < 1/10 (10%)

uncommon

≥ 1/1000 (0.1%) and < 1/100 (1%)

rare

≥ 1/10000 (0.01%) and < 1/1000 (0.1%)

very rare

< 1/10000 (<0.01%)

Haematological

Common

: Anaemia

In clinical trials haemorrhages were the most commonly reported reaction. These included major

haemorrhages, reported at most 4.2% in surgical patients receiving prophylaxis. Bleeding may

occur in the presence of associated risk factors such as: organic lesions liable to bleed, invasive

procedures or the use of medications affecting haemostasis (see section 4.4 and 4.5). Major

haemorrhage including retroperitoneal and intracranial bleeding has been reported. Some of these

cases have been fatal.

Haemorrhages -

MedDRA

system

organ class

Prophylaxis in

surgical patients

Prophylaxis in

medical patients

Treatment in

patients with DVT

with or without PE

Treatment in

patients with

unstable angina

and non-Q-wave

Treatment in

patients with acute

STEMI

Vascular

Disorders

Very common:

Haemorrhage*

Rare:

Retroperitoneal

haemorrhage

Common:

Haemorrhage*

Very common:

Haemorrhage*

Uncommon:

Intracranial

haemorrhage,

Retroperitoneal

haemorrhage

Common:

Haemorrhage*

Rare:

Retroperitoneal

haemorrhage

Common:

Haemorrhage*

Uncommon:

Intracranial

haemorrhage,

Retroperitoneal

haemorrhage

* such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria,

epistaxis and gastro-intestinal haemorrhage.

Blood Disorders

Mild, transient, asymptomatic thrombocytopenia has been reported during the first days of

therapy.

Thrombocytopenia and thrombocytosis -

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MedDRA

system

organ class

Prophylaxis in

surgical patients

Prophylaxis in

medical patients

Treatment in

patients with DVT

with or without PE

Treatment in patients with

unstable angina and non-

Q-wave MI

Treatment in patients

with acute STEMI

Blood and

lymphatic

system

disorders

Very common:

Thrombocytosis*

Common:

Thrombocytopenia

Uncommon:

Thrombocytopenia

Very common:

Thrombocytosis*

Common:

Thrombocytopenia

Uncommon:

Thrombocytopenia

Common:

Thrombocytosis*

Thrombocytopenia

Very rare:

Immuno-allergic

thrombocytopenia

*Platelet increased >400 10

Hepatobiliary Disorders

Very common

: Asymptomatic and reversible increases in liver enzymes levels (eg. transaminases)

have been reported [NOTE: Liver enzymes were not assessed in the Unstable Angina Population].

Gastrointestinal

Common:

Nausea, Diarrhoea

Other

Common:

Peripheral oedema, Fever

Psychiatric Disorders

Common:

Confusion

Immune System Disorders

Common

: Allergic reaction

Rare:

Anaphylactic/ anaphylactoid reaction (see also

Post-Marketing Experience

Skin and Subcutaneous Tissue Disorders

Common:

Urticaria, pruritus, erythema

Uncommon:

Bullous dermatitis

General Disorders and Administration Site Conditions

Common:

Injection site haematoma, injection site pain, other injection site reaction (such as

injection site oedema, haemorrhage, hypersensitivity, inflammation, mass, pain or reaction)

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Uncommon:

Local irritation, skin necrosis at injection site

Investigations

Rare:

hyperkalaemia

Post-Marketing Experience

The following information relates to events observed following the marketing of CLEXANE.

Voluntary reports of adverse events that have been received since market introduction (without

causal relationship) that are not listed previously are cited below.

Immune System Disorders

Anaphylactic/ anaphylactoid reactions including shock have been reported.

Nervous System Disorders

Headaches have been reported.

Haematological

Rare

: There have been rare reports of spinal or neuraxial haematomas with the concurrent use of

CLEXANE and spinal/epidural anaesthesia, spinal puncture or post-operative indwelling

catheters. These events have resulted in varying degrees of neurologic injuries including long-

term or permanent paralysis (see section 4.4).

Blood Disorders

Rare cases of immuno-allergic thrombocytopenia with or without thrombosis have been reported.

In some cases, thrombosis was complicated by organ infarction or limb ischaemia (see section

4.4).

Asymptomatic and reversible increases in platelet counts, haemorrhagic anaemia and eosinophilia

have been reported.

Hypersensitivity and Skin - Injection site

Very rare

: Pain, haematoma and mild local irritation may follow the subcutaneous injection of

CLEXANE.

Hard inflammatory nodules, which are not cystic enclosures of CLEXANE, have been observed at

the injection site. They resolve after a few days and should not cause treatment discontinuation.

Rare cases of skin necrosis, usually occurring at the injection site, have been reported with both

unfractionated and low molecular weight heparins. These phenomena are usually preceded by

purpura or erythematous plaques, infiltrated and painful. Treatment with CLEXANE must be

discontinued immediately.

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Alopecia has also been reported.

Systemic Allergic Reactions

Rare:

Cutaneous (bullous) or systemic allergic reactions (such as pruritis, rash and urticaria),

including anaphylactic/anaphylactoid reactions may occur. In some cases discontinuation of the

treatment may be necessary.

Cases of hypersensitivity cutaneous vasculitis have been reported.

Metabolism Disorders

Cases of hyperkalaemia have been reported with heparins and low molecular weight heparins.

Use of low molecular weight heparins over extended periods has been reported to be associated

with development of osteopenia. Very rare cases of hyperlipidemia have also been reported.

Hepatobiliary Disorders

Hepatocellular liver injury and cholestatic liver injury have been reported.

Musculoskeletal and Connective Tissue Disorders

Osteoporosis following long-term therapy (greater than 3 months) has been reported.

Reporting of suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are

asked to report any suspected adverse reactions using the following website

link:https:/nzphvc.otago.ac.nz/reporting

4.9

OVERDOSE

Symptoms

Accidental overdosage with CLEXANE after intravenous, extracorporeal or subcutaneous

administration may lead to haemorrhagic complications through anti-coagulant activity.

Oral ingestion of CLEXANE (no reported cases) should lead to no serious consequences, taking

into account the very low gastric and intestinal absorption of the product. This may be checked by

carrying out a plasma assay of the anti-Xa and anti-IIa activities.

Treatment

The anticoagulant effects can be largely neutralised by the slow intravenous injection of

protamine. Particular care should be taken to avoid overdosage with protamine, as even with high

doses of protamine, the anti-Xa activity of CLEXANE is never completely neutralised (maximum

reversal of 60%), even though the anti-coagulant activity is neutralised. (See the prescribing

information for protamine salts).

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The dose of protamine depends on the dose of CLEXANE injected. If CLEXANE was

administered in the previous 8 hours 1 mg protamine neutralises the anticoagulant effect of 1 mg

or 100 anti-heparin units of protamine neutralises the anti-IIa activity generated by 1 mg (100 IU

anti-Xa activity) of CLEXANE(see the Prescribing Information for protamine salts). An infusion

of 0.5 mg protamine per 1 mg of CLEXANE may be administered if CLEXANE was

administered greater than 8 hours previously, or if it has been determined that a second dose of

protamine is required. Protamine administration may not be required 12 hours after the

CLEXANE injection. However, depending on the clinical circumstances, eg the size of the dose

of CLEXANE, whether or not a therapeutic level of anticoagulation needs to be retained and

whether or not the patient is actively bleeding, the administration of a reduced dose of protamine

may not be advisable.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

5

PHARMACOLOGICAL PROPERTIES

CHEMICAL STRUCTURE

X= 15 to

n= 0 to 20

100 - X

n =1 to 21

X = Percent of polysaccharide chain containing 1, 6 anhydro derivative on the reducing end

5.1

Pharmacodynamic properties

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5.1

PHARMACODYNAMIC PROPERTIES

Enoxaparin sodium is a low molecular weight heparin, LMWH (mean molecular weight of

approximately 4,500 daltons). The drug substance is the sodium salt.

The molecular weight distribution is:

<2000 daltons 12 to 20%

2000 to 8000 daltons 68 to 82%

>8000 daltons ≤18%

Enoxaparin sodium is obtained by alkaline depolymerisation of heparin benzyl ester derived from

porcine intestinal mucosa. Its structure is characterised by a 4-enopyranose uronate group at the

non-reducing end. About 20% (ranging between 15% and 25%) of the enoxaparin structure

contains a 1,6 anhydro derivative on the reducing end of the polysaccharide chain.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100

U/mg) and a low anti-IIa or anti-thrombin activity (approximately 28 IU/mg). Pharmacodynamic

parameters studied in healthy volunteers at enoxaparin sodium concentration over the range 100 -

200 mg/ mL were comparable.

5.2

PHARMACOKINETIC PROPERTIES

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of

the time course of anti-Xa activity and also by anti-IIa activity, at the recommended dosage ranges

after single and repeated subcutaneous administration and after single intravenous administration.

The quantitative determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted

by validated amidolytic methods with specific substrates and an enoxaparin standard calibrated

against the international standard for LMWH’s (NIBSC).

Bioavailability and Absorption

After subcutaneous (SC) injection of 20 to 80 mg and 1 or 2 mg/kg, enoxaparin sodium is rapidly

and completely absorbed. The absorption is directly proportional to the dose administered

indicating that, unlike unfractionated heparin, absorption of enoxaparin sodium is linear. The

absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa

activity, is close to 100%. Injection volume and dose concentration over the range 100-200

mg/mL does not affect pharmacokinetic parameters in healthy volunteers.

The mean maximum plasma anti-Xa activity is observed 3 to 5 hours after subcutaneous injection

and achieved approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single-subcutaneous

administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg doses respectively.

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A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak

anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of

steady-state levels. Steady-state is achieved on the second day of treatment.

Enoxaparin pharmacokinetics appears to be linear over the recommended dosage ranges. Intra-

patient and inter-patient variability is low. After repeated subcutaneous administration of 40 mg

once daily and 1.5 mg/kg once daily regimens in healthy volunteers, the steady-state is reached on

day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state

enoxaparin activity levels are well predicted by single dose pharmacokinetics. After repeated

subcutaneous administration of the 1 mg/kg twice daily regimen, the steady-state is reached from

day 3 to 4 with mean exposure about 65% higher than after a single dose and mean peak and

trough levels of about 1.2 and 0.52 IU/mL, respectively. Based on enoxaparin sodium

pharmacokinetics, this difference in steady state is expected and within the therapeutic range.

Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than

anti-Xa activity. The mean maximum plasma anti-IIa activity is observed approximately 3 to 4

hours following subcutaneous injection and reaches 0.13 IU/mL and 0.19 IU/mL following

repeated administration of 1 mg/kg twice daily and 1.5 mg/kg once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 5 litres and is close to

the blood volume.

Elimination and Metabolism

Enoxaparin sodium is a low clearance drug with a mean anti-Xa plasma clearance of 0.74 L/h

after a 1.5 mg/kg 6-hour intravenous infusion.

Elimination appears monophasic with a half-life of about 4 hours after a single-subcutaneous dose

to about 7 hours after repeated dosing.

Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerisation to

lower molecular weight species with much reduced biological potency. Renal clearance of active

fragments represents about 10% of the administered dose and total renal excretion of active and

non-active fragments 40% of the dose.

5.3

PRECLINICAL SAFETY DATA

Carcinogenicity

No long-term studies in animals have been performed to evaluate the carcinogenic potential of

enoxaparin.

Genotoxicity

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Enoxaparin was not genotoxic in

in vitro

tests, including the Ames test, mouse lymphoma cell

forward mutation test and human lymphocyte chromosomal aberration test and the

in vivo

bone marrow chromosomal aberration test.

CLINICAL TRIALS

Hip Replacement Surgery

Two randomised single-centre clinical trials were conducted in patients undergoing hip

replacement surgery to determine if extended prophylaxis with CLEXANE 40 mg SC daily, given

for up to 3 weeks post hospital discharge was effective in reducing the incidence of deep vein

thrombosis (DVT) as compared to placebo. All patients were initially treated with CLEXANE 40

mg SC daily, beginning up to 12 hours prior to surgery in an open-label fashion. Patients who did

not exhibit venous thromboembolic disease (either by negative venography in one study or by

absence of clinical signs or symptoms in the other study) at the completion of in-hospital

treatment were randomised to receive extended prophylaxis with either CLEXANE (n = 221) or

placebo (n = 220) post-discharge in a blinded fashion. The incidence of deep vein thrombosis

(total and proximal) during extended prophylaxis was significantly lower for CLEXANE (total:

12%; proximal: 6%) compared to placebo (total: 28%; proximal: 16%) in both studies. Bleeding

events were limited to minor haemorrhages which were 11% for the CLEXANE treatment group

versus 3% for the placebo treatment group. The majority of the bleeding events for both groups

were injection site haemorrhages (9% CLEXANE vs 2% placebo).

Thromboembolism Prophylaxis in Medical Patients

One randomised, double-blind, placebo-controlled, parallel group study was conducted to

compare enoxaparin 20 mg once daily (E20), enoxaparin 40 mg once daily (E40) and placebo in

the prophylaxis of VTE in patients hospitalised with acute heart failure, acute respiratory disease,

acute infectious disease, acute rheumatic disorders, or acute inflammatory bowel disease. The

treatment lasted 6-14 days. The primary efficacy endpoint was assessed in 866 patients – 288

placebo, 287 E20 and 291 E40 (respectively, 77.6%, 78.8% and 79.3% of those randomised to

each group). The incidence of VTE was significantly lower in the E40 group (16/291, 5.5%) than

in the placebo group (43/288, 14.9%), with a relative risk of 0.37 (95% CI 0.22-0.63, p = 0.0002).

The incidence of VTE in the E20 group (43/287, 15%) was not significantly different from that in

the placebo group, with a relative risk of 1.03 (95% CI 0.70-1.51, p = 0.90).

Unstable Angina and Non-Q-Wave Myocardial Infarction

In an international multicentre study [ESSENCE], 3171 patients enrolled at the acute phase of

unstable angina or non-Q-wave myocardial infarction were randomised to receive in association

with aspirin (100 to 325 mg once daily), either subcutaneous CLEXANE 1 mg/kg every 12 hours

(n = 1607) or intravenous unfractionated heparin adjusted based on activated partial

thromboplastin time (aPPT; n = 1564). Patients had to be treated in hospital for a minimum of 2

days and a maximum of 8 days, until clinical stabilisation, revascularisation procedures or

hospital discharge; the median duration of treatment was 2.6 days in both groups and patients

were followed up to 30 days. CLEXANE significantly decreased the incidence of recurrent

angina, myocardial infarction and death, with an absolute event rate of the composite triple

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endpoint at day 14 of 16.6% in the CLEXANE group, compared to 19.8% in the heparin group (p

= 0.02). This represented a relative risk reduction of 16.2%, which remained statistically

significant at 30 days of follow up. Furthermore, the need for revascularisation with percutaneous,

transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) was

significantly less frequent in the CLEXANE group (27.0% vs 32.2%, p = 0.001). The 30 day

incidence of major bleeding was not significantly different between the two treatment groups

(6.5% in the CLEXANE group vs 7.0% in the heparin group, p = 0.566), with an increase in

minor bleeding observed in the CLEXANE group (18.4% vs 14.2%, p = 0.001), primarily

constituting ecchymoses at injection sites.

Acute ST-segment Elevation Myocardial Infarction (STEMI)

In a multicentre, double-blind, double-dummy, parallel group study, 20479 patients with STEMI

who were eligible to receive fibrinolytic therapy were randomised to receive either CLEXANE or

unfractionated heparin. All patients were also treated with aspirin for a minimum of 30 days.

Study medication was administered between 15 minutes before and 30 minutes after the initiation

of fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of

60 IU/kg (maximum 4000 IU) and followed by an infusion of 12 IU/kg per hour (initial maximum

1000 IU per hour) that was adjusted to maintain an aPTT of 1.5 to 2.0 times the control value. The

IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted

according to the patient’s age and renal function. For patients younger than 75 years of age,

enoxaparin was given as a single 30 mg intravenous bolus plus a 1 mg/kg SC dose followed by an

SC injection of 1 mg/kg every 12 hours. For patients 75 years of age or older, the IV bolus was

not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe

renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to

be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given until hospital

discharge or for a maximum of eight days (whichever came first).

When percutaneous coronary intervention (PCI) was performed during the study medication

period, patients were to receive antithrombotic support with blinded study drug. Therefore, for

patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen

established in previous studies, i.e. no additional dosing if the last SC administration was given

less than 8 hours before balloon inflation; IV bolus of 0.3 mg/kg enoxaparin if the last SC

administration was given more than 8 hours before balloon inflation.

A total of 20506 patients were enrolled in the study, and 20479 patients were included in the

intention to treat (ITT) population. The primary efficacy endpoint was the composite of death

from any cause or myocardial reinfarction in the first 30 days after randomisation. The efficacy

data show that the rate of the primary efficacy endpoint (death or myocardial re-infarction) was

9.9% in the enoxaparin group, as compared with 12.0% in the unfractionated heparin group, that

is a 17% reduction in the relative risk (P<0.001).

The treatment benefits of enoxaparin, evident for a number of efficacy outcomes, emerged at 48

hours, at which time there was a 35% reduction in the relative risk of myocardial re-infarction, as

compared with unfractionated heparin (P <0.0001). The beneficial effect of enoxaparin on the

primary endpoint was consistent across key subgroups including age, gender, infarct location,

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history of diabetes, history of prior myocardial infarction, fibrinolytic administered and time to

treatment with study drug.

There was a significant treatment benefit of enoxaparin, as compared with unfractionated heparin,

in patients who underwent PCI within 30 days after randomisation (23% relative risk reduction) or

who were treated medically (15 % relative risk reduction, P = 0.27 for interaction).

The rate of the 30-day composite endpoint of death, myocardial re-infarction or intracranial

haemorrhage (a measure of net clinical benefit) was significantly lower (p<0.0001) in the

enoxaparin group (10.1%) as compared to the heparin group (12.2%), representing a 17% relative

risk reduction in favour of treatment with CLEXANE.

6

PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

Enoxaparin sodium solution for injection also contains water for injections as an inactive

ingredient.

6.2

INCOMPATIBILITIES

For subcutaneous use: do not mix CLEXANE with other injections or solutions.

Intravenous (Bolus) Injection Technique (for the treatment of acute STEMI):

CLEXANE should be administered through an intravenous line and should not be co-administered

with other medications. To avoid the possible mixture of CLEXANE with other drugs, the

intravenous access chosen should be flushed with a sufficient amount of saline or dextrose

solution prior to and following the intravenous bolus administration of CLEXANE to clear the

port of drug.

CLEXANE may be safely administered with normal saline solution (0.9%) or 5% dextrose in

water.

6.3

SHELF LIFE

CLEXANE 20 mg/0.2 mL, CLEXANE 40 mg/0.4 mL, CLEXANE 60 mg/0.6 mL, CLEXANE 80

mg/0.8 mL and CLEXANE 100 mg/1 mL injection syringes: 3 years.

CLEXANE FORTE 120 mg/0.8 mL, 150 mg/1 mL injection syringes and CLEXANE 40 mg/0.4

mL ampoules

: 2 years.

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6.4

SPECIAL PRECAUTIONS FOR STORAGE

Do not freeze CLEXANE.

CLEXANE 20 mg/0.2 mL, CLEXANE 40 mg/0.4 mL, CLEXANE 60 mg/0.6 mL, CLEXANE 80

mg/0.8 mL and CLEXANE 100 mg/1 mL injection syringes: Store below 25°C.

CLEXANE FORTE 120 mg/0.8 mL, 150 mg/1 mL injection syringes and CLEXANE 40 mg/0.4

mL ampoules

: Store below 25°C.

6.5

NATURE AND CONTENTS OF CONTAINER

Solution for injection in Type I glass prefilled syringes fitted with injection needle in packs of 10.

The needles on the pre-filled syringes of CLEXANE are covered in a silicon coating, to enable

ease of penetration.

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING

CLEXANE contains no antimicrobial agent and should be used only once and then discarded.

Do not wipe the needle or allow CLEXANE solution to crystallise on the needle prior to use, as

this will damage the silicon coating.

Intravenous (Bolus) Injection Technique (for the treatment of acute STEMI):

CLEXANE should be administered through an intravenous line and should not be co-administered

with other medications. To avoid the possible mixture of CLEXANE with other drugs, the

intravenous access chosen should be flushed with a sufficient amount of saline or dextrose

solution prior to and following the intravenous bolus administration of CLEXANE to clear the

port of drug.

7

MEDICINE SCHEDULE

Prescription Medicine

8

SPONSOR

sanofi-aventis new zealand limited

56 Cawley Street

Ellerslie, Auckland, New Zealand

Freecall No: 0800 283 684

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9

DATE OF FIRST APPROVAL

CLEXANE 40 mg/0.4 mL ampoules

: 24 February 1994

CLEXANE 20 mg/0.2 mL, CLEXANE 40 mg/0.4 mL, CLEXANE 60 mg/0.6 mL, CLEXANE 80

mg/0.8 mL and CLEXANE 100 mg/1 mL injection syringes: 28 May 1998

CLEXANE FORTE 120 mg/0.8 mL, 150 mg/1 mL injection syringes: 18 November 1999

10

DATE OF REVISION OF THE TEXT

16 June 2017

Non-marketed

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SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Corrected typographical errors

Amended section heading to Nature and

contents of container

Amended section heading to Special

precautions for disposal and other handling

Amended Date of Revision of Text to 16

June 2017

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