Consumer medicine information

Exarane/Exarane Forte

Enoxaparin sodium

BRAND INFORMATION

Brand name

Exarane and Exarane Forte

Active ingredient

Enoxaparin sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Exarane/Exarane Forte.

SUMMARY CMI

Exarane/Exarane Forte

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Exarane?

Exarane* contains the active ingredient enoxaparin sodium. Exarane is used to prevent clots from getting bigger or stopping new clots from forming following hospital procedures or illness. Exarane is also used to treat DVT and heart problems including unstable angina and heart attack when taken with aspirin. Exarane is used to stop blood clots forming in the tubes of your kidney dialysis machine.

For more information, see Section 1. Why am I using Exarane? In the full CMI.

2. What should I know before I use Exarane?

Do not use if you have ever had an allergic reaction to Exarane, heparin or any medicine derived from heparin, or any of the ingredients listed at the end of the CMI. Do not take Exarane if you have or have had major bleeding disorders, injury to the brain, stomach or bowel problems, or bacterial infections of the heart.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Exarane? In the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Exarane and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? In the full CMI.

4. How do I use Exarane?

  • Your doctor will decide what dose you will receive.
  • Exarane is usually administered by injection under the skin. It can also be injected into the tubing of a dialysis machine or into a vein by a doctor or nurse.

More instructions can be found in Section 4. How do I use Exarane? in the full CMI.

5. What should I know while using Exarane?

Things you should do
  • Remind any doctor, dentist, or pharmacist you visit that you are using Exarane.
  • Tell your doctor if you become pregnant.
  • Tell your doctor if you have an artificial heart valve.
  • Tell your doctor you are using Exarane if you will be having a spinal or epidural injection for anaesthesia.
Things you should not do
  • Do not stop using this medicine without checking with your doctor.
  • Do not mix Exarane with other injections or fluids.
  • Do not inject Exarane into a muscle.
Looking after your medicine
  • Store below 25°C. Do not freeze. Store in a cool dry place away from moisture, heat, or sunlight.
  • Keep the syringe in the pack until it is time to use it.

For more information, see Section 5. What should I know while using Exarane? in the full CMI.

6. Are there any side effects?

Less serious side effects include pain, bruising, bleeding, swelling, itch, or rash at the injection site. Serious side effects include allergic reactions, signs of abnormal bleeding such as prolonged bleeding or bruising easily, nausea, gut pain, or numbness.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Exarane/Exarane Forte

Active ingredient(s): enoxaparin sodium

Consumer Medicine Information (CMI)

This leaflet provides important information about using Exarane. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Exarane.

Where to find information in this leaflet:

1. Why am I using Exarane?
2. What should I know before I use Exarane?
3. What if I am taking other medicines?
4. How do I use Exarane?
5. What should I know while using Exarane?
6. Are there any side effects?
7. Product details

1. Why am I using Exarane?

Exarane contains the active ingredient enoxaparin sodium. Exarane is an anticoagulant that belongs to a group of medicines called Low Molecular Weight Heparin (LMWH). These medicines help to prevent clots from getting bigger and stopping new clots from forming.

Exarane is used to prevent clotting following hospital procedures or illness.

Exarane is also used to treat deep vein thrombosis and heart problems including unstable angina and heart attack when taken with aspirin.

Exarane is used to stop blood clots forming in the tubes of your kidney dialysis machine.

2. What should I know before I use Exarane?

Warnings

Do not use Exarane if:

  • you are allergic to enoxaparin sodium, heparin or any other medicines derived from heparin, or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.
  • you have, or have ever had any of the following medical conditions:
    - major bleeding disorders
    - certain types of injury to the brain including stroke
    - stomach or bowel problems, such as ulcers or ulcerative colitis
    - bacterial infections in your heart

Check with your doctor if you:

  • have or have had any of the following medical conditions:
    - major bleeding disorder or blood clotting problem including recent stroke or hereditary blood disorders
    - bacterial endocarditis, an inflammation of the lining of the heart caused by bacteria
    - an artificial heart valve particularly in women who are pregnant
    - uncontrolled high blood pressure
    - stomach or bowel problems such as ulcers or ulcerative colitis
    - kidney disease
    - liver disease
    - diabetes
    - eye disease related to diabetes
    - recent surgery on the brain, spine, or eye
    - spinal surgery or spinal deformity
    - underweight or overweight
    - high level of potassium in your blood
  • take any medicines for any other condition

If your doctor is planning for you to have an anaesthetic injection in your back (spinal or epidural injection), tell your doctor you are using Exarane.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Exarane is not recommended while you are breastfeeding.

Children

Do not give Exarane to a child.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Exarane and affect how it works such as:

  • medicines used to prevent or treat blood clots, such as clopidogrel or ticlopidine
  • medicines containing aspirin or salicylates
  • Dextran 40, a medicine used to treat shock
  • medicines used to treat inflammatory disease, such as non-steroidal inflammatory drugs, such as ibuprofen or diclofenac, or steroids such as prednisolone
  • medicines which increase the level of potassium in the blood, such as potassium salts, fluid tablets and some medicines for heart problems

Your doctor will monitor your potassium levels and your ability to form blood clots if you are using any of these medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Exarane.

4. How do I use Exarane?

How much to use and when to use Exarane

  • Your doctor will decide what dose you will receive.
  • Exarane is usually administered by injection under the skin.
  • Follow the instructions provided and use Exarane until your doctor tells you to stop.

For the prevention of blood clots

The usual dose for moderate risk patients is 20 mg once per day.

The usual dose for high risk patients is 40 mg once per day.

For the treatment of bloods clots in the leg or deep vein

The usual dose is 1 mg per kg of body weight twice per day or 1.5 mg per kg of body weight once per day.

Warfarin is usually started within 3 days of using Exarane.

For patients requiring dialysis

The usual dose is 1 mg per kg of body weight into the tubing of the dialysis machine at the start of the session.

Additional doses may be needed.

For patients who have had severe heart attacks

The usual dose is:

  • 30 mg injected into the vein and 1 mg per kg of body weight injected under the skin, then
  • 1 mg per kg of body weight twice per day.

For patients with other types of heart disease

The usual dose is 1 mg per kg of body weight twice per day. Your doctor may change this dose as needed.

How to use Exarane

  • Exarane may be given by your doctor, nurse, or you.
  • Exarane is usually given by injection under the skin or into the tubing of a dialysis machine. It can also be given by injection into a vein. This will be done in hospital by a doctor or nurse.

Prefilled syringes

The prefilled syringes are ready to use. The air bubble in syringe should not be expelled.

Graduated Prefilled Syringes

The graduated syringes have markings indicating the volume in the syringe. The volume (mL) or mass (mg) to be injected should be precisely measured according to the dosage recommended by your doctor.

Injection Technique

  • The recommended site for injection is the stomach area. A different injection site should be used for each injection.
  • The needle on the prefilled syringe is covered in a silicon coating. Do not wipe the needle or allow the solution to crystallise on the needle as this will damage the coating.
  • Gently fold the skin using a thumb and finger. Hold the fold of the skin for the duration of the injection.
  • Introduce the whole length of the needle vertically into the thickness of the skin fold and inject Exarane.
  • Do not rub the injection site after administration.
  • Exarane is for single use only. Use only once and discard after use.

If you use too much Exarane

If you think that you have used too much Exarane or have been given too much Exarane, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26 if you are in Australia),
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Exarane?

Things you should do

If you are about to be started on a new medicine tell your doctor, dentist, or pharmacist that you are using Exarane.

Tell your doctor immediately if you become pregnant.

Tell your doctor if you have an artificial heart valve.

If you plan to have surgery tell your doctor or dentist that you are using Exarane.

Tell your doctor that you are using Exarane if your doctor is planning for you to have an anaesthetic injection in your back (spinal or epidural injection).

Ask your doctor are there any activities, such as sports, you should avoid while using Exarane.

Tell your doctor if you experience any significant loss of weight or increase in weight.

Keep all your appointments with your doctor and any blood tests.

Remind any doctor, dentist or pharmacist you visit that you are using Exarane.

Exarane is not interchangeable with other medicines containing low molecular weight heparin medicines.

Things you should not do

  • Do not give Exarane to anyone else even if they have the same condition as you.
  • Do not use Exarane to treat any other complaints unless a doctor tells you to.
  • Do not stop using Exarane or change the dosage without checking with your doctor.
  • Do not mix Exarane with other injections or infusion fluids. Certain medicines or solutions contain ingredients that could interact with Exarane.
  • Do not inject Exarane into a muscle.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Exarane affects you.

Looking after your medicine

Store below 25°C

  • Do not freeze Exarane
  • Keep the syringes in the pack until it is time to use them

Product is for single use in one patient only.

Discard any residue. Contains no antimicrobial agent.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example:

  • do not store it in the bathroom or near a sink, or
  • do not store it in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Injection site-related
  • Pain, bruising or irritation
  • Hard, inflamed nodules
  • Itchy, red rash
  • Bleeding
  • Itchy skin
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergy-related
  • Difficulty in breathing, symptoms of hayfever, feeling faint, itching hives, blisters, or other symptoms of allergy
Injection site-related
  • Painful itchy red/purple rash
Bleeding-related
  • Bleeding, including nose bleeds or prolonged bleeding from cuts
  • Bruising more easily than normal
  • Red or dark brown urine, red or black bowel motions
  • A fine widespread rash, especially noticeable on your mouth or eyes or sudden onset of white or blue colour in fingers in toes suggesting poor blood supply.
Spinal or epidural injection related
  • Pain in the middle of your back
  • Numbness and weakness in your legs
  • Gut problems
  • Problems passing urine
Other
  • Nausea, diarrhoea, fever
  • Swelling of the hands, ankles, or feet.
  • Severe abdominal pain, chest pain and headache
  • Numbness (paralysis), problems with coordination, dizziness, tiredness, lightheadedness,
  • Blurred vision, confusion or difficulty speaking
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
These side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Exarane contains

Active ingredient
(main ingredient)		enoxaparin sodium
Other ingredients
(inactive ingredients)		water for injections
It also contains materials of porcine (pig) origin.
Potential allergensenoxaparin sodium

Do not take this medicine if you are allergic to any of these ingredients.

What Exarane looks like

Exarane is clear, colourless to pale yellow solution for injection.

It is available in the following syringes:

Exarane

Ready to use Prefilled Syringes

  • 20 mg of enoxaparin sodium per 0.2 mL (pack of 10); AUST R 375494
  • 40 mg of enoxaparin sodium per 0.4 mL (pack of 10); AUST R 375490

Ready to use Prefilled Syringes with graduated markings

  • 20 mg of enoxaparin sodium per 0.2 mL (pack of 10); AUST R 375494
  • 40 mg of enoxaparin sodium per 0.4 mL (pack of 10); AUST R 375490
  • 60 mg of enoxaparin sodium per 0.6 mL (pack of 10); AUST R 375495
  • 80 mg of enoxaparin sodium per 0.8 mL (pack of 10); AUST R 375493
  • 100 mg of enoxaparin sodium per 1.0 mL (pack of 10); AUST R 375491

Exarane Forte

Ready to use Prefilled Syringes with graduated markings

  • 120 mg of enoxaparin sodium per 0.8 mL (pack of 10); AUST R 375492
  • 150 mg of enoxaparin sodium per 1.0 mL (pack of 10); AUST R 375496

Who distributes Exarane/Exarane Forte

Juno Pharmaceuticals Pty Ltd,
15-17 Chapel St
Cremorne Vic 3121
www.junopharm.com.au

This leaflet was prepared in July 2024.

*References to “Exarane” refer to both Exarane and Exarane Forte

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Exarane and Exarane Forte

Active ingredient

Enoxaparin sodium

Schedule

S4

 

1 Name of Medicine

Enoxaparin sodium.
Exarane is a biosimilar medicine to Clexane. The evidence for comparability supports the use of Exarane for the listed indications.

2 Qualitative and Quantitative Composition

Exarane.

Ready-to-use, prefilled syringes.

20 mg injection: enoxaparin sodium 20 mg/0.2 mL (anti-Xa: 2,000 IU).
40 mg injection: enoxaparin sodium 40 mg/0.4 mL (anti-Xa: 4,000 IU).

Ready-to-use, prefilled syringes with graduated markings.

20 mg injection: enoxaparin sodium 20 mg/0.2 mL (anti-Xa: 2,000 IU).
40 mg injection: enoxaparin sodium 40 mg/0.4 mL (anti-Xa: 4,000 IU).
60 mg injection: enoxaparin sodium 60 mg/0.6 mL (anti-Xa: 6,000 IU).
80 mg injection: enoxaparin sodium 80 mg/0.8 mL (anti-Xa: 8,000 IU).
100 mg injection: enoxaparin sodium 100 mg/1 mL (anti-Xa: 10,000 IU).

Exarane Forte.

Ready-to-use, prefilled syringes with graduated markings.

120 mg injection: enoxaparin sodium 120 mg/0.8 mL (anti-Xa: 12,000 IU).
150 mg injection: enoxaparin sodium 150 mg/1 mL (anti-Xa: 15,000 IU).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Injection, solution.
Clear, colourless to pale yellow solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Prevention of thrombo-embolic disorders of venous origin in patients undergoing orthopaedic and general surgery.
Prophylaxis of venous thromboembolism in medical patients bedridden due to acute illness.
Prevention of thrombosis in extra-corporeal circulation during haemodialysis.
Treatment of established deep vein thrombosis.
Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin.
Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) as an adjunctive to thrombolytic treatment, including patients to be managed medically or with subsequent Percutaneous Coronary Intervention (PCI).

4.2 Dose and Method of Administration

For subcutaneous use: do not mix Exarane with other injections or solutions.
For intravenous use: see Treatment of acute ST-segment elevation myocardial infarction.

Prophylaxis of venous thrombosis.

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 Exarane 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.
The timing of the first dose may need to be modified if spinal/epidural anaesthesia is to be performed (see Section 4.4 Special Warnings and Precautions for Use, Spinal/epidural anaesthesia).

b) Moderate risk patients.

In patients with a moderate risk of thromboembolism, the recommended Exarane 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 Special Warnings and Precautions for Use, Spinal/epidural anaesthesia).
Duration of therapy.

High to moderate risk.

Prophylaxis should be continued 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, Exarane 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 should be 40 mg once daily by subcutaneous injection for a minimum of 6 days, continuing for a maximum of 14 days or less if the patient returns to full ambulation earlier than 14 days.

Treatment of deep venous thrombosis.

The initial clinical trials which established the efficacy of Exarane in the treatment of deep venous thrombosis were conducted on patients who were initially treated with heparin and then changed to Exarane when a definitive diagnosis was established. However, the use of heparin prior to Exarane 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 Exarane is 1.5 mg/kg body weight once daily (150 IU anti-Xa activity/kg bodyweight) or 1 mg/kg body weight (100 IU anti-Xa activity/kg bodyweight) twice daily subcutaneously. In high risk patients, e.g. 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 Exarane initiation). Exarane should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0).

Treatment of unstable angina and non-Q-wave myocardial infarction.

The recommended dose of Exarane is 1 mg/kg (100 IU anti-Xa activity/kg) every 12 hours by subcutaneous injection, administered concurrently with oral aspirin.
Treatment with Exarane in these patients should be prescribed for a minimum of 2 days and a maximum of 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 Exarane 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 Dose and Method of Administration, Renal impairment, Elderly.
When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), Exarane 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 Exarane treatment is 8 days or until hospital discharge, whichever comes first.
For patients further managed with Percutaneous Coronary Intervention (PCI): If the last Exarane SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Exarane SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of Exarane should be administered (see Section 4.4 Special Warnings and Precautions for Use, 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. This dose is usually sufficient for a 4-hour haemodialysis session. If fibrin rings are formed, a fresh injection 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 postoperative 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.

A dosage adjustment is required for patients with severe renal impairment (creatinine clearance < 30 mL/min) according to the following tables (see Table 1 and Table 2).
Although no dosage 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 for signs and symptoms of bleeding.

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; see Section 5.1 Pharmacodynamic Properties, Clinical trials). No dose reduction is necessary in the elderly for other indications, unless renal function is impaired, however careful clinical observation is advised (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment, Use in the elderly).

Children.

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

Hepatic impairment.

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

Subcutaneous injection technique.

Injection should be made preferably when the patient is reclining. Exarane is administered by deep subcutaneous injection. Injection of Exarane 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.
The needles on prefilled syringes of Exarane are covered in a silicon coating, to enable ease of penetration. Do not wipe the needle or allow Exarane 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 Exarane. Do not rub the injection site after administration.

Intravenous (bolus) injection technique (for the treatment of acute STEMI).

 For intravenous injection, the graduated prefilled syringes should be used, see subsection below. Exarane should be administered through an intravenous line and should not be coadministered with other medications. To avoid the possible mixture of Exarane 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 Exarane to clear the port of drug. Exarane may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.

Prefilled syringes.

The prefilled syringes are ready for immediate use. The whole length of the needle should be introduced vertically (at a 90° angle to the skin) 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.

Graduated prefilled 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 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.

4.3 Contraindications

Allergy to Exarane, heparin or its derivatives including other low molecular weight heparins.
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).
Thrombocytopenia associated with a positive in vitro test for anti platelet antibody in the presence of enoxaparin sodium.
History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Low molecular weight heparin 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 low molecular weight heparins 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.

Exarane 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. 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 Exarane (see Section 4.8 Adverse Effects (Undesirable Effects)). 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.

Exarane 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 Contraindications). Circulating antibodies may persist for several years.
Exarane 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. Circulating antibodies may persist for several years. If history of heparin-induced thrombocytopenia is suspected, in vitro platelet aggregation tests have limited predictive value. The decision to use Exarane in such a case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments are considered, and only in consultation with an expert in the field.

Spinal/epidural anaesthesia.

There have been rare cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and spinal/epidural anaesthesia resulting in long-term or permanent paralysis.
These events are rare with Exarane dosage regimens 40 mg once daily or lower. The risk is greater with higher Exarane 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 4.5 Interactions with Other Medicines and Other Forms of Interactions). 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 Exarane and epidural or spinal anaesthesia/analgesia or spinal puncture, the pharmacokinetic profile of the drug should be considered (see Section 5.2 Pharmacokinetic Properties). Placement and removal of the needle/catheter is best performed when the anticoagulant effect of enoxaparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
Placement or removal of an epidural or spinal needle or catheter should be delayed for at least 12 hours after administration of lower doses (20 mg once daily or 40 mg once daily) of enoxaparin, and at least 24 hours after the administration of higher doses (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/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 0.75 mg/kg twice daily dose or the 1 mg/kg 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 < 30 mL/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 (20 mg once daily or 40 mg once daily) and at least 48 hours for the higher dose (0.75 mg/kg/twice daily, 1 mg/kg/twice daily or 1.5 mg/kg/once daily). The patient's regular Exarane dose may need to be delayed to ensure this. If blood is present during needle/catheter placement, the subsequent dose of Exarane 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, extreme vigilance and 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.

Skin necrosis/cutaneous vasculitis.

Skin necrosis and cutaneous vasculitis have been reported with low molecular weight heparins and should lead to prompt treatment discontinuation.

Thrombocytopenia.

Thrombocytopenia can occur with the administration of Exarane. Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 1.3% in patients given Exarane, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials. Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Exarane, 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/mm3, Exarane 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 Exarane 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 higher risk for thromboembolism (see Section 4.6 Fertility, Pregnancy and Lactation). The use of Exarane cannot be recommended for this purpose.

Percutaneous coronary revascularisation procedures.

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 Exarane 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 Exarane 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.

Use in renal impairment.

In patients with renal impairment, there is an increase in exposure of Exarane which increases the risk of bleeding. Since exposure of Exarane 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 dosage 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 Dose and Method of Administration, 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.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration.

Low weight.

An increase in exposure of Exarane 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/m2) 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.

Hyperkalaemia.

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see Section 4.8 Adverse Effects (Undesirable Effects)), particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, taking medicinal products known to increase potassium (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Plasma potassium should be monitored regularly especially in patients at risk.

Use in the elderly.

No increased bleeding tendency is observed in the elderly with the prophylactic dosage ranges. Elderly patients (especially 80 years or older) may be at an increased risk for 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 Dose and Method of Administration, 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 Dose and Method of Administration).
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 Section 5.1 Pharmacodynamic Properties, Clinical trials).

Paediatric use.

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

Effects on laboratory tests.

At doses used for prophylaxis of venous thromboembolism, Exarane 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 Exarane antithrombotic activity and therefore are unsuitable and unreliable for monitoring Exarane activity.
Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with Exarane. 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 Exarane activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of Exarane in patients with significant renal impairment. If during Exarane therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of Exarane.

Monitoring of platelet counts.

The risk of antibody-mediated heparin-induced thrombocytopenia also exists with low molecular weight heparins. Should thrombocytopenia occur, it usually appears between the 5th and 21st day following the beginning of Exarane treatment. Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with Exarane 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), Exarane treatment must be immediately discontinued and the patient switched to another therapy.

Acute generalized exanthematous pustulosis.

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as appropriate).

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 Exarane therapy unless strictly indicated. These agents include medications such as: anticoagulants, 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, Exarane should be used with careful clinical and laboratory monitoring of the haemostatic factors, when appropriate.

Medicinal products increasing potassium levels.

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin sodium under careful clinical and laboratory monitoring (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous and intravenous doses up to 20 mg/kg/day.
(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 Exarane 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 drug 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.
There have been post-marketing reports of foetal death when pregnant women received enoxaparin sodium. 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 enoxaparin (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, Exarane is not recommended for use in pregnant women with mechanical prosthetic heart valves (see Section 4.4, Prosthetic heart valves).
 It is unknown whether enoxaparin is excreted into the breast milk of humans. In lactating rats, the concentration of 35S-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 Exarane on lactating women have not been studied.
As a precaution, women should be advised not to breast feed while using Exarane.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (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 enoxaparin sodium 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 enoxaparin sodium for the treatment of unstable angina or non-Q-wave myocardial infarction, administered concurrently with aspirin (n = 1578) or with patients given enoxaparin sodium for the treatment of acute ST-segment elevation myocardial infarction (n = 10,176).
Exarane is biosimilar to Clexane and the bioequivalence has been demonstrated by a pharmacokinetic study after subcutaneous administration in healthy patients.
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 ≥ 1/10,000 (0.01%) and < 1/1000 (0.1%); very rare < 1/10,000 (< 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 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Major haemorrhage including retroperitoneal and intracranial bleeding has been reported. Some of these cases have been fatal. See Table 3.

Blood disorders.

Mild, transient, asymptomatic thrombocytopenia has been reported during the first days of therapy. See Table 4.

Hepatobiliary disorders.

Very common: asymptomatic and reversible increases in liver enzymes levels (e.g. transaminases) have been reported [Note: Liver enzymes were not assessed in the Unstable Angina Population].

Gastrointestinal disorders.

Common: nausea, diarrhoea.

Other.

Common: peripheral oedema, fever.

Psychiatric disorders.

Common: confusion.

Immune system disorders.

Common: allergic reaction.
Rare: anaphylactic/ anaphylactoid reaction (also see 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).
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 enoxaparin sodium. Voluntary reports of adverse events that have been received since market introduction (without causal relationship) that are not listed previously are cited below.

Blood and lymphatic system disorders.

Common: haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis.
Rare: eosinophilia.
Rare: cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia (see Section 4.4 Special Warnings and Precautions for Use).

Immune system disorders.

Anaphylactic/ anaphylactoid reactions including shock 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.

Nervous system disorders.

Headaches have been reported.

Vascular disorders.

Rare: there have been rare reports of spinal or neuraxial haematomas with the concurrent use of enoxaparin sodium 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 Special Warnings and Precautions for Use).

Hepatobiliary disorders.

Hepatocellular liver injury and cholestatic liver injury have been reported.

Skin and subcutaneous tissue disorders.

Rare: cutaneous (bullous) or systemic allergic reactions (such as pruritus, 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.
Alopecia has also been reported.

Musculoskeletal and connective tissue disorders.

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

General disorders and administration site conditions.

Common: injection site haematoma, injection site pain, other injection site reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction).
Uncommon: local irritation, skin necrosis at injection site.
Hard inflammatory nodules, which are not cystic enclosures of enoxaparin sodium, 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 must be discontinued immediately.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

Oral ingestion of Exarane (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.
Accidental overdosage after intravenous, extracorporeal or subcutaneous administration of massive doses of Exarane may lead to haemorrhagic complications through anti-coagulant activity. This may be largely neutralised by the slow intravenous infusion of protamine.
Particular care should be taken to avoid overdosage with protamine, as even with high doses of protamine, the anti-Xa activity of Exarane is never completely neutralised (maximum reversal of 60%), even though the anti-coagulant activity is neutralised. (See the prescribing information for protamine salts).
The dose of protamine depends on the dose of Exarane injected. If Exarane was administered in the previous 8 hours, 1 mg or 100 anti-heparin units of protamine neutralises the anti-IIa activity generated by 1 mg (100 IU anti-Xa activity) of Exarane. An infusion of 0.5 mg protamine per 1 mg of Exarane may be administered if Exarane 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 Exarane injection. However, depending on the clinical circumstances, e.g. the size of the dose of Exarane, 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 general advice on overdose management, contact the Poisons Information Centre, telephone number 13 11 26 (Australia) or the National Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antithrombotic agent, heparin group, ATC code: B01A B05.
Enoxaparin sodium is a low molecular weight heparin (MW approx. 4500 D). 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.

Mechanism of action.

In comparison with natural heparin enoxaparin sodium is characterised by a clear increase in the ratio between anti-Xa and anti-IIa activities which is always greater than 4.
It has several actions on the coagulation pathway through binding to anti-thrombin III. The anti-thrombotic activity is related to inhibition of thrombin generation and inhibition of two main coagulation factors: Factor Xa and Thrombin. Enoxaparin sodium also induces a sustained release of the Tissue Factor Pathway Inhibitor in vivo.
In the experimental animal, enoxaparin sodium was found to have potent anti-thrombotic properties with a minimum effect on bleeding.

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 enoxaparin sodium 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 enoxaparin sodium 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 enoxaparin sodium (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 enoxaparin sodium (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 enoxaparin sodium treatment group versus 3% for the placebo treatment group. The majority of the bleeding events for both groups were injection site haemorrhages (9% enoxaparin sodium 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 enoxaparin sodium 1 mg/kg every 12 hours (n = 1607) or intravenous UFH 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. Enoxaparin sodium significantly decreased the incidence of recurrent angina, myocardial infarction and death, with an absolute event rate of the composite triple endpoint at day 14 of 16.6% in the enoxaparin sodium 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 enoxaparin sodium 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 enoxaparin sodium group vs 7.0% in the heparin group, p = 0.566), with an increase in minor bleeding observed in the enoxaparin sodium 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, 20,479 patients with STEMI within 6 hours of onset and eligible to receive fibrinolytic therapy were randomised to receive either enoxaparin or UFH. 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). The mean treatment duration for enoxaparin was 6.6 days. The mean treatment duration of UFH was 54 hours.
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 20,506 patients were enrolled in the study, and 20,479 patients were included in the intention to treat (ITT) population. Patients ranged in age from 20-99 years (mean age 59.8 years), with 23.5% of patients female and 76.5% male. Race was distributed as follows: 87.2% Caucasian, 0.2% Black, 9.8% Asian and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56% and both in 1%. All patients were treated with aspirin at a dose of 75 to 325 mg for a minimum of 30 days. A fibrinolytic agent was administered to all but 4 patients, with 79.8% receiving a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20.2% receiving streptokinase. Following inclusion in this trial, 4716 patients underwent further PCI.
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 provided in Table 5 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 UFH group, that is a 17% reduction in the relative risk, representing an absolute risk reduction of 2.1% (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 reinfarction, as compared with UFH (P < 0.0001), representing an absolute risk reduction of 0.5%. The beneficial effect of enoxaparin on the primary endpoint was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, fibrinolytic administered and time to treatment with study drug, however it is necessary to interpret such subgroup analyses with caution (see Figure 1).
The beneficial effect of enoxaparin on the primary endpoint observed during the first 30 days was maintained over a 12 month follow-up period (see Figure 2).
There was a significant treatment benefit of enoxaparin, as compared with UFH, in patients who underwent PCI within 30 days after randomisation (23% relative risk reduction, representing an absolute risk reduction of 3.1%) or who were treated medically (15% relative risk reduction, representing an absolute risk reduction of 1.7%, P = 0.27 for interaction).
The rates of major haemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in hematocrit or clinically overt bleeding, including intracranial haemorrhage) at 30 days were 2.1% in the enoxaparin group and 1.4% in the UFH group. The rates of intracranial haemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the UFH group.
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 enoxaparin, representing an absolute risk reduction of 2.1%.

Renal impairment.

A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. Anti-Xa exposure represented by AUC, at steady-state, is increased by 20% in mild (creatinine clearance 50-80 mL/min) and 21% in moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated subcutaneous 40 mg once daily doses. In patients with severe renal impairment (creatinine clearance < 30 mL/min), the AUC at steady-state is significantly increased on average by 65% after repeated subcutaneous 40 mg once daily doses.

Weight.

In obese subjects, after repeated subcutaneous 1.5 mg/kg daily dosing, mean AUC of anti-Xa activity is 19% higher at steady-state in obese healthy volunteers (BMI > 30 kg/m2) compared to non-obese healthy control subjects (18 < BMI = < 25 kg/m2), while maximal plasma activity is not increased. There is a lower weight-adjusted clearance (L/h/kg) in obese subjects compared to non-obese subjects.
In low-weight subjects, anti-Xa exposure is 52% higher in healthy low-weight women (< 45 kg but BMI > 18 kg/m2) and 27% higher in healthy low-weight men (< 57 kg but BMI > 18 kg/m2) when compared to healthy normal weight subjects (< 60 kg for women and > 72 kg for men with BMI of 18-28 kg/m2 for both genders). The maximal plasma activity was also increased by 45% for low-weight women and 31% for low-weight men compared to their respective normal weight controls.

Elderly.

Based on the results of a pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not different in elderly subjects compared to younger subjects when renal function is normal.
However, since renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin sodium.

Comparability of Exarane and Clexane.

The bioequivalence of Exarane and Clexane was established using a pharmacokinetic study (411/13) using surrogate markers such as anti-Xa, anti-IIa, Tissue Factor Pathway Inhibitor (TFPI) activity, as well as the ratio of anti-FXa and anti-FIIa activity. The AUC(0-t) and Amax of anti-Xa and anti-IIa activities as primary parameters for enoxaparin evaluation were used to assess bioequivalence. From the pharmacokinetic study conducted, both, Exarane and Clexane were found to be bioequivalent.

5.2 Pharmacokinetic Properties

The pharmacokinetic parameters of enoxaparin sodium were studied from the changes in plasma anti-Xa activity.
The anti-Xa activity generated by enoxaparin sodium does not cross the placental barrier during the second trimester of pregnancy.
Anti-Xa activity generated by enoxaparin sodium is localised within the vascular space.

Absorption.

After injection of enoxaparin sodium by the subcutaneous route (SC), the product is rapidly and completely absorbed. The absolute bioavailability is over 90%.

Distribution.

The maximum plasma activity is observed after 3 hours and is, on average, 1.6 microgram/mL after the SC injection of a 20 mg dose and 3.8 microgram/mL after the injection of a 40 mg dose. The anti-Xa activity, measured like that of unfractionated heparin (UFH), gives values of approximately 0.16 and 0.38 IU/mL respectively.
A 30 mg intravenous (IV) bolus immediately followed by 1 mg/kg SC provided initial peak anti-Xa levels of 1.16 IU/mL (n = 16) and an average exposure corresponding to 84% of steady-state levels. Steady-state is achieved on the second day of treatment following continued SC dosing of 1 mg/kg every 12 hours. The aPTT (activated partial thromboplastin time) immediately after the first SC injection was 49.6 seconds. The average aPTT prolongation value on Day 1 was about 16% higher than on Day 4.

Metabolism.

Metabolic breakdown of enoxaparin sodium is slight and takes place mainly in the liver (desulphation and depolymerisation). Small amounts of the product are eliminated by the kidneys in an intact or slightly degraded form.

Excretion.

The elimination of enoxaparin (based on anti-Xa activity levels) is characterised by a half-life of approximately 4.4 hours for a dose of 40 mg. At higher doses of 73.8 mg to 132.6 mg, a study has shown that anti-Xa activity levels exhibit a first phase elimination half-life of ~ 5 hours and a second stage elimination half-life of ~ 9 hours. Following a 40 mg dose, anti-Xa activity may persist in the plasma for 24 hours.
Elimination of enoxaparin sodium at prophylactic dosages is not significantly modified in patients with mild (creatinine clearance 50-80 mL/min) to moderate (creatinine clearance 30-50 mL/min) renal insufficiency. It is slightly reduced in the elderly (t½ = 6-7 hours). This modification has no effect on the doses or the frequency of injections, as there is no plasma accumulation in elderly subjects.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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 rat bone marrow chromosomal aberration test.

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

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

See Section 6.4 Special Precautions for Storage.

6.4 Special Precautions for Storage

Store in a cool dry place away from moisture, heat, or sunlight.
Keep the syringe in the pack until it is time to use it.
Do not freeze Exarane.

Exarane 20 mg/0.2 mL, Exarane 40 mg/0.4 mL, Exarane 60 mg/0.6 mL, Exarane 80 mg/0.8 mL and Exarane 100 mg/1 mL injection syringes.

Store for three years below 25°C.

Exarane Forte (120 mg/0.8 mL, 150 mg/1 mL) injection syringes.

Store for two years below 25°C.
Product is for single use in one patient only. Discard any residue. Contains no antimicrobial agent.

6.5 Nature and Contents of Container

Exarane.

Ready-to use, pre-filled syringe.

20 mg/0.2 mL (anti-Xa: 2,000 IU) ready-to-use, prefilled syringes, 10s.
40 mg/0.4 mL (anti-Xa: 4,000 IU) ready-to-use, prefilled syringes, 10s.

Ready-to use, pre-filled syringe with graduated markings.

20 mg/0.2 mL (anti-Xa: 2,000 IU) ready-to-use, prefilled syringes, 10s.
40 mg/0.4 mL (anti-Xa: 4,000 IU) ready-to-use, prefilled syringes, 10s.
60 mg/0.6 mL (anti-Xa: 6,000 IU) ready-to-use, prefilled syringes, 10s.
80 mg/0.8 mL (anti-Xa: 8,000 IU) ready-to-use, prefilled syringes, 10s.
100 mg/1 mL (anti-Xa: 10,000 IU) ready-to-use, prefilled syringes, 10s.

Exarane Forte.

Ready-to use, pre-filled syringe with graduated markings.

120 mg/0.8mL (anti-Xa: 12,000 IU) ready-to-use, prefilled syringes, 10s.
150 mg/1 mL (anti-Xa: 15,000 IU) ready-to-use, prefilled syringes, 10s.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

9041-08-1.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes