Consumer medicine information

Fraxiparine Forte Injection

Nadroparin calcium

BRAND INFORMATION

Brand name

Fraxiparine Forte

Active ingredient

Nadroparin calcium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fraxiparine Forte Injection.

What is in this leaflet

This leaflet answers some common questions about Fraxiparine Forte injections. It does not contain all the available information. It does not take the place of talking to your doctor, pharmacist or nurse.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Fraxiparine Forte against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the injection. You may need to read it again.

What Fraxiparine Forte is used for

Fraxiparine Forte belongs to a group of medicines called Low Molecular Weight Heparins.

Fraxiparine Forte is used to treat existing blood clots that are blocking blood vessels.

It is a medicine that works by delaying the action by which blood clots form. This results in the blood remaining thin and prevents formation of clots which may become lodged in blood vessels and treats blood clots if they have already formed.

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

There is not enough information to recommend how the use of this medicine can affect your ability to drive a car or operate machinery.

There is not enough information to recommend the use of this medicine for patients aged less than 18 years. Therefore, Fraxiparine Forte is not recommended for use in children or adolescents.

Before you use Fraxiparine Forte

When you must not use it

Do not use Fraxiparine Forte if you have an allergy to:

  • any medicine containing nadroparin calcium
  • heparin or low-molecular weight heparins
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not use Fraxiparine Forte if you:

  • have had thrombocytopenia (a low blood platelet count) due to using Fraxiparine Forte before
  • have an increased risk of bleeding or a bleeding disorder
  • have a history of ulcers in the stomach or intestine
  • have had a burst blood vessel in your brain
  • have infective endocarditis (an infection of the lining of the heart)
  • have severe kidney failure and are being treated for a blood clot

Do not use this medicine after the expiry date printed on the carton or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Do not take this medicine if you are pregnant or planning to become pregnant unless you and your doctor have discussed the risks and benefits involved. It is not known whether Fraxiparine Forte can harm your baby if used during pregnancy.

Do not breast-feed if you are taking this medicine. The active ingredient in Fraxiparine Forte can pass into breast milk. The effect on the baby is not known; therefore Fraxiparine Forte should not be used when you are breast-feeding.

Tell your doctor if you have or have had any of the following medical conditions or procedures:

  • an increased risk of bleeding including:
    - liver problems or liver failure
    - very high blood pressure
    - history of stomach ulcers
    - bleeding disorders
    - disorder of the blood vessels in the eye
    - recent surgery of the brain, spinal cord or eye
  • kidney disease
  • problems with your heart including angina or heart attack
  • high potassium levels in the blood
  • diabetes
  • metabolic acidosis (too much acid in the blood)
  • thrombocytopenia (a low blood platelet count)
  • a recent or planned spinal or epidural injection (an injection around the spinal cord)
  • an allergy to latex, as the needle shield of the syringe may contain latex
  • dead skin tissue (cutaneous necrosis) around injection sites

Tell your doctor if you are elderly or aged less than 18 years.

If you have not told your doctor about any of the above, tell him/her before you start taking Fraxiparine Forte.

Taking other medicines

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

Some medicines and Fraxiparine Forte may interfere with each other. These include:

  • aspirin or other medicines used to reduce pain and inflammation (non steroidal anti-inflammatory drugs or salicylates)
  • ticlopidine or other medicines used to thin the blood and prevent it from clotting (oral anticoagulants and anti-platelet agents)
  • corticosteroids (medicines used to reduce inflammation)
  • dextrans (medicines used to thin the blood)
  • ACE inhibitors (medicines used to treat high blood pressure and some other heart conditions)

These medicines may be affected by Fraxiparine Forte or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How Fraxiparine Forte is given

The dose of Fraxiparine Forte you will need will depend on why you are being treated with Fraxiparine Forte and also on your body weight.

If you are injecting this medicine yourself you will be instructed by your doctor, nurse or pharmacist on how to prepare and give the injection subcutaneously (under the skin). Use it exactly as prescribed and do not exceed the prescribed dosage.

How much to take and how long to take Fraxiparine Forte for

Treatment of existing blood clots:
For the treatment of existing blood clots, Fraxiparine Forte will be given by an injection subcutaneously (under the skin) once daily for 10 days. The dose will be calculated by your doctor according to your body weight.

If you have moderate or severe kidney impairment, you may need a reduced dose.

Follow your doctor's instructions on how much Fraxiparine Forte should be taken.

How to self administer Fraxiparine Forte

In some cases, you may be allowed to treat yourself with Fraxiparine Forte. You should follow the guidelines below to make sure that you inject Fraxiparine Forte properly. You should speak with your doctor if you have any concerns about how to give the injection. Most people, however, will be given the injection by a nurse or doctor.

Removal of packaging prior to injection:
To divide the syringes, carefully fold the twin pack several times, so that the syringes are back to back, then slowly using an even pressure divide the two syringes starting from the plunger end of the pack.

To remove the syringe from its plastic packaging, gently tear the top backing film completely from the plastic tray (starting from the plunger end), then allow the syringe to roll onto the palm of your other hand. The rubber cap over the needle may appear to be off-centre on the syringe, however, this occurs during packaging and does not mean that the needle is bent.

Preparation of syringe for subcutaneous injection:
To remove the cap from the syringe needle:

  • hold the syringe vertically (grey cap uppermost)
  • hold the grey cap by its collar, and the syringe barrel in your other hand, then slowly rotate the syringe barrel gently pulling downwards at the same time, until the needle is fully withdrawn from the cap
  • do not pull the cap upwards from the syringe - this may bend the needle

Hold the syringe vertically with the needle uppermost and ensure the air bubble is at the top of the syringe. Advance the plunger to the volume/dosage required, expelling air and any excess.

Method for subcutaneous administration:

  • A suitable site for injection is the skin on the lower part of the stomach, away from any wound or joints. Alternatively injection may be made into the thigh.
  • Pinch a skin fold. Note: the use of alcohol may toughen the skin, making later injection difficult.
  • Maintain the fold and insert the needle vertically to its full depth then inject Fraxiparine Forte over 10 to 15 seconds. There may be a small air bubble in the barrel of the syringe but this does not have to be removed.
  • Still holding the skin fold, withdraw the needle vertically. Do not rub the site of injection.
  • After the injection is given, install the safety system on the Fraxiparine Forte syringe and dispose of carefully.

Any unused portion of Fraxiparine Forte should be disposed of at once.

Fraxiparine Forte is not intended for injection directly into muscle or into a vein.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Fraxiparine Forte.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Increased or excessive bleeding is the major sign of overdose. Overdose may be treated by reducing or delaying the next doses of Fraxiparine Forte or in more serious cases, a drug called protamine sulphate can partly reverse the effect of Fraxiparine Forte.

While you are using Fraxiparine Forte

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Fraxiparine Forte.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take Fraxiparine Forte to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Fraxiparine Forte affects you.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while being treated with Fraxiparine Forte.

Like other medicines, Fraxiparine Forte can cause some side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

More common side effects:

  • small blood clot under the skin at the injection site
  • abnormal bleeding
  • injection site reactions

Less common side effects:

  • rash, hives, redness or itching around the injection site
  • calcium deposits at the injection site
  • dead skin tissue (cutaneous necrosis) at the injection site

Your doctor may monitor you with blood tests for:

  • high levels of proteins
  • high levels of potassium
  • low platelet count or raised white blood cell count

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • allergic reactions such as skin rash, swelling of the face including mouth, lips and/or tongue, throat, wheezing or shortness of breath
  • persistent painful erection of the penis (priapism)

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using it

Storage

Fraxiparine Forte should be stored below 25°C. Do not freeze. Do not refrigerate, as cold injections may be painful.

Keep it 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

Use Fraxiparine Forte once only and discard any unused portion of each syringe.

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Fraxiparine Forte is a sterile solution for subcutaneous injection.

Fraxiparine Forte is presented as 0.6 mL, 0.8 mL and 1.0 mL graduated syringes in packs of 2, 6 and 10 syringes.

Ingredients

Fraxiparine Forte contains nadroparin calcium 19,000IU anti-Xa per 1.0mL as the active ingredient.

  • water for injections
  • calcium hydroxide or dilute hydrochloric acid

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Suppliers

Fraxiparine is supplied in Australia by:

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St. Leonards, 2065, NSW.

Fraxiparine® is a registered trade mark of Aspen Global Inc.

0.6 mL Syringe AUST R 67149
0.8 mL Syringe AUST R 67148
1.0 mL Syringe AUST R 67145

This leaflet was prepared in September 2017.

Version 5.0


Published by MIMS November 2017

BRAND INFORMATION

Brand name

Fraxiparine Forte

Active ingredient

Nadroparin calcium

Schedule

S4

 

1 Name of Medicine

Nadroparin calcium.

2 Qualitative and Quantitative Composition

Sterile, clear preservative-free solution for subcutaneous injection containing nadroparin calcium 19,000 IU anti-Xa per 1.0 mL dissolved in water for injections.
Nadroparin is a low molecular weight heparin made by depolymerisation of standard heparin. It is a glycosaminoglycan with a mean molecular weight around 4,500 daltons. It possesses a high ratio of anti-Xa activity to anti-IIa activity, between 2.5 to 4.0 compared to unfractionated heparin for which this ratio is one.
Anti-Xa denotes anti factor Xa activity. The ratio of anti-Xa to anti-IIa activity is 2.5 to 4.0.
One ICU is equivalent to 0.38 IU anti-Xa.
The excipients contained in the Fraxiparine Forte solution are:
Calcium hydroxide solution or dilute hydrochloric acid (to adjust pH) and water for injections. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Disposable glass pre-filled single use syringes containing a clear solution for subcutaneous injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of deep vein thrombosis (DVT).

4.2 Dose and Method of Administration

Particular attention should be paid to the specific dosing instructions for each proprietary LMWH as different units of measurement (units or mg) are used to express doses. Fraxiparine Forte should therefore not be used interchangeably with other low weight molecular weight heparins during ongoing treatment. In addition, care should be taken to use the correct formulation of nadroparin, either Fraxiparine or Fraxiparine Forte, as this will affect the dosing regimen.
Platelet count must be monitored throughout treatment with Fraxiparine Forte (see Section 4.4 Special Warnings and Precautions for Use).
Specific recommendations regarding the timing of Fraxiparine Forte dosing surrounding spinal/ epidural anaesthesia or spinal lumbar puncture should be followed (see Section 4.4 Special Warnings and Precautions for Use).

Administration.

Administer by subcutaneous injection into the lateral abdominal wall.
When Fraxiparine Forte is given by subcutaneous injection, the usual site for injection is the lateral abdominal wall, although the thigh may be used as an alternative. The needle should be inserted perpendicularly into a pinched-up fold of skin which should be held gently but firmly until the injection has been completed. Do not rub the injection site.
Fraxiparine Forte is not intended for intramuscular administration.

Removal of packaging prior to injection.

To divide the syringes, carefully fold, several times, the twin pack so that the syringes are back to back, then slowly using an even pressure divide the two syringes starting from the plunger end of the pack.
To remove the syringe from its plastic packaging, gently tear the top backing film completely from the plastic tray (starting from the plunger end), then allow the syringe to roll onto the palm of your other hand.
The rubber cap over the needle may appear to be asymmetrical on the syringe, however, this occurs during packaging and does not mean that the needle is bent.

Preparation of syringe for subcutaneous injection.

To remove the cap from the syringe needle.
Hold the syringe vertically (grey cap uppermost).
Hold the grey cap by its collar, and the syringe barrel in your other hand, then slowly rotate the syringe barrel gently pulling downwards at the same time, until the needle is fully withdrawn from the cap. Do not pull the cap upwards from the syringe, this may bend the needle.
Hold the syringe vertically with the needle uppermost and ensure the air bubble is at the top of the syringe. Advance the plunger to the volume/ dosage required, expelling air and any excess.

Method for subcutaneous administration.

1. A suitable site for injection is the subcutaneous tissue of the lateral abdominal wall, away from any wound or weight bearing site. Alternatively injection may be made into the thigh.
2. Pinch a skin fold.

Note.

The use of alcohol may toughen the skin, making subsequent injection difficult.
3. Maintain the fold and insert the needle vertically to its full depth then inject Fraxiparine Forte over 10 to 15 seconds. There may be a small air bubble in the barrel of the syringe, but this does not have to be removed.
4. Still holding the skin fold, withdraw the needle vertically. Do not rub the site of injection.
5. After the injection is given, install the safety system on the Fraxiparine Forte syringe and dispose of carefully.
Fraxiparine Forte is not intended for intramuscular or intravenous administration.

Dosage.

Fraxiparine Forte should only be administered by subcutaneous route.

Treatment of DVT.

In the treatment of DVT, oral anticoagulant therapy should be initiated as soon as possible unless contraindicated. Treatment with Fraxiparine Forte should not be stopped before the target International Normalisation Ratio (INR) is reached.
It is recommended that Fraxiparine Forte is administered subcutaneously once daily for a usual duration of 10 days. The dose is adjusted to the patient's weight according to Table 1, which is based on 171 anti-Xa IU per kg bodyweight.

Dosage for the elderly.

No dosage adjustment is necessary in the elderly, unless renal function in impaired. It is recommended that renal function is assessed before initiating treatment (see Dosage for the renally impaired; see Section 5.2 Pharmacokinetic Properties).

Dosage for the renally impaired.

The following dose reduction recommendations are based on population pharmacokinetic modelling and the efficacy and safety of the dose reductions have not been evaluated in clinical trials.

Treatment of DVT.

Dose reduction is not required in patients with mild renal impairment (creatinine clearance greater than or equal to 50 mL/min).
Moderate and severe renal impairment is associated with increased exposure to nadroparin. These patients are at increased risk of thromboembolism and haemorrhage.
If a dose reduction is considered appropriate by the prescribing physician, taking into account the individual risk factors for haemorrhage and thromboembolism in patients with moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min and less than 50 mL/min) the dose should be reduced by 25 to 33%.
Fraxiparine Forte is contraindicated in patients with severe renal impairment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Children and adolescents.

Fraxiparine Forte is not recommended in children and adolescents as there are insufficient safety and efficacy data to establish dosage in patients aged less than 18 years.

Hepatic impairment.

There have been no studies conducted in patients with hepatic impairment.

4.3 Contraindications

Fraxiparine Forte is contraindicated in patients hypersensitive to nadroparin, or any of the excipients of nadroparin injections;
with a history of thrombocytopenia with nadroparin (see Section 4.4 Special Warnings and Precautions for Use);
with an increased risk of haemorrhage including those with bleeding disorders (except for disseminated intravascular coagulation not induced by heparin);
with active bleeding or organic lesions likely to bleed (such as active peptic ulceration), haemorrhagic cerebrovascular accident or infective endocarditis;
with severe renal failure (creatinine clearance < 30 mL/min) receiving treatment for DVT.

4.4 Special Warnings and Precautions for Use

Heparin induced thrombocytopenia.

Because of the possibility of heparin induced thrombocytopenia, regular monitoring of platelet count is recommended throughout the course of treatment with Fraxiparine Forte.
Rare cases of thrombocytopenia, occasionally severe, have been reported, which may be associated with arterial or venous thrombosis. Such diagnosis should be considered in the following situations:
thrombocytopenia;
any significant reduction in platelet level;
worsening of the initial thrombosis while on therapy;
thrombosis occurring on treatment; disseminated intravascular coagulation.
In this event, Fraxiparine Forte treatment must be discontinued.
These effects are probably of an immunoallergic nature and in the case of a first treatment are reported mainly between the 5th and the 21st day of therapy, but may occur much earlier if there is a history of heparin induced thrombocytopenia.
If there is a history of thrombocytopenia occurring with heparin (either standard or low molecular weight heparin (LMWH)), treatment with Fraxiparine Forte may be considered if necessary. In such cases, careful clinical monitoring and assessment of platelet count should be performed at least daily. If thrombocytopenia occurs, treatment should be discontinued immediately.
When thrombocytopenia occurs with heparin (either standard or LMWH), substitution with a different antithrombotic class should be considered. If not available, then substitution with another low molecular weight heparin may be considered if the administration of heparin is necessary. In such cases, platelet count monitoring should be performed at least daily and the treatment should be discontinued as soon as possible, since cases of initial thrombocytopenia continuing after substitution have been described (see Section 4.3 Contraindications).
In vitro platelet aggregation tests are only of limited value in the diagnosis of heparin induced thrombocytopenia.

Increased risk of bleeding.

Caution should be exercised when nadroparin is administered in the following situations as they may be associated with an increased risk of bleeding:
hepatic insufficiency/ hepatic failure;
severe arterial hypertension;
history of peptic ulceration or other organic lesion likely to bleed;
vascular disorder of the chorioretina;
during the postoperative period following surgery of the brain, spinal cord or eye.

Use in renal impairment.

Nadroparin is known to be mainly excreted by the kidney, which results in increased nadroparin exposure in patients with renal impairment. Patients with impaired renal function are at increased risk of bleeding and should be treated with caution.
The decision on whether a dose reduction is appropriate for patients with creatinine clearance 30 to 50 mL/min should be based on the physician's assessment of an individual patient's risk of bleeding versus the risk of thromboembolism (see Section 4.2 Dose and Method of Administration).

Hyperkalaemia.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients with raised plasma potassium or at risk of increased plasma potassium levels (such as patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis or taking drugs that may cause hyperkalaemia [e.g. angiotensin converting (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs)].
The risk of hyperkalaemia appears to increase with duration of therapy, but is usually reversible.
Plasma potassium should be monitored in patients at risk.

Spinal/ epidural haematomas.

The risk of spinal/ epidural haematomas is increased by indwelling epidural catheters or by concomitant use of other drugs which may affect haemostasis such as NSAIDs, platelet inhibitors or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
Therefore, the concomitant prescription of a central nervous blockade or spinal puncture and of an anticoagulant therapy should be decided only after careful individual benefit/ risk assessment in the following situations:
in patients already treated with anticoagulant therapy, the benefits of central nervous blockade or spinal puncture must be carefully balanced against the risks;
in patients planned to undergo elective surgery with central nervous blockade or spinal puncture, the benefits of anticoagulant therapy must be carefully balanced against the risks.
In the case of patients with spinal lumbar puncture, spinal anaesthesia or epidural anaesthesia, a minimum of 12 hours should elapse between the Fraxiparine Forte injection at prophylactic doses or 24 hours at treatment doses and the insertion or the removal of the spinal/ epidural catheter or needle. For patients with renal impairment longer intervals may be considered.
Where concomitant prescription of central nervous blockade or spinal puncture and LMWH is used, patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Use in the elderly.

Elderly patients and patients with renal insufficiency may show delayed elimination of nadroparin calcium. It is recommended that renal function is assessed before initiating treatment. Reduced doses should be considered.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

Cutaneous necrosi.

Cutaneous necrosis has been reported very rarely. It is preceded by purpura or infiltrated or painful erythematous blotches, with or without general signs. In such cases, treatment should be immediately discontinued.

Latex allergy.

The needle shield of the prefilled syringe may contain dry natural latex rubber that has the potential to cause allergic reactions in latex sensitive individuals.
The low molecular weight heparins are clinically not interchangeable as they differ from one another in having different molecular weight profiles, different specific activities (anti Xa to anti IIa activities), different rate of plasma clearance, different dosage regime etc.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Combined therapy with the following drugs is not recommended.

In the treatment of deep vein thrombosis (DVT) the concomitant use of aspirin, other salicylates, NSAIDs, ticlopidine and other antiplatelet agents is not recommended, as they may increase the risk of bleeding. Where such combinations cannot be avoided, careful clinical and biological monitoring should be undertaken.

Combinations requiring caution.

Fraxiparine Forte should be administered with caution in patients receiving oral anticoagulant agents, systemic (gluco-) corticosteroids and dextrans. When oral anticoagulant therapy is initiated in patients receiving nadroparin, treatment with Fraxiparine Forte should be continued until the International Normalisation Ratio (INR) is stabilised at the target value. Careful clinical and biological monitoring should be undertaken.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no clinical studies on the effect of nadroparin on fertility in humans.
Nadroparin at subcutaneous doses up to 40 mg/kg (approximately 3,800 anti-Xa IU/kg) did not affect the fertility or reproductive performance of male and female rats.
(Category C)
Category C - Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
In animal studies, nadroparin did not cause teratogenic or embryotoxic effects when administered to pregnant rats and rabbits at subcutaneous doses up to 3,800 anti-Xa IU/kg/day. A study in rats showed that only minimal amounts of radiolabelled nadroparin calcium were able to cross the placental barrier (0.002% of applied dose per fetus). However, there is only limited clinical data concerning transplacental passage of nadroparin in pregnant women. Therefore, the use of Fraxiparine Forte during pregnancy is not advised, unless the therapeutic benefits outweigh the possible risks.
An increased incidence of fetal loss and prematurity may be associated with maternal haemorrhage.
A study with radiolabelled nadroparin calcium at 2.5 mg/kg/day (230 anti-Xa IU/kg/day) in lactating rats has shown that drug related material is excreted in milk with about the same concentration in the milk as in maternal plasma. There is limited information on the excretion of nadroparin in breast milk.
Therefore, the use of nadroparin during breastfeeding is not advised.

4.7 Effects on Ability to Drive and Use Machines

Ability to perform tasks that require judgement, motor or cognitive skills: There are no data on the effects of nadroparin on driving performance or the ability to operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions are listed by system organ class and frequency.
The following convention has been used for the classification of adverse reactions in terms of frequency: very common ≥ 1/10, common ≥ 1/100 to < 1/10, uncommon ≥ 1/1000 to < 1/100, rare ≥ 1/10,000 to < 1/1000, very rare < 1/10,000.

Blood and lymphatic system disorders.

Very common: haemorrhagic manifestations at various sites, more frequent in patients with other risk factors (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Rare: thrombocytopenia (including heparin induced thrombocytopenia) (see Section 4.4 Special Warnings and Precautions for Use), thrombocytosis. Very rare: eosinophilia, reversible following treatment discontinuation.

Immune system disorders.

Very rare: hypersensitivity reactions (including angioedema and cutaneous reactions), anaphylactoid reaction.
Hypersensitivity reactions sometimes require discontinuation of treatment.

Metabolism and nutrition disorders.

Very rare: reversible hyperkalaemia related to heparin induced aldosterone suppression, particularly in patients at risk (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary disorders.

Common: raised transaminases, usually transient.

Reproductive system and breast disorders.

Very rare: priapism.

Skin and subcutaneous tissue disorders.

Rare: rash, urticaria, erythema, pruritus. Very rare: cutaneous necrosis (see Section 4.4 Special Warnings and Precautions for Use) usually occurring at the injection site.

General disorders and administration site conditions.

Very common: small haematoma at the injection site.
In some cases, the emergence of firm nodules, which do not indicate an encystment of the heparin may be noted. These nodules usually disappear after a few days.
Common: injection site reaction. Rare: calcinosis at the injection site.
Calcinosis is more frequent in patients with abnormal calcium phosphate product, such as in some cases of chronic renal failure.
Very rare: headache, migraine.
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 http://www.tga.gov.au/reporting-problems

4.9 Overdose

Haemorrhage is the major clinical sign of subcutaneous or intravenous overdosage. The platelet count and other coagulation parameters should be measured. Minor bleeding rarely requires specific therapy, and reducing or delaying subsequent doses of Fraxiparine Forte is usually sufficient.

Treatment.

There is no clinical experience on the use of protamine sulphate to neutralise the effect of nadroparin overdosage. It should be considered only in emergency situations. Serious overdosage may be partly 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 nadroparin calcium may remain, even though the anticoagulant activity is neutralised. 6 mg of protamine sulphate neutralises about 0.05 mL (950 IU AXa) Fraxiparine Forte. The amount of protamine injected should take into account the time elapsed from the injection of Fraxiparine Forte, and a reduction in protamine dose may be required. If transfusion is required, fresh frozen plasma should be used.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nadroparin has both immediate and prolonged antithrombotic action.
Nadroparin exhibits a high affinity binding to the plasma protein antithrombin III (ATIII). This binding leads to an accelerated inhibition of factor Xa, and to a lesser extent, factor IIa (anti-Xa:anti-IIa ratio of 3.6:1), which contributes to the antithrombotic potential of nadroparin.
Other mechanisms that contribute to the antithrombotic activity of nadroparin include stimulation of tissue factor pathway inhibitor (TFP1), activation of fibrinolysis via direct release of tissue plasminogen activator from endothelial cells, and the modification of haemorrheological parameters (decreased blood viscosity and increased platelet and granulocyte membrane fluidity).
Compared with unfractionated heparin, nadroparin has less effect on thrombocyte function and aggregation in vitro and only a slight effect on primary haemostasis.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of nadroparin have been assessed in plasma on the basis of biological activity, i.e. measurement of anti-factor Xa activity.

Absorption.

Following subcutaneous administration, the peak anti-Xa activity (Cmax) is reached after approximately 3 to 6 hours (Tmax).
Bioavailability is almost complete (around 88%).
After IV injection, the peak plasma anti-Xa level is reached within less than 10 minutes, and the half-life is around 2 hours.

Elimination.

The elimination half-life is approximately 3.5 hours. However, in one study anti-Xa activity was detectable for at least 18 hours following a subcutaneous dose of 100 anti-Xa IC U/kg (38 anti-Xa IU/kg) in nine out of twelve study subjects.

Special patient populations.

Elderly.

Renal function generally decreases with age so elimination is slower in the elderly (see Section 5.2 Pharmacokinetic Properties, Renal impairment). The possibility of renal impairment in this age group must be considered and the dosage adjusted accordingly (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

In patients with severe renal failure, a reduced dosage should be considered as elimination of anti-Xa activity is prolonged in such patients.
In a clinical study investigating the pharmacokinetics of nadroparin administered intravenously in patients with varying degrees of renal impairment, a correlation was found between nadroparin clearance and the creatinine clearance. In patients with moderate renal impairment (creatinine clearance 36-43 mL/min), both mean AUC and half-life were increased by 52 and 39% respectively compared with healthy volunteers. In these patients, mean plasma clearance of nadroparin was decreased to 63% of normal. Wide interindividual variability was observed in the study. In subjects with severe renal impairment (creatinine clearance 10-20 mL/min) both mean AUC and half-life were increased by 95 and 112% respectively compared with healthy volunteers. Plasma clearance in patients with severe renal impairment was decreased to 50% of that observed in patients with normal renal function. In subjects with severe renal impairment (creatinine clearance 3-6 mL/min) on haemodialysis, both mean AUC and half-life were increased by 62 and 65% respectively compared with healthy volunteers. Plasma clearance in haemodialysis patients with severe renal impairment was decreased to 67% of that observed in patients with normal renal function (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Preclinical data has revealed no special hazard based on conventional studies of genotoxicity.

Carcinogenicity.

Nadroparin calcium has not been tested in long-term animal studies of carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients contained in the Fraxiparine solution are water for injections with sufficient calcium hydroxide or dilute hydrochloric acid to adjust the pH to between 4.5 and 7.5.

6.2 Incompatibilities

Fraxiparine should not be used interchangeably with other low weight molecular weight heparins during ongoing treatment.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 25°C but do not freeze. Do not refrigerate as cold injections may be painful.
Use once only and discard any unused portion of each syringe. Do not mix with other preparations. Do not use after the expiry date shown on the carton.

6.5 Nature and Contents of Container

Disposable glass prefilled single use syringes containing nadroparin calcium 19,000 IU anti-Xa/mL. Each syringe bears a safety device which should be locked into place after the injection is given. See Table 2.

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

Low molecular weight heparin (LMWH).

CAS number.

37270-89-6.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes