Consumer medicine information

Fragmin

Dalteparin sodium

BRAND INFORMATION

Brand name

Fragmin

Active ingredient

Dalteparin sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fragmin.

What is in this leaflet

This leaflet answers some common questions about FRAGMIN.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using FRAGMIN against the expected benefits it will have for you.

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

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

What FRAGMIN is used for

FRAGMIN is used to prevent blood clots forming in blood vessels. It is used in the following conditions:

  • treatment of deep vein thrombosis (also known as DVT, a blood clot in the veins of the leg)
  • treatment of DVT and pulmonary embolism (blood clot in the veins of the lungs) for up to 6 months in patients with certain types of cancers
  • prevention of DVT before and after an operation
  • treatment of unstable heart disease (e.g. angina and heart attack), which is caused by poor blood flow in the blood vessels of the heart.
  • FRAGMIN is also used to prevent blood clotting during haemodialysis, a procedure that uses a machine to remove waste products from the blood in people with kidney failure.
  • FRAGMIN belongs to a group of medicines called low molecular weight heparins (LMWHs). These medicines work by reducing blood clotting activity.

Ask your doctor if you have any questions about why FRAGMIN has been prescribed for you.

  • Your doctor may have prescribed FRAGMIN for another reason.
  • This medicine is available only with a doctor's prescription.

Before you use FRAGMIN

When you must not use it

  • Do not use FRAGMIN if you have an allergy to:
    - any medicine containing dalteparin sodium
    - any other low molecular weight heparin or similar medicines such as heparin
    - pork products
    - 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 FRAGMIN if you have or ever had any of the following medical conditions:

  • low platelet count caused by heparin
  • stomach or bowel problems such as ulcers or ulcerative colitis
  • a certain type of stroke caused by bleeding in the brain
  • uncontrolled high blood pressure
  • severe problems with blood clotting
  • infection and inflammation of the heart valves.

Do not use FRAGMIN:

  • following an injury or operation on your brain, spinal cord, eyes or ears
  • if you are being treated for deep vein thrombosis (a blood clot in the veins of the leg), pulmonary embolism (blood clot that has travelled to the lungs) or unstable heart disease (e.g. angina and heart attack), and you are going to have surgery that requires a local anaesthetic
  • if you will be given an anaesthetic injection in your back (spinal or epidural injection).

Do not use FRAGMIN after the expiry date printed on the pack.

Do not use FRAGMIN if the packaging is torn or shows signs of tampering. If the product has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start treatment with FRAGMIN, talk to your doctor or pharmacist.

FRAGMIN is not recommended for use in children, as its safety and effectiveness have not been established in children.

Before you start to use it

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

Tell your doctor if you have an allergy to latex (natural rubber). The needle shield on the pre-filled syringe may contain latex.

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

  • eye disease related to diabetes or high blood pressure
  • kidney or liver disease
  • thinning of the bones (osteoporosis)
  • problems with bleeding or bruising
  • an artificial heart valve.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. FRAGMIN is not recommended for use during pregnancy or breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor or pharmacist about any of the above, tell them before you start treatment with FRAGMIN.

Taking other medicines

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

Some medicines may alter the effects of FRAGMIN. These include:

  • medicines or substances used to prevent or treat blood clots
  • Dextran, a medicine used to treat shock, which occurs when you have dangerously low blood pressure
  • aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis
  • probenecid, a medicine used to treat gout
  • medicines used to treat some cancers
  • ethacrynic acid, a medicine used to help the kidneys get rid of salt and water by increasing the amount of urine produced
  • antihistamines, medicines used to prevent or relieve the symptoms of allergy, hay fever or rashes
  • digoxin, a medicine used to treat heart failure
  • tetracycline, an antibiotic used to treat some infections
  • medicines that contain ascorbic acid (vitamin C).

If you are taking any of these medicines while using FRAGMIN, your doctor will need to carefully monitor your blood clotting factors.

These medicines may be affected by FRAGMIN or may affect how well it works. You may need to use different amounts of your medicine or you may need to use different medicines. Your doctor or pharmacist will advise you.

Your doctor or pharmacist has a complete list of medicines to be careful with or avoid while using FRAGMIN.

Using FRAGMIN

How it is given

FRAGMIN is given by injection, either under the skin (subcutaneously) or into a vein (intravenously). The dose and length of treatment will depend on your condition. Your doctor or nurse will usually give you your injection.

If you are being treated for deep vein thrombosis, your doctor may tell you to start taking another oral medicine to prevent blood clots, such as warfarin tablets.

If you are being treated for unstable heart disease, e.g. unstable angina or heart attack, your doctor might tell you to take aspirin as well.

Using it at home

In certain conditions you might have to use FRAGMIN after you have left hospital. In that case, your doctor or nurse will teach you how to self-inject before you leave the hospital.

To inject FRAGMIN, you should be sitting or lying down. Do not expel the air bubble from the syringe before injection. This should ensure delivery of the full dose.

The injection is given under the skin. You can inject yourself in either your stomach or the fleshiest part of your upper buttock.

Your doctor or nurse will tell you which of these two areas is better for you to use. Whichever area you use, try to make sure that you inject yourself in slightly different spots each time to avoid soreness at the injection site.

Before you inject, make sure that the injection site is clean by wiping the area with an antiseptic swab, or by washing it with soap and water and patting it dry with a clean towel.

If you are injecting yourself in the stomach, you will need to lift up a fold of skin to make a slight bulge, as the layer of fat may be quite thin. Keep a firm grip of the skin throughout the whole injection without pinching yourself too tightly.

If you are injecting yourself in the buttock, there is no need to lift a fold of skin, as the layer of fat is thick enough.

Hold the base of the rubber cover that protects the needle, twist to remove from the needle. Insert the needle into the skin vertically, as far as it will go. Press on the plunger and withdraw the needle when you have injected the whole content of the syringe.

Dispose of the used syringe and needle in a safe manner. If you have any questions, ask your doctor or nurse for help.

If you forget to use it

TWICE DAILY INJECTIONS
If it is less than 6 hours since you should have injected, give yourself an injection and then continue as usual. If more than 6 hours has passed, give yourself the next injection when it is time to do so.

ONCE DAILY INJECTIONS
If it is less than 12 hours since you should have injected, give yourself an injection as soon as you can and then continue as usual. If more than 12 hours have passed, give yourself the next injection when it is time to do so.

In either case, contact your doctor if you are concerned or have any questions.

If you use too much (overdose)

Immediately telephone the Poisons Information Centre (telephone 13 11 26) or go to the Accident and Emergency department at your nearest hospital, if you think that you or anyone else may have used too much FRAGMIN.

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

Keep telephone numbers of these facilities handy.

While you are using FRAGMIN

Things you must do

Use FRAGMIN exactly as your doctor has prescribed.

If you are about to be started on any new medicine, remind your doctor, dentist and pharmacist that you are using FRAGMIN.

If you are going to have surgery, tell your doctor, anaesthetist or dentist that you are being treated with this medicine. It may affect other medicines used during surgery.

Tell your doctor that you are using FRAGMIN if you are going to have a local anaesthetic or an anaesthetic injection in your back (spinal or epidural injection).

If you become pregnant while using FRAGMIN, tell your doctor immediately.

Things you must not do

Do not use FRAGMIN to treat any other complaints unless your doctor tells you to.

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

Do not stop using your medicine or change the dosage without checking with your doctor.

Do not mix FRAGMIN with other injections or infusion solutions.

Do not inject FRAGMIN into a muscle.

Things to be careful of

FRAGMIN is not interchangeable with other low molecular weight heparins (LMWHs) or heparin products.

Follow your doctor's instructions carefully and be sure to keep all medical appointments.

Your doctor may ask you to have blood tests to prevent unwanted side effects.

Side effects

Tell your doctor, pharmacist or nurse as soon as possible if you do not feel well during or after treatment with FRAGMIN.

All medicines can have 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.

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 side effects and they worry you:

  • pain and bruising at the injection site
  • hair loss.

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

  • low blood platelet count, which you may notice as unusual bleeding or bruising such as blood in the urine or bowel motions, black tarry bowel motions or black vomit
  • symptoms of high potassium level in the blood, such as, nausea, fatigue, muscle weakness, tingling or numbness of the hands or feet, a slow or irregular heartbeat.
  • allergic reactions, including rash, hives, itching, blisters, skin necrosis (black-purple skin), low blood pressure (dizziness or light-headedness) and fever
  • back pain, tingling, numbness or weakness in your legs, which could mean bleeding around your spinal cord.

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

Tell your doctor, nurse or pharmacist immediately if you notice anything that is making you feel unwell during or after treatment with FRAGMIN.

Other side effects not listed above may also occur in some patients. Some of these side effects can be found only when your doctor does tests from time to time to check your progress. (e.g. changes in liver function shown in blood tests, increased blood potassium level).

After using FRAGMIN

Storage

Keep the syringes in the pack until it is time to use them. If you take the syringes out of the pack, they may not keep well.

Keep FRAGMIN in a cool dry place where the temperature stays below:

  • 30 degrees Celsius for FRAGMIN 2,500 IU and 5,000 IU
  • 25 degrees Celsius for the other FRAGMIN products.

The recommended storage conditions for your product are shown on the carton.

Do not store FRAGMIN or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Discard any unused solution. A solution for infusion should be used within 12 hours of its preparation.

Keep FRAGMIN 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

Dispose of the used syringe and needle safely in a 'sharps' container or similar puncture proof container made of hard plastic.

If your doctor tells you to stop using FRAGMIN or you find that the syringes have passed their expiry date, ask your doctor or pharmacist what to do with any that are left over.

Product description

What it looks like

FRAGMIN is a clear, colourless or straw-coloured solution. The solution is contained in a pre-filled glass syringe. A non-removable needle is attached to each syringe.

FRAGMIN comes in five sizes of single fixed dose syringes and two sizes of graduated single dose syringes. The 7,500 IU and 10,000 IU graduated syringes have measurement markings to allow the dose to be adjusted.

Ingredients

FRAGMIN contains 2500, 5000, 7500, 10000, 12500, 15000 or 18000 IU of dalteparin sodium as the active ingredient. FRAGMIN also contains water for injections and sodium chloride (only 2500 IU, 7,500 IU and 10,000 IU).

Supplier

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

Australian registration numbers

Fixed single dose syringes

  • 2,500 IU/0.2 mL: AUST R 25347
  • 5,000 IU/0.2 mL: AUST R 25349
  • 12,500 IU/0.5 mL: AUST R 61939
  • 15,000 IU/0.6 mL: AUST R 61938
  • 18,000 IU/0.72 mL: AUST R 61937.

Graduated single dose syringes

  • 7,500 IU/0.75 mL: AUST R 66625
  • 10,000 IU/1 mL: AUST R 66626.

This leaflet was revised on April 2020.

® Registered trademark

© Pfizer Australia Pty Ltd 2020.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Fragmin

Active ingredient

Dalteparin sodium

Schedule

S4

 

1 Name of Medicine

Dalteparin sodium.

6.7 Physicochemical Properties

The active substance of Fragmin is the sodium salt of low molecular weight heparin extracted from the intestinal mucosa of pig and is manufactured by controlled depolymerisation of heparin to produce sulphated polysaccharide chains having an average molecular weight of 5,000 Da with 90% between 2,000 and 9,000 Da.
One unit anti-Xa of Fragmin is equivalent in effect to the activity of one unit of the 1st international standard for low molecular weight heparin with regard to inhibition of coagulation factor Xa in plasma.

Chemical structure.


CAS number.

9041-08-1.

2 Qualitative and Quantitative Composition

2,500 IU (anti-Xa) dalteparin sodium/0.2 mL injection syringe.
5,000 IU (anti Xa) dalteparin sodium/0.2 mL injection syringe.
7,500 IU (anti-Xa) dalteparin sodium/0.75 mL injection syringe.
10,000 IU (anti-Xa) dalteparin sodium/1 mL injection syringe.
12,500 IU (anti-Xa) dalteparin sodium/0.5 mL injection syringe.
15,000 IU (anti-Xa) dalteparin sodium/0.6 mL injection syringe.
18,000 IU (anti-Xa) dalteparin sodium/0.72 mL injection syringe.
The 10,000 IU (anti-Xa)/1 mL syringe, 7,500 IU (anti-Xa)/0.75 mL syringe, 5,000 IU (anti-Xa)/0.2 mL syringe and 2,500 IU (anti-Xa)/0.2 mL syringe have the following anti-IIa factor potencies 3900, 2940, 1960 and 980 respectively.
The 0.5, 0.6 and 0.72 mL single dose syringe presentations have the same anti-IIa factor potency per mL as the 5,000 IU (anti-Xa)/0.2 mL single dose syringe, corresponding to 4900, 5880 and 7060 IU anti-IIa respectively per syringe.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
A clear colourless or straw-coloured solution.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fragmin is composed of molecules with and without the specially characterised pentasaccharide (the antithrombin binding site). Fragmin, therefore, acts antithrombotically by accelerating the rate of the neutralisation of certain activated coagulation factors, largely factor Xa, but also factor XIIa and kallikrein by antithrombin. Other mechanisms may also be involved. Coagulation time, e.g. activated partial thromboplastin time (APTT), and inhibition of thrombin are influenced to only a small degree. Compared with heparin, Fragmin has relatively little effect on platelet function and adhesion and thus has little effect on primary haemostasis. In addition, some of the antithrombotic properties of Fragmin are thought to be mediated through the effect on the vessel wall or the fibrinolytic system.

Clinical trials.

Unstable coronary artery disease (unstable angina and non-ST-elevation myocardial infarction).

In a double blind, randomised, placebo controlled clinical trial, patients who recently experienced unstable angina with ECG changes or non-ST-elevation myocardial infarction were randomised to Fragmin Injection 120 IU/kg every 12 hours subcutaneously (s.c.) or placebo every 12 hours s.c. In this trial, unstable angina was defined to include only angina with ECG changes. All patients, except when contraindicated, were treated concurrently with aspirin (75 mg once daily) and beta blockers. Treatment was initiated within 72 hours of the event (the majority of patients received treatment within 24 hours) and continued for 5 to 8 days. A total of 1506 patients were enrolled and treated; 746 received Fragmin and 760 received placebo. The mean age of the study population was 68 years (range 40 to 90 years) and the majority of patients were white (99.7%) and male (63.9%). The combined incidence of the double endpoint of death or myocardial infarction was lower for Fragmin compared with placebo at 6 days after initiation of therapy. These results were observed in an analysis of all randomised and all treated patients. The combined incidence of death, myocardial infarction (MI), need for intravenous (i.v.) heparin or i.v. glyceryl trinitrate, and revascularisation was also lower for Fragmin than for placebo (see Table 8).
In a second randomised, controlled trial designed to evaluate long term treatment with Fragmin (days 6 to 45), data were also collected comparing 1 week (5 to 8 days) treatment of Fragmin 120 IU/kg every 12 hours s.c. with heparin at an APTT adjusted dosage. All patients, except when contraindicated, were treated concurrently with aspirin (100 to 165 mg per day). Of the total enrolled study population of 1499 patients, 1482 patients were treated; 751 received Fragmin and 731 received heparin. The mean age of the study population was 64 years (range 25 to 92 years) and the majority of patients were white (96.0%) and male (64.2%). The incidence of the combined triple endpoint of death, myocardial infarction, or recurrent angina during this 1 week treatment period (5 to 8 days) was 9.3% for Fragmin and 7.6% for heparin (p = 0.323).
There are insufficient data regarding the benefits from treatment beyond 6 days.

Prolonged thromboprophylaxis in orthopaedic surgery.

Two placebo controlled studies conducted in Denmark and Norway with a total of 496 patients have been performed to study the effect and safety of extended thromboprophylaxis after hip replacement surgery. Fragmin 5,000 IU was given subcutaneously once daily up to 35 days postoperatively and was compared with placebo. In both studies Fragmin achieved a significant reduction of the frequency of phlebographically detected venous thrombosis. None of the patients receiving Fragmin developed pulmonary embolism (PE) in either of the studies, while two cases of PE were reported in the placebo group of the Norwegian study. The difference in the incidence of PE between the Fragmin and placebo groups was not significant. There were no serious haemorrhagic complications.

Patients with cancer and acute symptomatic venous thromboembolism.

In a prospective, multicentre, open label, clinical trial (CLOT* study), 676 patients with cancer and newly diagnosed, objectively confirmed acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were studied. Patients were randomised to either Fragmin 200 IU/kg (max 18,000 IU subcutaneously (s.c.) daily for one month) then 150 IU/kg (maximum 18,000 IU s.c. daily for five months) (Fragmin arm) or Fragmin 200 IU/kg (max 18,000 IU s.c. daily for five to seven days) and oral anticoagulant (OAC) for six months. In the OAC arm, oral anticoagulation was adjusted to maintain an International Normalised Ratio (INR) of 2 to 3. Patients were evaluated for recurrence of symptomatic venous thromboembolism (VTE) every two weeks for six months.
The median age of patients was 64 years (range: 22 to 89 years); 51.5% of patients were females; 95.3% of patients were Caucasians. Types of tumours were: gastrointestinal tract (23.7%), genitourinary (21.5%), breast (16%), lung (13.3%), haematological tumours (10.4%) and other tumours (15.1%). Venous thrombotic events were adjudicated by a blinded central committee.
A total of 27 (8.0%) and 53 (15.7%) patients in the Fragmin and OAC arms, respectively, experienced at least one episode of an objectively confirmed, symptomatic DVT and/or PE during the 6 month study period. Most of the difference occurred during the first month of treatment (see Table 9). The benefit was maintained over the 6 month study period.
* CLOT study: randomized comparison of low molecular weight heparin (dalteparin) versus oral anticoagulant therapy for long term anticoagulation in cancer patients with venous thromboembolism.
In the intent to treat population that included all randomised patients, the primary comparison of the cumulative probability of the first VTE recurrence over the 6 month study period was statistically significant (p = 0.0017) in favour of the Fragmin arm, with most of the treatment difference evident in the first month.
There was no significant difference in mortality between the two groups in deaths at 6 and 12 months (131 vs. 137 and 190 vs. 194 in the dalteparin and OAC arms, respectively).

5.2 Pharmacokinetic Properties

Absorption.

Bioavailability is approximately 90% after subcutaneous injection.

Elimination.

Half-life after intravenous injection is two hours and after subcutaneous injection is 3 - 4 hours. Pharmacokinetic activity is not dose dependent with regard to anti-Xa half-life within the therapeutic interval.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No carcinogenicity tests have been performed with this agent.

4 Clinical Particulars

4.1 Therapeutic Indications

Prophylaxis against thrombotic complications during haemodialysis and treatment of acute deep vein thrombosis (DVT).
Extended treatment of symptomatic venous thromboembolism (VTE) (proximal deep vein thrombosis and/or pulmonary embolism) to reduce the recurrence of VTE in patients with solid tumour cancers.
Treatment of unstable coronary artery disease, i.e. unstable angina and non-ST-elevation myocardial infarction (also known as non-Q-wave myocardial infarction).
Prophylaxis against thromboembolic complications in the peri- or postoperative period of surgery.

4.3 Contraindications

Hypersensitivity to Fragmin or other low molecular weight heparins and/or heparins, or pork products, e.g. history of confirmed or suspected immunologically mediated heparin induced thrombocytopenia.
Ulcerative conditions showing a tendency to haemorrhage (e.g. gastrointestinal ulcer, ulcerative colitis).
Cerebral haemorrhage.
Severe coagulation disorder.
Acute or subacute septic endocarditis.
Sympathetic block.
Spinal and epidural puncture (Fragmin in the dosage of 2,500 to 5,000 IU can however be used as a thromboprophylactic; see Section 4.4 Special Warnings and Precautions for Use).
Fragmin should not be used following injuries to or surgery involving brain, spinal cord, eye or ears.
In patients being treated for venous thromboembolism (VTE) or unstable coronary artery disease where the patients receive high doses of Fragmin, regional anaesthesia is contraindicated due to an increased risk of bleeding.
Since it is derived from heparin, it cannot be excluded that the same contraindications are valid also for Fragmin, viz; haemorrhagic diathesis, haemorrhagic stroke, severe hypertension, endocarditis lenta.
It is not known whether Fragmin passes the placental barrier.

4.4 Special Warnings and Precautions for Use

Epidural or spinal anaesthesia.

When neuraxial anaesthesia (epidural/ spinal anaesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting haemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Patients should be monitored frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment (decompression) is necessary. The physician should consider the potential benefit versus the risk before neuraxial intervention in patients anticoagulated for thromboprophylaxis (see Section 4.3 Contraindications).
Insertion or removal of the epidural or spinal catheter should be postponed to 10-12 hours after dalteparin doses administered for thrombosis prophylaxis, while in those receiving higher therapeutic dalteparin doses (such as 100 IU/kg-120 IU/kg every 12 hours or 200 IU/kg once daily), the interval should be a minimum of 24 hours. Extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction.

Interchangeability with other anticoagulants.

As low molecular weight heparins are unique and separate entities with regard to potency, kinetics and possible modes of action, these products are not interchangeable clinically.
Dalteparin cannot be used interchangeably (unit for unit) with unfractionated heparin, other low molecular weight heparins, or synthetic polysaccharides. Each of these medicines differ in their starting raw materials, manufacturing process, physicochemical, biological and clinical properties, leading to differences in biochemical identity, dosing, and possibly clinical efficacy and safety. Each of these medicines is unique and has its own instructions for use.

Intracranial bleeding.

Limited data are available regarding the safety and efficacy of antithrombotic therapy in patients with primary or metastatic tumours of the brain who develop concurrent thromboembolic events. There is a risk of fatal intracranial bleeding with use of anticoagulation in this category of patients. Therefore, if the treatment with Fragmin was considered, it should be monitored closely with regular reassessment of the status of tumour involvement of the brain and other individual risks.

Prosthetic heart valves.

Cases of prosthetic valve thrombosis have been reported in patients who have received low molecular weight heparins for thromboprophylaxis. Some of these patients were pregnant women in whom thrombosis led to maternal and/or foetal deaths. Pregnant women are at higher risk of thromboembolism (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Fragmin is not approved for use in prosthetic heart valve thromboprophylaxis.

Thrombocytopenia.

Thrombocytopenia of any degree should be monitored closely. Special precautions should be taken with Fragmin use in conjunction with thrombocytopenia or disorders of platelet function. It is recommended that platelets be counted before starting treatment with Fragmin and monitored regularly. Special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (< 100,000/microL) during administration of Fragmin. In these patients a positive or unknown result with in vitro tests for antiplatelet antibody in the presence of Fragmin or other low molecular weight heparins and/or heparins contraindicates Fragmin (see Section 4.3 Contraindications).
In Fragmin clinical trials supporting noncancer indications, platelet counts of < 100,000/microL and < 50,000/microL occurred in < 1% and < 1% of patients, respectively.
In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the Fragmin treatment arm, platelet counts of < 100,000/microL occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/microL. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the Fragmin arm and 8.1% of patients in the oral anticoagulant (OAC) arm. Fragmin dose was decreased or interrupted in patients whose platelet counts fell below 100,000/microL.

Haemorrhage.

As with all antithrombotic agents, there is a risk of systemic bleeding with Fragmin administration. Fragmin should be used with caution in patients who have a potentially higher risk of haemorrhage, such as patients with cancer, thrombocytopenia, platelet disorders, severe liver or kidney insufficiency, and in the thromboprophylaxis and treatment of patients with uncontrolled hypertension or hypertensive or diabetic retinopathy, and in patients receiving concurrent anticoagulant/ antiplatelet agents.
High doses of dalteparin, such as those needed to treat deep vein thrombosis, pulmonary embolism or unstable coronary artery disease should be used with caution in patients who had a recent surgical procedure. After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain and periodic measurements of haemoglobin, and anti-Xa determinations.
Higher doses probably carry an increased risk of postoperative bleeding (about two-fold compared with standard heparin), so that the prescribing clinician will need to balance the opposing probabilities of enhanced efficacy versus increased bleeding in forming a judgement about the appropriate dose in an individual patient. The anticoagulant effect of Fragmin is enhanced by concurrent treatment with antithrombin III and fresh frozen plasma in patients with hereditary antithrombin III deficiency, thus in order to avoid bleeding, reduced dosage of Fragmin is recommended.
If a transmural myocardial infarction occurs in patients with unstable coronary artery disease, i.e. unstable angina and non-ST-elevation myocardial infarction, thrombolytic treatment might be appropriate. However, since combined Fragmin and thrombolytic therapy confers a high risk of major bleeding events, patients who develop ST-elevation myocardial infarction should cease Fragmin therapy and commence thrombolytic therapy in combination with aspirin.

Hyperkalaemia.

Heparin and low molecular weight heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium or taking potassium sparing drugs. Plasma potassium should be measured in patients at risk.

Osteoporosis.

Long term treatment with heparin has been associated with a risk of osteoporosis. The risk of osteoporosis with dalteparin cannot be excluded. Caution should be observed in patients with known osteoporosis and spontaneous fractures.

Monitoring anti-Xa levels.

Monitoring of the anticoagulant effect of dalteparin is generally not necessary but should be considered for specific patient populations such as those with cancer, renal failure, those who are very thin or morbidly obese, pregnant or those at increased risk of bleeding or rethrombosis.
Patients with severely disturbed hepatic function, significant renal failure or chemotherapy induced thrombocytopenia may need a reduction in dosage and should be monitored accordingly.
Do not administer by the intramuscular route.

Allergic reactions.

For labels with the prefilled syringes (fixed dose and graduated syringes).

The needle shield of Fragmin prefilled syringes may contain latex (natural rubber) which may cause severe allergic reactions in individuals with hypersensitivity to latex (natural rubber).

Use in the elderly.

Fragmin should be used with caution in the elderly. Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised.

Paediatric use.

Fragmin should not be used in children. There is limited safety and efficacy information on the use of dalteparin in paediatric patients.

Effects on laboratory tests.

A nonspecific increase of hepatic enzymes (AST/SGOT, ALT/SGPT, GGT) has been reported. It is of the same magnitude as occurs with standard heparin and is reversible.
In Fragmin clinical trials supporting noncancer indications where hepatic transaminases were measured, asymptomatic increases in transaminase levels (AST/SGOT and ALT/SGPT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with Fragmin.
In the Fragmin clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with Fragmin for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) scoring system, were 3% and 3.8%, respectively. Grades 2, 3 and 4 combined have been reported in 12% and 14% of patients, respectively.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As with heparin therapy, the following interactions with other drugs may occur:
1. Enhancement of anticoagulant effect by thrombolytic agents, aspirin and other NSAIDs with effects on platelets, vitamin K antagonists, dipyridamole, dextran, sulphinpyrazone, probenecid, ethacrynic acid and cytostatics. However, unless specifically contraindicated, patients with unstable coronary artery disease (unstable angina and non-ST-elevation myocardial infarction), should also receive oral low dose aspirin.
2. Reduction of anticoagulant effect by antihistamines, digitalis glycosides, tetracycline and ascorbic acid.
Because NSAIDs and aspirin analgesic/ anti-inflammatory doses reduce production of vasodilatatory prostaglandins, and thereby renal blood flow and the renal excretion, particular care should be taken when administering dalteparin concomitantly with NSAIDs or high dose aspirin in patients with renal failure.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
(Same as standard heparin). The use of heparin in pregnancy has the usual risks for the mother, in particular osteoporosis and thrombocytopenia. Although heparin does not cause malformations, an increased incidence of human foetal loss and prematurity associated with haemorrhage has been reported.
Caution is recommended when treating patients with an increased risk of haemorrhage, such as perinatal women (see Section 4.4 Special Warnings and Precautions for Use, Haemorrhage).
There are also postmarketing reports of prosthetic valve thrombosis in pregnant women with prosthetic heart valves while receiving low molecular weight heparins for thromboprophylaxis. These events led to maternal death or surgical interventions.
Pregnant women with prosthetic heart valves appear to be at exceedingly high risk of thromboembolism. An incidence of thromboembolism approaching 30% has been reported in these patients, in some cases even with apparent adequate anticoagulation at treatment doses of low molecular weight heparins or unfractionated heparin.
Fragmin is not approved for use in prosthetic heart valve thromboprophylaxis.
Not recommended for lactating women as there is limited data available as to whether Fragmin passes into breast milk. One study in 15 lactating women receiving prophylactic doses of dalteparin detected small amounts of anti-Xa activity in breast milk, equivalent to a milk/ plasma ratio of < 0.025-0.224. As oral absorption of low molecular weight heparin is extremely low the clinical implications, if any, of this small amount of anticoagulant activity on the breastfeeding infant are unknown.

4.8 Adverse Effects (Undesirable Effects)

In Table 4, the adverse reactions are listed by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
Within each frequency grouping, adverse effects are presented in order of decreasing seriousness.

Unstable angina and non-ST-elevation myocardial infarction.

Table 5 summarises the major bleeding events that occurred with Fragmin, heparin, and placebo in clinical trials of unstable angina and non-ST-elevation myocardial infarction.

Hip replacement surgery.

Table 6 summarises:
1. All major bleeding events.
2. Other bleeding events possibly or probably related to treatment with Fragmin (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.
Six of the patients treated with Fragmin experienced seven major bleeding events. Two of the events were wound haematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial haemorrhage nor died of bleeding complications.
In the third hip replacement surgery clinical trial, the incidence of major bleeding events was similar in all three treatment groups: 3.6% (18/496) for patients who started Fragmin before surgery; 2.5% (12/487) for patients who started Fragmin after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.

Patients with cancer and acute symptomatic venous thromboembolism.

Table 7 summarises the number of patients with bleeding events that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was considered major if it met one the following criteria:
1. Accompanied by a decrease in haemoglobin of ≥ 20 g/L in connection with clinical symptoms.
2. Occurred at a critical site (intraocular, spinal/ epidural, intracranial, retroperitoneal, or pericardial bleeding).
3. Required transfusion of ≥ 2 units of blood products.
4. Led to death.
Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.
At the end of the six month study, a total of 46 (13.6%) patients in the Fragmin arm and 62 (18.5%) patients in the oral anticoagulant (OAC) arm experienced any bleeding event. One bleeding event (haemoptysis in a patient in the Fragmin arm at day 71) was fatal.

Post-marketing experience.

Blood and lymphatic system disorders.

A small number of immunologically mediated heparin induced thrombocytopenia (type II) with or without associated thrombotic complications (arterial and/or venous thrombosis or thromboembolism) have been reported.

Immune system disorders.

Anaphylactic reactions.

Endocrine disorders.

Hypoaldosteronism.

Cardiac disorders.

Prosthetic cardiac valve thrombosis.

Nervous system disorders.

Intracranial bleeds have been reported and some have been fatal.

Gastrointestinal disorders.

Retroperitoneal bleeds have been reported and some have been fatal.

Skin and subcutaneous tissue disorders.

Skin necrosis, alopecia, rash.

Vascular disorders.

Haemorrhage (bleeding at any site), some cases reported have been fatal.

Injury, poisoning and procedural complications.

Spinal or epidural haematoma.

Reporting suspected adverse effects.

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.

4.2 Dose and Method of Administration

Thromboprophylaxis in conjunction with surgery.

2,500 IU administered subcutaneously (s.c.) 1-2 hours before the operation and thereafter 2,500 IU subcutaneously each morning until the patient is mobilised, in general 5-7 days.

Thromboprophylaxis in conjunction with general surgery associated with high risk of thrombosis (e.g. malignancy).

5,000 IU is given subcutaneously the evening before the operation and 5,000 IU subcutaneously the following evenings. As an alternative 2,500 IU subcutaneously 1-2 hours before operation and 2,500 IU subcutaneously twelve hours later. On the following days 5,000 IU subcutaneously each morning. Treatment is continued until the patient is mobilised, in general 5-7 days.

Prolonged thromboprophylaxis in orthopaedic surgery (e.g. hip replacement surgery).

Additional risk factors for developing venous thromboembolism, such as previous DVT or PE, malignancy, advanced age, family history, obesity and immobilisation should be considered.
5,000 IU is given subcutaneously the evening before the operation and 5,000 IU subcutaneously the following evenings. Treatment is continued for five postoperative weeks.
As an alternative 2,500 IU is given subcutaneously 1-2 hours before the operation and 2,500 IU subcutaneously 8-12 hours later. On the following, days 5,000 IU s.c. each morning for five postoperative weeks.

Treatment of acute deep vein thrombosis.

For patients with acute deep vein thrombosis Fragmin can be given either as a continuous intravenous (i.v.) infusion or as twice daily s.c. injections.
The following initial dosage is recommended:
Subcutaneous injections of 100 IU/kg twice daily or 100 IU/kg administered during 12 hours as a continuous i.v. infusion.
Doses up to 120 IU/kg/12 hours do not give a significant accumulation of anti-Xa activity.
As a rule parallel treatment with vitamin K antagonists should be started immediately. Treatment with Fragmin should be continued until the levels of the prothrombin complex factors (F II, F VII, F IX, F X) have decreased to a therapeutic level, usually for at least 5 days.

Extended treatment of symptomatic venous thromboembolism to reduce recurrence of VTE in patients with solid tumours.

In patients with cancer and symptomatic venous thromboembolism, the recommended dosing of Fragmin is as follows.

Month 1.

Administer Fragmin 200 IU/kg total body weight subcutaneously once daily for the first 30 days of treatment. The total daily dose should not exceed 18,000 IU. Table 1 lists the dose of Fragmin to be administered once daily during the first month for a range of patient weights.

Months 2 to 6.

Administer Fragmin at a dose of approximately 150 IU/kg s.c. once daily during months 2 through 6. The total daily dose should not exceed 18,000 IU. Table 2 lists the dose of Fragmin to be administered once daily for a range of patient weights during months 2-6.
Recommended duration of treatment is 6 months (first month of Fragmin treatment is included). Relevance of continuing treatment beyond this period should be evaluated according to individual risk/ benefit ratio, taking into account particularly the progression of cancer. No data is available with dalteparin beyond 6 months of treatment in the CLOT study.

Dose reductions for chemotherapy induced thrombocytopenia in patients with cancer and acute symptomatic VTE.

In patients receiving Fragmin who experience platelet counts between 50,000/microL and 100,000/microL, reduce the daily dose of Fragmin according to the dosage schedule in Table 3 until the platelet count recovers to ≥ 100,000/microL. In patients receiving Fragmin who experience platelet counts < 50,000/microL, Fragmin should be discontinued until the platelet count recovers above 50,000/microL.

Dose reductions for renal insufficiency in extended treatment of acute symptomatic venous thromboembolism in patients with cancer.

In patients with severely impaired renal function (creatinine clearance < 30 mL/min), monitoring for anti-Xa levels is recommended to determine the appropriate Fragmin dose. Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, sampling should be performed 4-6 hrs after Fragmin dosing and only after the patient has received 3-4 doses.

Treatment of unstable coronary artery disease.

120 IU/kg bodyweight is administered subcutaneously twice daily. Maximum dose is 10,000 IU/12 hours. Treatment should be continued for 6 days. There are insufficient data regarding the benefits from treatment beyond 6 days.
Concomitant therapy with low dose aspirin is recommended.

Anticoagulation for haemodialysis.

Chronic renal failure - patients with no known bleeding risk.

Haemodialysis for more than 4 hours: i.v. bolus injection of 30-40 IU/kg bodyweight followed by i.v. infusion of 10-15 IU/kg bodyweight per hour.
Haemodialysis for a maximum of 4 hours: dose as above or only i.v. bolus injection of 5,000 IU.
Plasma level should be in the interval 0.5-1.0 IU anti-Xa/mL.

Acute renal failure - patients with high bleeding risk.

Intravenous bolus injection of 5-10 IU/kg bodyweight followed by i.v. infusion of 4-5 IU/kg bodyweight per hour.
Plasma level should be in the interval 0.2-0.4 IU anti-Xa/mL.

Compatibility.

Fragmin injection is compatible with isotonic sodium chloride and isotonic glucose infusions. Prepared infusion solution should be used within 12 hours.

Monitoring advice.

Fragmin has an anticoagulant effect which may, for example, induce a certain elevation of activated partial thromboplastin time (APTT) and thrombin time. For laboratory monitoring of effect, however, anti-Xa methods based on chromogenic peptide substrate are to be recommended for measuring anti-Xa levels. Prolongation of APTT on haemodialysis and treatment of acute deep vein thrombosis should only be used as a criterion of overdose. Dose increases aiming at prolonging APTT may result in overdosing and haemorrhage. APTT or thrombin time should not be used because these tests are relatively insensitive to the activity of dalteparin.

Haemodialysis.

New patients undergoing haemodialysis should be regularly checked with respect to anti-Xa levels during the first few weeks. As a rule, subsequent checks will be needed less frequently. Patients undergoing acute haemodialysis have a narrower therapeutic interval and should be subjected to comprehensive monitoring of anti-Xa levels.

Other indications.

Available data suggest that routine monitoring of anti-Xa levels is not required when Fragmin is used for indications other than haemodialysis, provided that the recommended dosages are not exceeded. However, monitoring should be considered for the specific patient populations identified, see Section 4.4 Special Warnings and Precautions for Use.

4.7 Effects on Ability to Drive and Use Machines

Fragmin does not affect the ability to drive or operate machinery.

4.9 Overdose

Signs and symptoms.

Doses of Fragmin exceeding the recommended dose may result in overanticoagulation or bleeding.

Treatment of overdosage.

These may generally be stopped by the slow intravenous injection of protamine sulfate (1% solution), at a dose of 1.0 mg protamine for every 100 anti-Xa IU of Fragmin given. A second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of Fragmin may be administered if the APTT measured 2 to 4 hours after the first infusion remains prolonged. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of conventional heparin. In all cases, the anti-Factor Xa activity is never completely neutralised (maximum about 60 to 75%).
Protamine has an inhibiting effect on primary haemostasis and should only be used in an emergency. Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotension and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride q.s. (in the 2,500 IU/0.2 mL, 7,500 IU/0.75 mL and 10,000 IU/1 mL syringe presentations only); water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Fixed single dose syringes 2,500 IU and 5,000 IU anti-Xa/0.2 mL: Store below 30°C.
Graduated single-dose syringes 7,500 IU anti-Xa/0.75 mL and 10,000 IU anti-Xa/1 mL: Store below 25°C.
Fixed single-dose syringes 12,500 IU anti-Xa/0.5 mL, 15,000 IU anti-Xa/0.6 mL and 18,000 IU anti-Xa/0.72 mL: Store below 25°C.

6.5 Nature and Contents of Container

Fixed single-dose syringes 2,500 IU anti-Xa/0.2 mL. Packs of 5s#, 10s.
Fixed single-dose syringes 5,000 IU anti-Xa/0.2 mL. Packs of 5s#, 10s, 15s#.
Graduated single-dose syringes 7,500 IU anti-Xa/0.75 mL. Packs of 2s#, 5s#, 6s#, 10s, 15s#.
Graduated single-dose syringes 10,000 IU anti-Xa/1 mL. Packs of 2s#, 5s#, 6s#, 10s, 15s#.
Fixed single-dose syringes 12,500 IU anti-Xa/0.5 mL. Packs of 2s#, 5s#, 10s.
Fixed single-dose syringes 15,000 IU anti-Xa/0.6 mL. Packs of 2s#, 5s#,10s.
Fixed single-dose syringes 18,000 IU anti-Xa/0.72 mL. Packs of 2s#, 5s#, 10s.
To assist with preventing needle stick injuries, the single-dose syringes are available with a Needle-Trap feature# (needle catcher), which forms part of the syringe label attached directly to the glass barrel of the syringe.
# Not currently marketed in Australia.

6.6 Special Precautions for Disposal

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

Summary Table of Changes