Consumer medicine information

Orgaran

Danaparoid sodium

BRAND INFORMATION

Brand name

Orgaran Solution for injection

Active ingredient

Danaparoid sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Orgaran.

What is in this leaflet

This leaflet is designed to provide you with information on Orgaran.

It does not contain all the available information.

It does not take the place of talking to your doctor.

Please read it carefully. If you still have any questions or concerns regarding Orgaran and its use, please ask your doctor.

Always carry a medical information card stating which medicines you are taking. This may be very important should you become involved in an accident.

What Orgaran is used for

Orgaran is used to help prevent blood clots forming in your veins. Blood clots which form in veins may restrict the blood flow resulting in tissue death through lack of blood. Furthermore, parts of the clot are liable to break off and may block the blood circulation in the lungs. This may have fatal consequences.

If you are bedridden, you have an increased risk of clot formation in the veins of the legs, especially if you have undergone an operation. You may receive Orgaran to help prevent the formation of blood clots.

Before you are given it

Your doctor will assess your need before using Orgaran.

When Orgaran should not be administered:

  • If you suffer from a birth condition which causes you to bleed severely e.g. haemophilia
  • If you have a known sensitivity to Orgaran or any of the ingredients of the product e.g. sulfite.
  • If you have a severe kidney and/ or liver disorder.
  • If you have severe high blood pressure.
  • If you have a severe gastric or duodenal ulcer unless it is the reason for your operation.
  • If you test positive to an in vitro aggregation test in the presence of Orgaran.
  • If your retina is affected by diabetes.
  • If you have acute infection of the inner lining and valves of the heart (acute bacterial endocarditis).
  • If you are in the acute stage of a stroke caused by bleeding.
  • If you are bleeding uncontrollably.

Extra medical supervision by your doctor may be necessary in certain circumstances.

Before you are administered this medicine, you must inform your doctor if you have or ever have had any of the following conditions:

  • Kidney or liver damage with impaired blood circulation.
  • Ulcers of the stomach or intestine
  • Other conditions or diseases which may lead to an increased risk of bleeding into a vital organ or site.
  • A sensitivity to sulfite, which, especially in asthma patients can result in severe allergic reactions.
  • Any other undesirable effects that you think may be due to this medication.

If you are pregnant, or may suspect that you are or if you want to start breast feeding then you must consult your doctor.

How Orgaran is given

How much

The normal dose administered is 750 anti-Xa units (0.6 mL ampoule), twice a day, for up to 10 post-operative days.

How it is injected

Orgaran is administered by subcutaneous (under the skin) injection by a doctor or nurse.

Overdosage

An overdose of Orgaran may result in an unusual loss of blood which in the first instance is corrected by stopping further administration of Orgaran. In some cases, a blood transfusion will be necessary.

While you are using Orgaran

Other medicines may influence the effect of Orgaran or vice-versa. Inform your doctor if you are taking (or intend to take) other medicines such as:

  • Medicines which interfere with platelet function such as aspirin and non-steroidal anti- inflammatory drugs (e.g. these include common painkillers such as ibuprofen and naproxen).
  • Medicines which may cause peptic ulcers such as corticosteroids.

The combination of Orgaran with aspirin may cause an extension to bleeding time.

Side effects

Orgaran may have unwanted side effects in a few people. All medicines have side effects. Sometimes they are serious but usually they are not. Do not be alarmed by the list below. You may not experience any of them.

Ask your doctor to answer any questions you may have.

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

  • bruising and/or pain at the site of injection
  • skin rashes
  • other localised or general sensitivity

If you are on Orgaran and are given an epidural anaesthetic (a medicine injected in the spine during surgery to reduce pain) there is an increased risk of developing a spinal bruise which could possibly result in long term or even permanent paralysis. Your doctor can advise you further on this.

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

After using it

Storage

It is unlikely that you will have to store Orgaran as it is not self administered. Orgaran is a prescription only product with a shelf-life of 3 years when stored below 30°C. Orgaran must not be administered beyond the expiry date shown on the ampoule and carton.

Disposal

If you have any unused medicine, return it to your pharmacist. This is unlikely for Orgaran, as the doctor will normally not give the product to you to keep.

Product Description

Orgaran is a liquid contained within a 0.6 mL ampoule.

Active ingredient:

  • danaparoid sodium

Other ingredients:

  • sodium sulfite heptahydrate
  • sodium chloride
  • hydrochloric acid (to adjust pH)
  • water for injections.

Distributed by:

Aspen Pharmacare 34-36
Chandos St
St Leonards
NSW 2065

This leaflet was revised in September 2017.

Australian registration number:

AUST R 46096

BRAND INFORMATION

Brand name

Orgaran Solution for injection

Active ingredient

Danaparoid sodium

Schedule

S4

 

1 Name of Medicine

Danaparoid sodium.

6.7 Physicochemical Properties

CAS number.

83513-48-8.
Orgaran is supplied in ampoules each containing 750 anti-Xa units (approx. 55 mg) danaparoid sodium, as a sterile, isotonic solution of pH 7 in 0.6 mL.
Orgaran contains danaparoid sodium, which is a mixture of low molecular weight sulfated glycosaminoglycuronans derived from animal mucosa, comprising heparan sulfate, dermatan sulfate and a minor amount of chondroitin sulfate. One mL contains 1250 amidolytic anti-Factor Xa units (approx. 90 mg) danaparoid sodium and 0.15% (w/v) sodium sulfite. The anti-Xa unit is derived from the international heparin standard in an antithrombin-III containing buffer system.

2 Qualitative and Quantitative Composition

Orgaran is supplied in ampoules each containing 750 anti-Xa units (approx. 55 mg) danaparoid sodium. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ampoule.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacology.

Danaparoid sodium has been shown both in animal models and in human studies to be an effective antithrombotic substance. Danaparoid sodium has a negligible effect on haemostatic plug formation, platelet function and platelet aggregability. In animal models it produces less bleeding enhancing activity than heparin whilst in human studies the effects of Orgaran and heparin were found to be similar.
The ultimate step in blood coagulation, the fibrinogen-fibrin conversion, is critically dependent on thrombin generation, to which Factor Xa and thrombin contribute substantially. The anticoagulant profile of danaparoid sodium is characterised by a high ratio of anti-Factor Xa/antithrombin activities (approx. 20/1), resulting in an effective inhibition of thrombin generation and thrombus formation with minimal bleeding enhancing activity. The anti-Xa activity is mediated by antithrombin-III and is not inactivated by endogenous heparin-neutralising factors. The small antithrombin activity is mediated by heparin co-factor II and antithrombin-III. The heparan sulfate fraction with low affinity for antithrombin-III, lacking significant effects on coagulation Factors Xa and IIa in vitro, has been shown in animal studies to contribute substantially (approx. 50%) to the antithrombotic activity by an as yet unexplained mechanism. The risk of haemorrhage with this drug is not related to plasma anti-Xa activity, within the therapeutic dose range.

Clinical trials.

Clinical studies have demonstrated that the clinical activity of danaparoid sodium may not relate to the dose expressed as either milligrams or anti-Xa activity.

5.2 Pharmacokinetic Properties

Pharmacokinetic studies were primarily based on the kinetics of relevant anticoagulant activities of danaparoid sodium, as no specific chemical assay methods are available.
The absolute bioavailability of danaparoid sodium after subcutaneous administration approaches 100%. In humans, the time to reach peak plasma anti-Xa activity levels is approximately 4-5 hours.
The half-lives of elimination of anti-Xa and thrombin generation inhibiting activities of approximately 25 hours and 7 hours, respectively, after both subcutaneous and intravenous administration, are independent of the dose and route of administration. Although plasma clearance of anti-Xa activity was found to be 20% lower in female volunteers than in male volunteers, this difference is not significant. Steady-state levels of plasma anti-Xa activity are usually reached within 4-5 days of dosing. Measured by thrombin generation inhibiting activity, steady-state levels are reached earlier, i.e. within 1-2 days. Danaparoid sodium is mainly eliminated by renal excretion. Animal experiments indicate that the liver is not involved in its metabolism. In patients with severely impaired renal function, the half-life of elimination of plasma anti-Factor Xa activity may be prolonged (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Long-term animal carcinogenicity studies of Orgaran have not been done. A standard battery of mutagenicity tests has not shown any evidence of genotoxic potential.

4 Clinical Particulars

4.1 Therapeutic Indications

Orgaran is indicated for the prevention of postoperative venous thromboembolism in patients undergoing general or orthopaedic surgery.

4.3 Contraindications

Severe haemorrhagic diathesis e.g. haemophilia and idiopathic thrombo-cytopenic purpura.
Haemorrhagic stroke in the acute phase.
Uncontrollable active bleeding state.
Hypersensitivity to Orgaran.
Hypersensitivity to sulfite.
A positive in vitro aggregation test in the presence of Orgaran in patients with a history of thrombocytopenia induced by heparin-like anticoagulants.
Severe renal and/or hepatic insufficiency.
Severe hypertension.
Severe gastric or duodenal ulcer, unless it is the reason for operating.
Acute bacterial endocarditis.
Diabetic retinopathy.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Orgaran and low molecular weight heparins are not interchangeable clinically.
Orgaran should not be given by the intramuscular route.
Orgaran contains sodium sulfite. In asthmatic patients hypersensitive to sulfite, the latter can result in bronchospasm and/or anaphylactic shock.
Orgaran has very little cross-reactivity in producing thrombocytopenia in patients with a previous history of heparin-induced thrombocytopenia syndrome (HITS). Cross-reactivity in vitro between danaparoid sodium and heparin in producing immune platelet aggregation occurred in only 9% of patients tested. Orgaran can be administered to patients sensitised by heparin after cross-reactivity with Orgaran has been ruled out by an in vitro test.
The anticoagulant activity of Orgaran is characterised by a very flat dose-response curve in clotting assays such as prothrombin time, activated partial thromboplastin time, kaolin cephalin clotting time and thrombin clotting time, therefore these routine clotting assays are unsuitable for monitoring its anticoagulant activity.
No incidences of osteoporosis have been reported in patients treated with the recommended dose of Orgaran. However, as for heparin, treatment with a glycosaminoglucoronan may result in osteoporosis if the dosage is inappropriate.
It should be noted that the anti-Xa units of Orgaran have a different relationship to clinical efficacy than those of heparin and low molecular weight heparins.

Spinal/epidural haematomas.

When neuraxial anaesthesia (epidural/spinal anaesthesia) or spinal puncture is employed, patients anticoagulated or scheduled 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 non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anti-coagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurologic compromise is noted, urgent treatment is necessary.
The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Use in hepatic and renal impairment.

Orgaran should be used with caution in patients with moderately impaired renal and/or liver function with impaired haemostasis, ulcerative lesions of the gastro-intestinal tract or other diseases/conditions which may lead to an increased danger of haemorrhage into a vital organ or site.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In clinical studies no clinically significant interactions with other medications have been found.
Orgaran may be used together with oral anticoagulants, or drugs which interfere with platelet function, such as aspirin and non-steroidal anti-inflammatory drugs, or potentially ulcerogenic drugs (such as corticosteroids), but caution remains necessary. Combination of Orgaran with aspirin may cause a prolongation of the bleeding time.
Monitoring of anticoagulant activity of oral anticoagulants by prothrombin time and Thrombotest is unreliable within 5 hours following Orgaran administration.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
In rats, doses of danaparoid greater than 100 anti-Xa units/kg/day administered IV during gestation reduced postnatal weight gain of the offspring. Higher doses, up to 1600 anti-Xa units/kg/day, did not cause any other maternotoxic or teratogenic effects. In rabbits, IV doses up to 800 anti-Xa units/kg/day did not cause any foetal malformations, but the highest dose used was insufficient to rule out the possibility of teratogenic activity in this species. The use of Orgaran in human pregnancy has only been studied incidentally. Observations in pregnant women have so far given no indication that the use of Orgaran during pregnancy leads to foetal abnormalities or to exacerbation of bleeding in mother or infant during delivery.
There is no data available on Orgaran secretion into breast milk.

4.8 Adverse Effects (Undesirable Effects)

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.
Bruising and/or pain may occur at injection sites. Skin rashes and other local or generalised hypersensitivity reactions have occasionally been observed (see Table 1).
As with heparin, Orgaran may induce thrombocytopenia, although to date this has not been observed. The platelet count should therefore be monitored at regular intervals.
Liver abnormalities such as changes in transaminase and alkaline phosphates, have been observed, but no clinical significance has been demonstrated.

4.2 Dose and Method of Administration

Orgaran is administered by subcutaneous injection at a dose of 750 anti-Factor Xa units twice daily for 7 to 10 days. In human studies, its safety has only been demonstrated for the use of up to 10 postoperative days duration.

In surgical patients.

It is recommended to give the last pre-operative dose 1-4 hours before surgery.

Dosage in the elderly.

Clearance of anti-Factor Xa activity has not been shown to be markedly reduced in the elderly and the usual dosage is recommended.
Plasma anti-Xa activity is linearly related to the dose of Orgaran given. The steady state plasma anti-Xa response is 0.15-0.35 units per mL following the recommended subcutaneous dose of Orgaran. If it is necessary to monitor anticoagulant activity, and for individual dose setting, a functional anti-Factor Xa test using a chromogenic peptide substrate should be used. In this test, Orgaran should be used as the standard.

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.

4.9 Overdose

In the event of serious bleeding other than caused by a surgical error, Orgaran should be stopped and blood transfusion considered. Although protamine partially neutralises the anticoagulant activity of Orgaran, it is likely to be of little use in reversing the potential bleeding complications associated with overdosage and therefore cannot be recommended.
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

Water for injections suitable for subcutaneous injection.

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

Store below 30°C. Protect from light.

6.5 Nature and Contents of Container

Pack of ten ampoules.

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