Danaparoid Sodium, 750 IU/0.6 ml, 10 – patient leaflet, side effects, dosage

1. What Danaparoid Sodium is and what it is used for

Danaparoid sodium, the active ingredient in Danaparoid Sodium, is a medicine that prevents blood from clotting (anticoagulant), and belongs to a group of medicines called heparinoids.

Danaparoid Sodium prevents the formation of blood clots in blood vessels, and is used in patients who have an increased risk of blood clot formation, and in patients who are allergic to another medicine called heparin. You should ask your doctor if you are unsure why you have been given Danaparoid Sodium.

2. What you need to know before you use Danaparoid Sodium

Do not use Danaparoid Sodium:

• if you are allergic to

  danaparoid sodium, or any of

  the other ingredients of this medicine (listed in section 6);

  • if you had a haemorrhagic

    stroke (due to a bleed in the brain) in the last three months;

  • if you are bleeding and it can’t

    be stopped;

  • if you have very high blood

    pressure that cannot be controlled;

  • if you have damage to the

    retina of the eye due to diabetes;

  • if you have an infection of

    the inner lining and valves of the heart (acute bacterial endocarditis);

  • if you are using danaparoid to

    treat blood clots in your body and going to receive spinal or epidural anaesthesia or lumbar puncture within 24 hours. Warnings and precautions

Talk to your doctor before using Danaparoid Sodium if you have or ever have had any of the following conditions, as extra supervision may be necessary:

• you have a tendency to

  bleeding severely, for example, haemophilia, or an increased bleeding risk

• kidney or liver disease

• if you have an ulcer(s) in the

  stomach or small intestine

• if you are allergic to sulphite,

  as this can cause severe allergic reactions and breathing difficulties in asthma patients.

• if you ever had a diagnosis

  of heparin-induced

  thrombocytopenia (HIT)

• if previous treatment with

  heparins (a group of medicines often used to treat blood clots) caused a large drop in the number of a type of blood cell called platelets, and if a blood test showed that this may happen with Danaparoid Sodium

• if a spinal or epidural

  anaesthetic is necessary; extra supervision may be needed Children and adolescents

There is limited experience with Danaparoid Sodium in children and adolescents.

Other medicines and Danaparoid

Sodium

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Some medicines can affect the way Danaparoid Sodium works,

or Danaparoid Sodium itself can affect how other medicines taken at the same time work.

Medicines which may increase the risk of bleedings when taken at the same time as Danaparoid Sodium include:

• medicines used to prevent blood clots like Vitamin K Antagonist, for example, warfarin;
• medicines used to dissolve blood clots, for example, alteplase;

• aspirin and other anti-

  inflammatory drugs (like NSAIDs), for example, for treatment of rheumatic disorders

• medicines that may

  cause ulcers (such as

  corticosteroids).

Pregnancy, breast-feeding and fertility

Pregnancy and breast-feeding If you are pregnant or

breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Danaparoid Sodium may be used while breast-feeding if alternative treatments are unacceptable for medical reasons.

Fertility

There is no available information on effect of Danaparoid Sodium on fertility.

Driving and using machines

Danaparoid Sodium is not known to have any effects on the ability to drive or use machinery. Danaparoid Sodium contains sodium

This medicine contains less than 1 mmol sodium (23mg) per dose - that is essentially ‘sodium free’. Danaparoid Sodium contains sodium sulphite which may rarely cause severe hypersensitivity reactions and a difficulty in breathing (bronchospasm). Symptoms include: tightening of the chest, swelling, itching or rash.

3. How to use Danaparoid Sodium

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Adults and elderly

The medicine is given as an injection under the skin or as an

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time and thrombotest is unreliable within 5 hours after danaparoid sodium administration.

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data with the use of danaparoid sodium during pregnancy. Case reports indicate no harmful effects. In the limited number of umbilical cord blood samples checked after delivery, there was no evidence of anti-Xa activity due to danaparoid sodium.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Danaparoid sodium is not

recommended for general use in pregnancy.

Breast-feeding

Breast milk samples tested for anti-Xa activity showed no or negligible amounts of anti-Xa activity (which would be

hydrolysed in the infant’s stomach and rendered harmless).

Fertility

There is no data available on the effect of danaparoid sodium on human fertility.

4.7 Effects on ability to drive and use machines

Danaparoid sodium is not known to have any effect on the ability to drive and use machines.

4.8 Undesirable effects

Danaparoid sodium has the potential to increase the risk of bleeding.

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 ≥1/1,000 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, undesirable effects are

presented in order of decreasing seriousness.

infusion (a slow injection) by your doctor or nurse.

The normal dose is 750 units, twice-a-day, for 7 to 10 days. Higher doses may be necessary in some patients.

Children

Danaparoid Sodium can be used in children, but the doctor will decide the dose as experience is limited. If you use more Danaparoid

Sodium than you should

Danaparoid Sodium will be given to you by a doctor or a nurse so you are unlikely to be given too much medicine. However, if too much Danaparoid Sodium is given you may bleed too much. This may show by:

• nosebleeds, bleeding gums;

• blackened stools (may indicate

  blood loss from stomach or intestines);

• blood in the urine;

• unusually severe periods in

  women.

If you have any of these symptoms or you think you have been given too much Danaparoid Sodium, tell your doctor immediately.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

When a heparin (an antithrombotic) is used at the same time as a spinal or epidural anaesthetic, bruising of the spine may occur. This occurs very rarely (see Section 2). Tell your doctor immediately if you experience any of the following symptoms after being given this medicine together with a spinal or epidural anaesthetic. Although they are very rare, these symptoms can be serious:

• back pain;

• tingling, numbness or

  weakness in the legs;

• bowel or bladder problems. Common: may affect up to 1 in 10

people

• a large drop in the number

  of cells that clot the blood (thrombocytopenia) in patients already hypersensitive to heparin;

• increased bleeding after the

  operation;

• skin rash;

  Uncommon: may affect up to 1 in

  100 people

  • bruises and/or pain around the

    injection site;

  • allergic reaction to Danaparoid

    Sodium. This may cause sudden wheeziness, difficulty in breathing, swelling of eyelids, face or lips, rash or itching (especially affecting the whole body);

Rare: may affect up to 1 in 1000 people

• increased bleeding or swelling

  containing blood at the operation site (haematoma). Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme (website: www.mhra.gov.uk/ yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Danaparoid Sodium

Keep out of the reach and sight of children.

Do not store above 30 ºC.

Do not freeze.

Keep the ampoules in the outer carton in order to protect from light.

Do not use Danaparoid Sodium after the expiry date which is stamped on the pack. The expiry date refers to the last day of that month.

6. Content of the pack and other information What Danaparoid Sodium

contains

• Each 1ml glass ampoule

  contains 750 anti-factor Xa units (0.6ml) of the active ingredient danaparoid

  sodium, corresponding to 1250 anti-factor Xa units per ml.

• The other ingredients are:

  Sodium sulphite, sodium chloride, hydrochloric acid and water for injections.

What Danaparoid Sodium looks like and contents of the pack

Danaparoid Sodium comes in glass ampoules. It is a solution for injection. Each ampoule of

Danaparoid Sodium contains 0.6ml of medicine, and is available in packs of 10 or 20 ampoules. More about Danaparoid Sodium Danaparoid Sodium contains a natural substance, derived from pig intestine, which prevents the formation of blood clots in blood vessels (thrombosis).

Blood clots which form in veins may restrict the blood flow causing tissue to die. Small parts of the clot can break off and may block the blood circulation in the lungs. A blood clot in the lungs may be very serious.

Patients who are bedridden have an increased risk of clot formation in the veins of the legs, especially if they have undergone an operation. These patients receive Danaparoid Sodium to prevent the formation of blood clots.

Marketing Authorisation Holder

Viatris Products Limited,

Station Close,

Potters Bar,

EN6 1TL,

United Kingdom.

Manufacturer

FAMAR Health Care Services Madrid, S.A.U

Avda. Leganés, 62,

Alcorcón 28923

Madrid,

Spain

And

Aspen Bad Oldesloe GmbH Industiestraβe 32-36

23843 Bad Oldesloe

Germany

This leaflet was last revised in

Other sources of information

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Please be ready to give the following information:

Product name: Danaparoid Sodium Reference Number:

PL 46302/0228

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Antibody induced

thrombocytopenia, as can be caused by (low molecular weight) heparin, was observed in rare cases during the use of danaparoid sodium, but only in patients who were already sensitised to either heparin or low molecular weight heparin (see section 4.4).

All above terms in this section and synonym terms (with same or less severity) coded with the MedDRA dictionary are considered as ‘listed’.

Haemorrhages are listed adverse events for danaparoid sodium. This also means that symptoms or signs which are clearly directly related to a haemorrhage (e.g. anaemia, decreased Hb, RBC, haematocrit, faintness, tiredness, tamponade) are listed adverse events.

Liver abnormalities such as changes in transaminase

and alkaline phosphatase have been observed, but no clinical significance has been demonstrated.

Very rarely, cases of epidural and spinal haematomas were reported in association with prophylactic use of heparin or low molecular weight heparin in the context of peridural or spinal anaesthesia and of spinal puncture. These haematomas have caused various degrees of neurological impairment, including prolonged or permanent paralysis (see Section 4.4).

assays such as prothrombin time, activated partial thromboplastin time, kaolin cephalin clotting time and prothrombin time is small, and characterised by a very flat dose-response curve up to relatively high doses.

The ultimate step in blood coagulation, the fibrinogen-fibrin conversion, is critically dependent on prothrombin 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, resulting in an effective inhibition of thrombin generation and thrombus formation. 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 sulphate 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 to the antithrombotic activity by an as yet unexplained mechanism. Danaparoid sodium shows low cross-reactivity (<10%) with the heparin induced antibody. This can be explained by the absence of heparin in danaparoid sodium and its low degree of sulphation (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system:

Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

In the event of serious bleeding other than caused by a surgical error, danaparoid sodium should be stopped and transfusion of fresh frozen plasma or, if uncontrollable, plasmapheresis should be considered. Although protamine partially neutralises the anticoagulant activity of danaparoid sodium the relevance for the reversal of the bleeding is not clear and therefore cannot be recommended. The effects of danaparoid sodium on anti-Xa activity cannot be antagonized with any known agent at this time.

1. 5.

   PHARMACOLOGICAL

   PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic agents - heparin group, ATC Code: B01AB06 Danaparoid sodium has been shown both in animal models and in human studies to be an effective antithrombotic substance. At therapeutic doses danaparoid sodium has no or only a minor effect on haemostatic plug formation, platelet function and platelet aggregability with no significant effect on bleeding time at the recommended doses. Occasionally, after high intravenous or subcutaneous doses, a prolonged bleeding time has been observed.

The anticoagulant activity of danaparoid sodium in clotting

Danaparoid sodium has also been shown to interfere with the interaction of the heparin-induced anti-platelet antibody and its target, thus potentially reducing platelet activation.

5.2 Pharmacokinetic properties

Pharmacokinetic studies have primarily been based on the kinetics of relevant anticoagulant activities of danaparoid sodium, because no specific chemical assay methods are available. In animal models the time courses of the thrombin

generation inhibitory activity and antithrombotic activities of danaparoid sodium were strongly related, but the simplest to measure is the effect on plasma anti-Xa activity hence its use for monitoring purposes.

The absolute bioavailability of danaparoid sodium, as estimated from its effect on plasma anti-Xa activity, 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 (representing a sub-fraction of danaparoid that accounts for 50% of its antithrombotic activity) and 7 hours (representing the total antithrombotic activity of danaparoid), respectively, after both subcutaneous and intravenous administration are independent of the dose. 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 and animal experiments indicate that the liver is not involved in its metabolism. Renal impairment

In patients with severely impaired renal function the half-life of elimination of plasma anti-factor Xa activity may be prolonged necessitating dose reduction (see Section 4.2).

5.3 Preclinical safety data

The results of pre-clinical studies do not add to the information included in the other sections of the SmPC.

1. 6.

   PHARMACEUTICAL

   PARTICULARS

6.1 List of excipients

Sodium sulphite

Sodium chloride

Hydrochloric acid

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

Do not freeze.

Keep the ampoules in the outer carton in order to protect from light.

6.5 Nature and contents of container

1-ml glass ampoules containing 750 anti-factor Xa units (0.6ml) danaparoid sodium per ampoule (1250 anti-factor Xa units/ml) in packs of 10 or 20 ampoules. 6.6 Special precautions for

disposal and other handling

Danaparoid sodium is compatible with, and therefore can be added to, infusions of saline (0.9%), dextrose (5%) and dextrose-saline.

It is advisable to discard

the product when the visual appearance has changed or when the container is damaged.

1. 7.

   MARKETING AUTHORISATION

   HOLDER

Viatris Products Limited,

Station Close,

Potters Bar,

EN6 1TL,

United Kingdom.

1. 8.

   MARKETING AUTHORISATION

   NUMBER

PL 46302/0228

1. 9.

   DATE OF FIRST

   AUTHORISATION/RENEWAL

   OF THE AUTHORISATION

Date of first authorisation: 14 April 1993

Date of latest renewal: 09 October 1998

1. 10.

   DATE OF REVISION OF THE TEXT

   3900497 11506841-02