4.1. Therapeutic indications

• Prevention of deep vein thrombosis and its possible consequences in patients undergoing general or orthopaedic surgery.

• Treatment of thrombo-embolic disorders in patients who require urgent parenteral anti-coagulation because of the development or history of heparin-induced thrombocytopenia (HIT).

4.2. Posology and method of administration

a) Non-HIT patients (DVT prophylaxis)

- In general, danaparoid sodium should be administered by subcutaneous injection at a dose of 750 U for patients ≤90 kg body weight, twice daily for a period of maximally 14 days unless it is required longer in patients for whom there is no reasonable antithrombotic alternative.

- For patients > 90 kg body weight, a dose of 750 U three times a day or 1250 U twice a day is recommended.

- In surgical patients it is recommended to start this dosing pre-operatively and to give the last pre-operative dose 1-4 hours before surgery.

Monitoring

Plasma anti-Xa activity is linearly related to the dose of danaparoid sodium given. In general, monitoring of plasma anti-Xa activity is not necessary. If monitoring of anticoagulant activity is performed then a functional anti-factor Xa test using a chromogenic peptide substrate should be used. In this test danaparoid sodium should be used as standard for constructing the reference curve.

Renal impairment and patients >90kg

In patients suffering from renal insufficiency and/or patients > 90kg body weight monitoring, once or twice a week during routine subcutaneous therapy, (using an amidolytic assay) is recommended to check for drug accumulation or underdosing, respectively.

b) HIT patients

The diagnosis of HIT should as a minimum be based on:

1) thrombocytopenia (platelet count<100x109/L) occurring during heparin administration and

2) exclusion of all other causes of thrombocytopenia

In general monitoring of plasma anti-Xa activity is not necessary. However, in patients suffering from renal insufficiency and/or patients weighing over 90kg, monitoring (using an amidolytic assay) is recommended.

Danaparoid Sodium should be administered intravenously as a bolus of 2500 anti-Xa units (for patients less than 55kg 1250 units, if over 90kg, 3750 units) followed by an intravenous infusion of 400units/h for 2 hours, then 300 units/h for 2 hours, then a maintenance infusion of 200 units/h for 5 days. The expected plasma anti-Xa levels are 0.5-0.7 units/ml 5-10 minutes after the bolus, not higher than 1.0 units/ml during the adjustment phase of maintenance infusion and 0.5-0.8 units/ml during the maintenance infusion.

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.

Children:

There is insufficient experience with the use of Danaparoid Sodium in children to suggest a dosage regimen for this group of patients.

Dosage in patients with moderately impaired renal and/or liver function:

Danaparoid Sodium should be used with caution in patients with moderately impaired renal and/or liver function with impaired haemostasis.

Conversion to anticoagulants is possible, however it is advisable only to start such a therapy once there is adequate antithrombotic control with Danaparoid Sodium.

Oral anticoagulants can be given with the infusion (maximum rate 300units/h) which can then be stopped when the international normalised ratio is ≥1.5. If the bleeding risk is high then either:

(a) stop the infusion and start Danaparoid Sodium 750 anti-Xa units/0.6 ml subcutaneously twice a day, then 24 hours later start anticoagulants 48-72 hours before Danaparoid Sodium is withdrawn to give time for the prothrombin time, Thrombotest and international normalised ratio to reach therapeutic levels (measurement of these parameters is not reliable within 5 hours of Danaparoid Sodium injection (See “Interactions with other medicaments and other forms of interactions”)) or

(b) stop the infusion, give no further Danaparoid Sodium then start the anticoagulants 12 hours later.

4.3. Contraindications

• hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• spinal or epidural anaesthesia or loco-regional anaesthesia when danaparoid sodium is used for treatment in the previous 24 hours (see section 4.4)

• severe haemorrhagic diathesis, e.g. haemophilia and idiopathic thrombocytopenic purpura, unless the patient also has HIT and no alternative anti-thrombotic treatment is available

• haemorrhagic cerebrovascular accident within the previous three months

• uncontrollable active bleeding state

• severe renal- and/or hepatic insufficiency, unless the patient also has HIT and no alternative anti-thrombotic treatment is available

• severe uncontrolled hypertension

• active gastroduodenal ulcer, unless it is the reason for operation

• diabetic retinopathy

• acute bacterial endocarditis

• hypersensitivity to sulphite

4.4. Special warnings and precautions for use

Danaparoid sodium cross-reactivity

The incidence of serological cross-reactivity of Danaparoid Sodium with the heparin-induced antibody before the start of therapy is approximately 5%; however, one of the main causes of pre-treatment danaparoid cross-reactivity appears to be due to residual heparin in the circulation as a result of a prior heparin administration. The incidence of clinical cross-reactivity developing during danaparoid sodium therapy is approximately 3% and many of these patients had a negative pre-treatment serological cross-reactivity test. Although the risk of antibody-induced thrombocytopenia and thrombosis during danaparoid sodium therapy (i.e. clinical cross-reactivity) is very small, it is advisable to check the number of platelets daily during the first week of treatment, on alternate days during the second and third weeks, and weekly to monthly thereafter. If a pre-treatment cross-reactivity test with danaparoid sodium is positive but it is decided to use danaparoid sodium, then the number of platelets should be checked daily until danaparoid sodium treatment is stopped. If antibody-induced thrombocytopenia occurs, one should stop the use of danaparoid sodium and consider alternative treatment.

Increased risk of haemorrhage

Danaparoid sodium should not be administered to patients with severe haemorrhagic diathesis, e.g. haemophilia and idiopathic thrombocytopenic purpura, unless the patient also has HIT and no suitable alternative antithrombotic treatment is available.

Danaparoid sodium should not be used in patients with severe renal and hepatic insufficiency unless the patient also has HIT and no alternative antithrombotic treatment is available.

Danaparoid sodium 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 which may lead to an increased danger of haemorrhage into a vital organ or site.

Danaparoid sodium should not be administered to patients with active gastric or duodenal ulceration, unless it is the reason for operation.

Since severe bleeding may occur post-operatively in HIT patients undergoing a cardiopulmonary bypass procedure, danaparoid sodium is not recommended during the procedure, unless no other antithrombotic treatment is available (see Section 4.2 Special Populations).

Immediate hypersensitivity reactions

Danaparoid sodium contains sodium sulphite. In asthma patients hypersensitive to sulphite the latter can result in bronchospasm and/or anaphylactic shock.

Risk of bleeding with spinal/epidural anaesthesia/spinal lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of danaparoid sodium (see also section 4.3).

As with heparins, in patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of danaparoid sodium may theoretically be associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. The risk is increased by the prolonged use of a peridural or spinal catheter for anaesthesia or analgesia, by the concomitant use of drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or anticoagulants, and by traumatic or repeated puncture. In decision-making on the interval between the last administration of danaparoid sodium at prophylactic doses and the placement or removal of a peridural or spinal catheter, the product characteristics and whether or not the spinal tap was traumatic or had to be repeated, as well as the patient profile should be taken into account. Subsequent dose should not take place before at least four hours have elapsed. Re-administration should be delayed until the surgical procedure is completed.

Should a physician decide to administer Danaparoid Sodium in the context of peridural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment, such as back pain, sensory and motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction. Nurses should be trained to detect such signs and symptoms. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these.

If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.

Danaparoid Sodium should not be given by the intramuscular route.

The safety and efficacy of danaparoid sodium in patients with non-haemorrhagic stroke remains to be confirmed.

No incidences of osteoporosis have been reported in patients treated with the recommended dose of danaparoid sodium. However, as for heparin, treatment with glycosaminoglycuronan may result in osteoporosis if the dosage is inappropriate.

It should be noted that the anti-Xa units of Danaparoid Sodium have a different relationship to clinical efficacy than those of heparin and low molecular weight heparins.

4.5. Interaction with other medicinal products and other forms of interaction

In clinical studies no clinically significant interactions with other medications have been found. Danaparoid sodium may be used together with oral anticoagulants vitamin K antagonists (VKA), 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 this is particularly important in patients undergoing peridural or spinal anaesthesia or spinal puncture (see section 4.4.). Monitoring of anticoagulant activity of oral anticoagulants by prothrombin 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.

Common

Uncommon

Rare

Blood and the lymphatic system disorders

thrombocytopenia*, heparin-induced thrombocytopenia

immune thrombocytopenic purpura

Immune system disorders

hypersensitivity, drug hypersensitivity

Skin and subcutaneous tissue disorders

rash

purpura, rash maculopapular, rash erythematous, pruritus, urticaria

rash generalised, rash maculovesicular, injection site rash, infusion site rash, rash macular

General disorders and administration site conditions

Injection site reaction

Injection (inj.) site:

- haemorrhage

- discomfort

- hypersensitivity

- irritation

- coldness

- pruritus

inj. or infusion site:

- erythema

- pain

- swelling

- warmth

infusion site:

- bruising

- reaction

Injury, poisoning and procedural complications

post procedural haemorrhage

post procedural hematoma,

procedural haemorrhage

incision site haemorrhage, anastomotic haemorrhage

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).

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.