DANAPAROID SODIUM Solution for injection Ref.[8539] Active ingredients: Danaparoid

Danaparoid Sodium should not be used if an in vitro test for the heparin-induced antibody in the presence of Danaparoid Sodium is positive in patients with thrombocytopenia induced by heparin or heparin-like anticoagulants, unless no suitable alternative antithrombotic treatment is available.

The incidence of serological cross-reactivity of Danaparoid Sodium with the heparin-induced antibody before the start of therapy is approximately 5%. 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.

Danaparoid Sodium should not be administered to patients with severe hemorrhagic diathesis, e.g. hemophilia 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.

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

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.

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 analgesia, by the concomitant use of drugs affecting haemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), 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 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.

In clinical studies no clinically significant interactions with other medications have been found. Danaparoid Sodium may be used together with oral anticoagulants, 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.

There is no data available on the effect of Danaparoid Sodium on thyroid function tests.

Interaction studies have only been performed in adults.

Pregnancy

Danaparoid Sodium has been used in over 60 pregnancies (starting during the first trimester in almost 50% of the pregnancies, the second trimester in approximately 20% of the pregnancies and the third trimester in 25% of the pregnancies. For a small number of patients the starting trimester is unknown). Overall, the use of Danaparoid Sodium was successful.

Animal studies have not demonstrated any teratogenic effect or placental transfer. In the few cases in which human umbilical cord blood was tested for the presence of anti-Xa activity, no activity was found.

Although Danaparoid Sodium has been used with success in a small number of pregnancies, the available information is still considered to be insufficient to assess whether deleterious effects may occur in pregnancy during the use of Danaparoid Sodium.

Caution should be exercised when prescribing to pregnant women. If alternative antithrombotic treatment is unacceptable for medical reasons (e.g. HIT patients) Danaparoid Sodium can be used.

Lactation

In five cases in which breast milk samples were tested for anti-Xa activity, all showed no or negligible amounts of anti-Xa activity (which would be hydrolyzed in the infant’s stomach and rendered harmless).

Although the data are limited, if alternative antithrombotic treatment is unacceptable for medical reasons (e.g. HIT patients) Danaparoid Sodium can be used during lactation.

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

Enhanced bleeding or haematoma may occur at the operation site.

Bruising and/or pain may occur at injection sites.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Common (≥1/100 to 1/10 of patients)
Uncommon (≥1/1,000 to 1/100 of patients)
Rare (≥1/10,000 to <1/1,000 of patients)

Blood and the lymphatic system disorders

Common: thrombocytopenia*, heparin-induced thrombocytopenia

Rare: auto-immune thrombocytopenia

Immune system disorders

Uncommon: hypersensitivity, drug hypersensitivity

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: purpura, rash maculo-papular, rash erythematous, pruritus, urticaria

Rare: rash generalised, rash maculovesicular, injection or infusion site rash, rash macular

General disorders and administration site conditions

Uncommon: Injection site reaction

Rare:

Injection (inj.) site: hemorrhage, discomfort, hypersensitivity, irritation, coldness, pruritus

Inj. or infusion site: erythema, pain, swelling, warmth

Infusion site: bruising, reaction

Injury, poisoning and procedural complications

Common: post procedural hemorrhage

Uncommon: post procedural hematoma, operative hemorrhage

Rare: incision site hemorrhage, anastomotic hemorrhage

Note: terms are coded with MedDRA dictionary version 8.1

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’.

All hemorrhages are listed adverse events for Danaparoid Sodium. This also means that symptoms or signs which are clearly directly related to a hemorrhage (e.g. anaemia, decreased Hb, rbc, hematocrit, 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 heparins 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 ‘Special warnings and precautions for use’).

When administered as an intravenous bolus or infusion, Danaparoid Sodium should be given separately and not mixed with other drugs. However, Danaparoid Sodium is compatible with, and therefore can be added to, infusions of saline, dextrose or dextrose-saline.