Drug information of Danaparoid
Mechanism of effect
In the coagulation cascade leading to clot formation, factor X and factor II requires activation to promote subsequent conversion of fibrinogen to fibrin. The mechanism of action of danaparoid resulting in anticoagulant and antithrombic effects involves a complex interaction between 2 components, factor IIa and in particular, factor Xa. Via binding to antithrombin and inducing a conformational change [A32579], danaparoid enhances and catalyzes the the binding of factor Xa to antithrombin, which induces antithrombin-mediated inactivation of factor Xa. This leads to inhibition of thrombin generation and subsequently, thrombus formation.
Danaparoid also weakly enhances antithrombin III and heparin cofactor II inactivation of factor IIa. There is evidence that danaparoid also suppresses the activation of factor IX which, in conjunction with simultaneous inhibition of factor X, may lead to antithrombic effects.
Danaparoid is as an antithrombotic agent that prevents the formation of fibrin in the coagulation pathway. Danaparoid has a minor effect on platelet function and aggregation. In healthy volunteers, danaparoid caused significantly less prolongation of the activated partial thromboplastin time (APTT) and was associated with a significantly lower thrombin time than unfractionated heparin (UFH) and low molecular weight heparins (LMWHs). Danaparoid displays lower lipolytic activity than UFH in vitro and in healthy individuals, leading to lower plasma levels of free fatty acids.
Absorption: Following administration of single subcutaneous doses of 750, 1500, 2250, and 3250 anti-Xa units of danaparoid, the peak plasma anti-Xa activities were 102.4, 206.1, 283.9, and 403.4 mU/mL, respectively. The time to reach maximum anti-Xa activity is approximately 2-5 hours.
Volume of distribution: The volumes of distribution of anti-Xa and anti-IIa activities are 9.1 L and 7.3-9.0 L, respectively.
Metabolism: There is no evidence of hepatic metabolism and danaparoid is unlikely to undergo cellular metabolism.
Route of elimination: Renal excretion is the main route of elimination, accounting for approximately 40-50% of the total clearance of antifactorXa activity following intravenous administration of danaparoid.
Half life: 19.2 to 24.5 hours during anti-Xa activity and ranges from 1.8 to 4.3 hours during anti-IIa activity.
Clearance: Total plasma clearance is about 0.36 L/h during anti-Xa activity, which may be accelerated with higher body surface area. Total plasma clearance during anti-IIa activity ranges from 2.3 to 3 L
Indicated for the prophylaxis of post-operative deep venous thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing elective hip replacement surgery.
- Non-HIT patients (DVT prophylaxis)
750 anti-factor Xa units, twice daily for 7 to 10 days or until the risk of thromboembolism has diminished.
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
- HIT patients
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.
There is insufficient experience with the use of Danaparoid Sodium in children to suggest a dosage regimen for this group of patients.
Drug contraindicationsHypersensitivity to this drug or components
Aswith heparins, in patients receiving Danaparoid Sodium for treatment rather than for prophylaxis, locoregionalanaesthesia in elective surgical procedures is contra-indicated.
• 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 stroke in the acute phase
• 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 gastroduodenalulcer, unless it is the reason for operation
• diabetic retinopathy
• acute bacterial endocarditis
• apositive in vitroaggregation test for the heparin-induced antibody in the presence of Danaparoid Sodium in patients with ahistory of thrombocytopenia induced by heparin or heparin-like anticoagulants
• hypersensitivity to sulphite.
• hypersensitivity to the active substance or to any of the excipients.
Side effectsallergic reactions , Rash
post procedural hemorrhage
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)
Interactionssulfinpyrazone , Phenindione , Desirudin , Tositumomab , Antithrombin III , Betrixaban , Ramucirumab , Oxaprozin , Urokinase , Ipilimumab , Dasatinib , cangrelor , defibrotide
Although the risk of antibody-induced thrombocytopenia and thrombosis during DanaparoidSodium 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. Ifantibody-induced thrombocytopenia occurs, one should stop the use of Danaparoid Sodium and consider alternative treatment.
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 avital organ or site.
Since severe bleeding may occur post-operatively in HIT patients undergoing acardiopulmonary bypass procedure, DanaparoidSodium is not recommended during the procedure, unless no other antithrombotic treatment is available.
Danaparoid Sodium contains sodium sulphite. Inasthma 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.
Aswith 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 haematomaresulting in prolonged or permanent paralysis. The risk is increased by the prolonged use of aperidural 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.•
Indecision-making on the interval between the last administration of DanaparoidSodium at prophylactic doses and the placement or removal of aperidural 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 aphysician decide to administer Danaparoid Sodium in the context of peridural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detectany 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 anurse or aclinician if they experience any of these.
Ifsigns or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.