Danaparoid
Danaparoid Uses, Dosage, Side Effects, Food Interaction and all others data.
Danaparoid is a low-molecular-weight heparinoid with an average molecular weight of 5500 Daltons consisting of a mixture of glycosaminoglycans . The active constituents are heparan, dermatan and Chondroitin sulfate , and they are isolated from the porcine intestinal mucosa . Danaparoid possesses a potent antithrombic activity that works by inhibiting activated factor X (Factor Xa) and activated factor II (Factor IIa). It is chemically distinct from heparin by containing different protein binding properties, thus has lower cross-reactivity in heparin-intolerant patients. Danaproid is used in the treatment of heparin-induced thrombocytopenia (HIT) as an off-label indication and prevention of post-operative deep venous thrombosis (DVT). While it was initially approved by the FDA as Orgaran™, danaparoid was withdrawn by Organon International on August 14, 2002, due to a shortage in drug substance by the manufacturer. The use of Orgaran™ was discontinued in the United States however it is available in several other countries including European countries and Japan. Danaparoid sodium is the common salt form in therapeutic preparations and is typically administered subcutaneously.
Danaparoid contains a mixture of heparan sulfate, dermatan sulfate and chondroitin sulfate in amounts of approximately 84%, 12% and 4%, respectively . Danaparoid is as an antithrombotic agent that prevents the formation of fibrin in the coagulation pathway. It has a high antifactor Xa to antifactor IIa (thrombin) activity that primarily works via antithrombin III-mediated inhibition of factor Xa . The ratio of antifactor Xa to antifactor II activity is ≥ 20:1 . Danaparoid has a minor effect on platelet function and aggregation . In a worldwide compassionate-use programme involving a total of 667 patients with heparin-induced thrombocytopenia (HIT), treatment with danaparoid resulted in 93% of successful outcomes in resolving HIT .
In healthy volunteers, danaparoid caused significantly less prolongation o f 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 . Danaparoid has been associated with the cross-reactivity with pathogenic heparin-induced platelet-factor 4 (PF4) antibodies, which occurs in about 10 % or more by in vitro testing . The clinical relevance of this effect is not fully understood .
| Trade Name | Danaparoid |
| Availability | Discontinued |
| Generic | Danaparoid |
| Related Drugs | Xarelto, Eliquis, enoxaparin, apixaban, rivaroxaban, heparin |
| Type | Subcutaneous |
| Groups | Approved, Withdrawn |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Danaparoid is a heparinoid with anticoagulant and antithrombotic activities used for the treatment of acute episode of Heparin-Induced Thrombocytopenia (HIT), and for prophylaxis in patients with a history of HIT.
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 .
Danaparoid is also used to associated treatment for these conditions: Deep Vein Thrombosis caused by Major Abdominal Surgery, Deep Vein Thrombosis caused by Orthopedic Surgery, Deep Vein Thrombosis caused by Thoracic Surgery, Heparin Induced Thrombocytopenia (HIT), Non-hemorrhagic stroke
How Danaparoid works
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 .
Toxicity
Subcutaneous administration of a single dose at 3800 anti-Xa units/kg, which is 20.5 times the recommended dose for humans based on body surface area, was found to be lethal to female rats. Lethal effects were seen in male rats when administering a single subcutaneous dose at 15200 anti-Xa units/kg, which is approximately 82 times the recommended human dose based on body surface area . In rats, the symptoms of acute toxicity following intravenous administration included respiratory depression, prostration and twitching .
Accidental overdosage of danaparoid may lead to severe bleeding complications. While protamine sulfate may partially neutralize the anti-Xa actions of danaparoid, there is no evidence that it is capable of reducing severe non-surgical bleeding during treatment of danaparoid. In case of serious bleeding, danaparoid should be discontinued and blood transfusions should be administered if necessary. Withdrawal of danaparoid is expected to restore the coagulation balance without rebound phenomenon .
There is no evidence of danaparoid to have a potential to induce carcinogenesis, mutagenesis and impairment of fertility .
Food Interaction
- Avoid excessive or chronic alcohol consumption. Ingesting alcohol increases the risk of bleeding.
- Avoid herbs and supplements with anticoagulant/antiplatelet activity. These may increase the risk of bleeding. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
Danaparoid Hypertension interaction
[Moderate] Anticoagulants should be used with extreme caution in patients at increased risk for hemorrhage, including those patients with severe hypertension.
Danaparoid Drug Interaction
Unknown: amoxicillin / clavulanate, amoxicillin / clavulanate, glucose, glucose, fentanyl, fentanyl, acetaminophen, acetaminophen, tiotropium, tiotropium
Danaparoid Disease Interaction
Major: hemophilia, liver disease, peptic ulcer disease, retinopathy, subacute bacterial endocarditisModerate: hypertension, kidney disease
Volume of Distribution
Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. The volumes of distribution of anti-Xa and anti-IIa activities are 9.1 L and 7.3-9.0 L, respectively .
Elimination Route
Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly antifactor Xa and antifactor IIa activities. The bioavailability of danaparoid is 100% following subcutaneous administration . 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 .
Half Life
Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. The elimination half-life ranges from 19.2 to 24.5 hours during anti-Xa activity and ranges from 1.8 to 4.3 hours during anti-IIa activity .
Clearance
Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. 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 .
Elimination Route
Renal excretion is the main route of elimination, accounting for approximately 40-50% of the total clearance of antifactor Xa activity following intravenous administration of danaparoid . Therefore in patients with severe renal impairment, the elimination half-life of anti-Xa activity may be prolonged .
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