Orgaran (Danaparoid)

ORGARAN®

Organon

Danaparoid Sodium

Antithrombotic

Action And Clinical Pharmacology: Danaparoid is a mixture of low molecular weight sulfated glycosaminoglycuronans derived from porcine intestinal mucosa. It consists of heparan sulfate with low affinity for antithrombin III (AT-III) (about 80%), heparan sulfate with high affinity for AT-III (about 4%), dermatan sulfate (8 to 16%) and chondroitin sulfate.

Compared to heparin, danaparoid has a much higher anti-factor Xa/anti-IIa ratio (more than 20:1). Danaparoid exerts a stronger catalytic effect on the inactivation of factor Xa than on the inactivation of thrombin. The anti-Xa activity is mediated by AT-III and is not inactivated by endogenous heparin neutralizing factors. The antithrombin activity is mediated by both AT-III and heparin cofactor II. Danaparoid inhibits thrombus formation with approximately the same potency as heparin, in animal models. In clinical trials, danaparoid showed improved antithrombotic activity when compared to heparin. Both of the heparan sulfate fractions, the high- and low-affinity for AT-III, contribute to the antithrombotic activity. Danaparoid has minimal or no effect on platelet function. It produces less bleeding-enhancing activity than heparin in experimental models. Danaparoid does not inhibit platelet deposition at therapeutic doses and has only minimal effects on platelet degranulation during hemostatic plug formation. In experimental models, the antithrombotic activity of danaparoid is more persistent and the hemorrhagic effects less persistent than those of heparin.

Cross-reactivity between danaparoid and heparin-associated antibody from the plasma of patients with heparin-induced thrombocytopenia (HIT) was less than 10%. Cross-reactivity testing is complex and incompletely understood. The clinical implications are unclear (see Precautions). A negative cross-reactivity test does not necessarily indicate that the patient will not develop danaparoid-induced thrombocytopenia during therapy.

Indications And Clinical Uses: In the prevention of deep vein thrombosis (DVT) following orthopedic, major abdominal and thoracic surgery. Patients with a positive diagnosis of nonhemorrhagic stroke may also be treated with danaparoid. The prophylactic treatment of patients with danaparoid does not preclude the use of other modalities of prophylaxis (see Precautions, Drug Interactions).

Contra-Indications: Danaparoid should not be administered i.m. Severe hemorrhagic diathesis, hemorrhagic stroke in the acute phase, uncontrollable active bleeding state, hypersensitivity to danaparoid or any of its components including sulfite, active gastric or duodenal ulcer (unless the reason for major abdominal surgery), bacterial endocarditis, major blood clotting disorders, history of thrombocytopenia with danaparoid or in patients in whom an in vitro platelet aggregation test is positive in the presence of danaparoid, severe untreated hypertension, diabetic or hemorrhagic retinopathy, other diseases involving an increased risk of hemorrhage.

Manufacturers’ Warnings In Clinical States: Danaparoid should be used with care in patients with a history of gastrointestinal ulceration.

Determination of anti-factor Xa levels in plasma is the only method available for monitoring danaparoid activity. Anticoagulant activity is characterized by a very flat dose response curve in clotting assays such as prothrombin time, activated partial thromboplastin time, kaolin cephalin clotting time and thrombin clotting time; therefore, these routine clotting assays are unsuitable for monitoring its anticoagulant activity.

Anti-Xa units of danaparoid have a different relationship to clinical efficacy than those of heparin and low molecular weight heparins.

Protamine is not a neutralizing agent for the activity of danaparoid.

Pregnancy, Lactation and Children: The safety of danaparoid in pregnant women and children has not been established. Animal studies have not demonstrated any teratogenic effects or placental transfer of danaparoid. The use of danaparoid in pregnancy has only been studied incidentally. Observations in pregnant women in the last trimesters have so far given no indication that the use of danaparoid during pregnancy leads to fetal abnormalities or to exacerbation of bleeding in mother or infant during delivery.

There are no data available about danaparoid secretion into breast milk. Mothers receiving danaparoid should avoid breast-feeding.

Precautions: Danaparoid should be used with caution in patients with severely impaired renal function because the main route of elimination is via the kidney. In studies with renal failure patients, it was observed that the individual pharmacokinetics of plasma anti-Xa effect is not readily predictable and may show widely different patterns of interpatient variability. The plasma anti-Xa activity may show accumulation between dialysis periods unless the predialysis bolus is suitably adjusted. The dose of danaparoid for DVT prophylaxis need not be increased for patients on the drug for long-term dialysis.

Danaparoid should be used with caution in patients undergoing epidural anesthesia. In cases of signs of impaired coagulation, it should be discontinued before considering epidural anesthesia.

In stroke patients, hemorrhagic stroke should be excluded by CT scan prior to the administration of danaparoid.

Bleeding Risk: There is a risk of systemic bleeding with danaparoid as with all antithrombotic drugs. Patients should be carefully monitored for bleeding complications. This should include regular physical examination of the patient, close observation of the surgical drain, and periodic hemoglobin determination. Bleeding complications in which hemoglobin has decreased by more than 2 g/dL, or if a transfusion of 2 or more units has been required, may be considered major. Determination of anti-factor Xa levels in plasma is the only method available for monitoring danaparoid. Routine clotting assays such as prothrombin time (PT), activated partial thromboplastin time (APTT), kaolin cephalin clotting time, and thrombin clotting time are unsuitable because of the very flat dose response curves.

Patient Monitoring: Platelet counts should be determined prior to commencement of treatment with danaparoid and twice weekly thereafter.

Cross-reactivity in Heparin-induced Thrombocytopenia Patients: The clinical implications of cross-reactivity testing in HIT patients are unclear. Danaparoid has been used as an alternative anticoagulant in patients who had developed thrombocytopenia with heparin. In HIT patients tested for initial therapy, the cross-reactivity with danaparoid (90%). Data on cross-reactivity development after repeated exposure to danaparoid in HIT patients is limited to 13 patients. The time course and frequency of antibody induction by danaparoid in HIT patients is unknown. Among patients who have not developed detectable cross-reactivity during danaparoid therapy, many have not developed thrombocytopenia, but others have developed life-threatening thrombocytopenia despite negative laboratory results for cross-reactivity.

Although the most certain test for HIT is a positive re-challenge platelet thrombocytopenia, the danger of inducing a serious thromboembolic event prohibits deliberate use in that manner. Reliance upon laboratory demonstration of platelet hypersensitivity with danaparoid is necessary.

Despite limitations with laboratory testing, a negative result should be obtained before beginning danaparoid treatment. The patients must be monitored with particular care, to include platelet counts at least daily. Treatment should be changed immediately if cross-reactivity develops.

The following salient points should be considered with platelet sensitivity testing in HIT patients but are not the only ones: 1. A negative platelet test in an acutely thrombocytopenic patient does not rule out a positive in vivo reaction.

2. Samples taken a few months, or later, after a thrombocytopenic reaction may test negative for cross-reactivity because the antibody has disappeared. However, commencement of danaparoid treatment may induce the production of cross-reaction antibody, with the accompanying risk of thrombocytopenia.

3. Use of a sensitizing agent that resulted in a positive HIT test in the past is not recommended even for a single occasion, because a fatal outcome with danaparoid has been reported.

Drug Interactions: In clinical studies no clinically significant interactions with other medications have been found. Danaparoid may be used together with oral anticoagulants or drugs which interfere with platelet function, such as ASA and nonsteroidal anti-inflammatory drugs, but caution remains necessary. Monitoring of anticoagulant activity of oral anticoagulants by prothrombin time and Thrombotest is unreliable within 5 hours after danaparoid administration.

Danaparoid is intended primarily for s.c. use. When administered as an i.v. bolus, it should be given separately and not mixed with other drugs.

The interaction of danaparoid with the following drugs has been studied. All effects on kinetic parameters mentioned below are considered of no clinical relevance. No clinically relevant effects have been observed on biochemical, hematological and urinary parameters.

ASA: no effects on hemostasis.

Acenocoumarol: slight decrease in anti-Xa clearance.

Cloxacillin: slight increase in elimination half-life of anti-Xa activity.

Ticarcillin: slight increase in anti-Xa clearance.

Digoxin: slight increase in anti-Xa clearance; slight decrease in digoxin area under the curve of plasma concentration versus time.

Chlorthalidone: slight decrease in anti-Xa clearance and central volume of distribution.

Pentobarbital: decrease of anti-IIa clearance.

Antipyrine: no significant effect on cytochrome P-450 system.

Adverse Reactions: Most Common Reactions: The most common reported adverse events with danaparoid are related to bleeding. Table I represents all adverse events reported by 2% or more of patients receiving danaparoid and as such represents the most commonly reported adverse events. This type of analysis provides a general picture of the safety profile of danaparoid in comparison to the reference drugs including placebo.

Most serious reactions and deaths: Table II summarizes the profile of the more serious adverse events, independent of causality, reported in 1 288 patients during treatment and follow-up for danaparoid and the control treatments according to an organ system classification. Follow-up data were available for more than two thirds of the patients. The individual adverse events reported within each organ system class are also described for danaparoid.

The most common serious adverse events considered to be probably or definitely related to danaparoid were hemorrhages or transient rashes. Three of the rashes were located around the injection site and the other 3 were generalized rashes which disappeared only after stopping treatment. In 2 other cases, generalized rashes occurred in which a relationship with danaparoid was considered to be less likely. Among the 1 288 patients treated with danaparoid in the Phase II and Phase III studies, a total of 59 deaths (4.6%) were registered. This percentage was not significantly different from heparin (4%), dextran (5.4%) or oral anticoagulants (5.1%). Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of serious bleeding, danaparoid should be stopped. Transfusion with fresh frozen plasma may be considered.

Dosage And Administration: In general, danaparoid is administered by s.c. injection at a dose of 750 anti-factor Xa units, twice daily up to 14 days for DVT prophylaxis.

In surgical patients it is recommended to start prophylaxis preoperatively and to give the last preoperative dose 1 to 4 hours before surgery. In nonhemorrhagic stroke patients the first dose of danaparoid can be given as an i.v. bolus injection of up to 1 000 anti-Xa units.

Plasma anti-Xa activity is linearly related to the dose of danaparoid given. If it is necessary to monitor anticoagulant activity, and for individual dose setting, a functional anti-factor Xa activity assay using a chromogenic peptide substrate should be used. For the results of this assay danaparoid should be used to construct the standard curve.

In patients with severely impaired renal function the second and subsequent doses of danaparoid may have to be reduced.

Dosage in the Elderly: Clearance of anti-factor Xa has not been shown to be markedly reduced in the elderly and the usual dosage is recommended.

Availability And Storage: Each glass ampul of sterile, isotonic solution contains: danaparoid sodium 750 anti-Xa units. Each mL contains: danaparoid sodium 1 250 anti-XA units. Nonmedicinal ingredients: hydrochloric acid to pH 7.0, sodium chloride, sodium sulfite and water for injection. The anti-XA unit is derived from the international heparin standard in an antithrombin-III-containing buffer system. Ampuls of 0.6 mL, boxes of 10. Store at 2 to 30°C. Protect from light.

ORGARAN® Organon Danaparoid Sodium Antithrombotic

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