| FRAXIPARINE™ |
|Nadroparin Calcium |
|Anticoagulant - Antithrombotic |
|Action And Clinical Pharmacology: Nadroparin is a low molecular weight heparin. It is a heterogeneous mixture of sulfated polysaccharide glycosaminoglycan chains obtained by depolymerisation of porcine mucosal sodium heparin, extraction/purification and conversion to the calcium salt. Of the low molecular weight heparins, nadroparin has the lowest mean molecular weight of approximately 4 300 daltons; 75 to 95% of the molecular masses are in the range of 2 000 to 8 000 daltons. Nadroparin is composed of molecules with and without a specially characterized pentasaccharide, which is the specific site for high affinity binding to the plasma protein antithrombin III (ATIII). This binding leads to an accelerated inhibition of factor Xa, which accounts for the antithrombotic effect of nadroparin.
Nadroparin is an anticoagulant/antithrombotic drug with high anti-Xa activity (95 to 130 IU/mg), but relative to unfractionated heparin has a low inhibitory effect on factor IIa activity. (The ratio of anti-Xa to anti-IIa activity for nadroparin is 2.5 to 4, whereas it is 1 for heparin.) This greater ratio of anti-Xa activity to anti-IIa activity has the potential to provide equivalent antithrombotic efficacy with reduced hemorrhagic complications. It has both immediate and prolonged antithrombotic action.
Following s.c. injection, nadroparin is almost completely absorbed. Peak plasma anti-Xa activity occurs at 2 to 3 hours. Maximal prolongation of APTT and thrombin time occurs at approximately 4 hours. Although anti-Xa activity persists for at least 18 hours after injection, the elimination half-life is approximately 3.5 hours.
After s.c. administration of prophylactic doses (i.e., 0.3 mL) of nadroparin in healthy volunteers, maximum APTT and thrombin time were increased by a negligible 2 seconds at 4 hours, and APTT returned to baseline by 8 hours. After administration of treatment doses, APTT was only slightly prolonged (1.2 times the control value; with unfractionated heparin, APTT values at curative dosage are aimed at obtaining 1.5 to 2.5 times the control value). In the pharmacokinetic studies, a linear relationship between nadroparin dose and plasma anti-Xa activity was observed.
Elimination of nadroparin is prolonged in patients suffering from renal insufficiency. In subjects with severe renal insufficiency, the anti-Xa activity was shown to have an elimination half-life of approximately 6 hours, and time to reach peak activity was approximately 4 hours.
Indications And Clinical Uses: Prophylaxis of thromboembolic disorders (particularly deep vein thrombosis and pulmonary embolism) in general surgery and in orthopedic surgery.
Treatment of deep vein thrombosis.
Prevention of clotting during hemodialysis.
Contra-Indications: Nadroparin must not be administered by the i.m. route. Hypersensitivity to nadroparin. Injuries to and operations on the CNS, eyes and ears. History of thrombocytopenia occurring with nadroparin, or in patients in whom an in vitro platelet aggregation test is positive in the presence of nadroparin. Severe uncontrolled hypertension. Signs of hemorrhage or increased risk of hemorrhage in relation with hemostasis disorders, except for disseminated intravascular coagulation not induced by heparin. Organic lesion which is likely to bleed (such as active peptic ulceration). Acute infective endocarditis. Hemorrhagic cerebrovascular event. tag_WarningWarnings
Manufacturers' Warnings In Clinical States: Nadroparin 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 nadroparin activity. Routine clotting assays are unsuitable for monitoring its anticoagulant activity. Only at very high plasma anti-Xa levels is APTT prolongation observed.
Drug Interactions: ASA and other salicylate drugs, nonsteroidal anti-inflammatory drugs increase the risk of hemorrhage due to the effect on platelets. Similarly, antiplatelet drugs increase the risk of hemorrhage due to the inhibition of the platelet function (see also Precautions).
Pregnancy and Lactation: Clinical experience of use in pregnant women is limited. Animals studies have not shown any teratogenic or fetotoxic effects. Clinical data concerning transplacental passage are limited; therefore, use of nadroparin during pregnancy is not advised unless the therapeutic benefits outweigh the possible risks. There are no clinical data concerning excretion in breast milk. Mothers receiving nadroparin should avoid breast-feeding.
Children: There are no trials to support the use of nadroparin in children. Therefore, the use of nadroparin is not advised unless the therapeutic benefits outweigh the possible risks.
Knee Surgery: Knee replacement is a delicate surgery, and may carry a greater risk of both deep vein thrombosis (DVT) and clinically important bleeding than hip replacement surgery. For this reason it is important to ensure appropriate dosing of this drug in this patient population.
Precautions: The various low molecular weight heparins have concentrations expressed in different units systems or in mg. These doses are not identical or interchangeable. Particular attention is therefore required to the doses and units in which the dose is expressed, and the specific instructions for the particular low molecular weight heparin should be strictly observed.
Monitoring: Nadroparin activity is monitored by measuring anti-factor-Xa activity in plasma. Standard global clotting tests, such as APTT, PT and TT cannot be used to monitor the activity of nadroparin. Only at very high plasma anti-Xa levels is APTT prolongation observed.
Because of the possibility of rare heparin-induced thrombocytopenia, platelet counts should be determined prior to the start treatment with nadroparin and, subsequently, twice weekly throughout the course of treatment.
Thrombocytopenia: Rare cases of thrombocytopenia have been reported. In the event of thrombocytopenia treatment should be discontinued immediately. Thrombocytopenia may be associated with arterial or venous thrombosis, exacerbation of the pre-existing thrombosis or disseminated intravascular coagulation; the platelet count should be assessed if these events are suspected. These effects are probably immunological in origin, and in the case of the first course of heparin treatment usually occur between the 5th and 21st day.
When there is a history of thrombocytopenia occurring with another heparin, careful clinical monitoring including assessment of platelet count at least once daily should be undertaken. Treatment should be discontinued immediately if thrombocytopenia occurs.
Reduced doses should be considered in patients with moderate to severe renal insufficiency. Nadroparin dosage should be carefully monitored in patients with severely impaired renal function. The main route of elimination is the kidney. After administration of prophylactic doses of nadroparin in patients with severe renal impairment, maximum plasma anti-Xa activity was reached 4 hours after injection at a mean of 0.64±0.22 IU/mL. The half-life for anti-Xa was 6 hours as compared to 3.5 hours for healthy volunteers and patients with normal kidney function.
Nadroparin should be administered with caution in cases of hepatic insufficiency.
Nadroparin should be used with caution in patients undergoing epidural anesthesia. Clinical studies of nadroparin in surgical patients were carried out primarily in patients undergoing general anesthesia. Nadroparin should be discontinued before administering epidural anesthesia when there are signs of impaired coagulation.
Hemodialysis: In clinical trials, patients undergoing chronic hemodialysis with nadroparin normally required few dose adjustments during the first few weeks of therapy. Thereafter, only occasional monitoring of anti-Xa levels would be required. Nadroparin was not studied in patients undergoing acute hemodialysis, but a narrower therapeutic interval would be anticipated. These patients should be subjected to comprehensive monitoring of anti-Xa levels.
Drug Interactions: Concomitant use of ASA (or other salicylates) or nonsteroidal anti-inflammatory drugs is not recommended, nor is the use of antiplatelet agents (see Warnings) as they may increase the risk of bleeding. Where such combinations cannot be avoided, careful clinical and biological monitoring should be undertaken.
Nadroparin should be administered with caution in patients receiving systemic (gluco-) corticosteroids or dextrans.
As with all other low molecular weight heparin preparations, during transfer to oral anticoagulant therapy increased monitoring is required (the treatment with nadroparin should be continued until the INR is stabilized at the target value).
Adverse Reactions: Bleeding: As with other low molecular weight heparin preparations, nadroparin increases the risk of overt or concealed hemorrhage, especially in patients with other risk factors (see Contraindications).
The most common side effect of nadroparin was the development of injection site hematomas, which occurred at a frequency of about 5%. Other bleeding side effects were rare in clinical trials and ranged in severity from minor local hematomas to major hemorrhagic events, including death. Frequently, the first signs of bleeding include epistaxis, hematuria or melena. Petechiae or unexpected bruising may precede overt hemorrhage. Bleeding may be from any site and may be difficult to detect; e.g., retroperitoneal bleeding. In surgical patients, bleeding may occur from the surgical site. Established risk factors for bleeding in response to heparin and low molecular weight heparins include the use of platelet inhibiting medication, chronic heavy alcohol consumption, serious concurrent illness, renal failure, and advanced age. Patients taking low molecular weight heparins who experience noticeable prolongation of APTT, are at risk for bleeding. Frequently this is associated with plasma anti-Xa activity of 2 IU/mL or more.
Thrombocytopenia: Rare cases of thrombocytopenia, sometimes thrombogenic, have been reported (see Precautions).
Other infrequent serious side effects include: cutaneous necrosis, usually occurring at the injection site, which has been reported both with unfractionated heparin and with low molecular weight heparins; it is preceded by purpura or infiltrated or painful erythematous blotches, which may or may not be manifested by systemic upset. In such cases, treatment should be discontinued immediately.
Cutaneous or generalized hypersensitivity reactions requiring discontinuation of treatment.
Other adverse events which occur occasionally at an incidence similar to that of treatment with unfractionated heparin include: elevations in transaminases (AST and ALT) which are transient and has not been correlated to long-term effects on liver function; reversible hypoaldosteronism which may be associated with hyperkalemia and/or hyponatremia.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Hemorrhage is the major clinical sign of overdosage. In case of accidental overdosage, the platelet count and other coagulation parameters should be measured. Minor bleeding rarely requires specific therapy, and reducing or delaying subsequent doses of nadroparin is usually sufficient.
The use of protamine sulfate should only be considered in more serious cases. It largely neutralizes the anticoagulant activity of nadroparin, but some anti-Xa activity will remain. A dose of 0.6 mL protamine (6 mg, 625 A.H.U.) neutralizes approximately 0.1 mL (950 AXa IU) of nadroparin. The rate of administration of protamine should not exceed 20 mg/min, since too rapid administration can cause severe hypotensive and anaphylactoid-like reactions.
Dosage And Administration: Nadroparin is a sterile solution for s.c. injection into the anterolateral abdominal wall, alternatively, on the right and left sides of the abdominal wall. The thigh may be used as an alternative site. The needle should be fully inserted, perpendicularly into a pinched-up fold of skin.
The use of the intravascular route is not necessary except for hemodialysis given the high degree of bioavailability of nadroparin by the s.c. route (approximately 98%). Nadroparin is contraindicated for i.m. administration.
Prophylaxis and Treatment of Thromboembolic Disorders: Prophylaxis in General Surgery: The dose of nadroparin required for adequate prophylaxis without increased bleeding varies depending on the risk factors: single daily s.c. injections of 2 850 anti-Xa IU (0.3 mL). The first dose should be given 2 to 4 hours before surgery. Treatment should continue for at least 7 days. In all cases, prophylaxis should continue throughout the risk period and at least until the patient is actively ambulant or is no longer at risk of deep vein thrombosis.
Prophylaxis in Orthopedic Surgery: Single daily s.c. doses should be adjusted according to the patient bodyweight, as follows: 38 anti-Xa IU/kg administered 12 hours before surgery, 38 anti-Xa IU/kg administered 12 hours after surgery, 38 anti-Xa IU/kg re-administered on a daily basis, up to and including postoperative Day 3, 57 anti-Xa IU/kg administered as of postoperative Day 4.
Treatment should continue for at least 10 days and should continue in all cases throughout the risk period and at least until the patient is actively ambulant.
Monitoring of the activity of nadroparin is performed as a functional method for anti-Xa. Blood samples drawn 3 to 4 hours postdosing should show anti-Xa levels of 0.5 to 1 IU anti-Xa/mL.
As with other low molecular weight heparins, concomitant therapy with vitamin K antagonists is usually started immediately. Nadroparin therapy should continue until the INR ratio is within the therapeutic range, usually at least 5 days.
Prevention of Clotting During Hemodialysis: All clinical trial patients were patients with chronic renal failure, and the following dosage recommendations are for that patient population, in patients with no risk of hemorrhage.
Optimisation of dosage is required for each individual patient (different clotting stimuli are produced by different dialysis circuits and membranes, and there is inter-patient variability).
Single dose of approximately 65 anti-Xa IU/kg into the arterial line at the start of each session, for a session lasting 4 hours or less in patients with no risk of hemorrhage. This dose normally produces plasma anti-Xa levels in the range 0.5 to 1 IU anti-Xa/mL.
An additional dose may be given during sessions lasting longer than 4 hours.
Doses in subsequent dialysis sessions should be adjusted as required.
In patients with a risk of hemorrhage, dialysis sessions may be carried out using halved doses. An additional smaller dose may be given during dialysis for sessions lasting longer than 4 hours. The dose in subsequent dialysis sessions should be adjusted as necessary to achieve plasma levels within the range of 0.2 to 0.4 IU anti-Xa/mL.
Special Populations: Reduced doses of nadroparin should be considered in patients with moderate to severe renal insufficiency.
As with all other low molecular weight heparins, nadroparin should be administered with caution in cases of hepatic insufficiency, and in those with a history of peptic ulceration or other organic lesion likely to bleed.
Availability And Storage: Each mL of aqueous solution contains: nadroparin calcium 9 500 IU anti-Xa. Single dose, disposable prefilled syringes of 0.2 mL (ungraduated syringes) 1 900 IU anti-Xa; 0.3 mL (ungraduated syringes) 2 850 IU anti-Xa; 0.4 mL (ungraduated syringes) 3 800 IU anti-Xa; 0.6 mL (graduated syringes) 5 700 IU anti-Xa; 0.8 mL (graduated syringes) 7 600 IU anti-Xa; and 1 mL (graduated syringes) 9 500 IU anti-Xa. Ungraduated 0.2 mL, 0.3 mL and 0.4 mL syringes are intended for administration of fixed dosages; 0.6 mL, 0.8 mL and 1 mL syringes are graduated so that adjusted dosages can be given. Cartons of 2 and 10. Store between 15 and 30°C. Do not freeze. Do not refrigerate, as cold injections may be painful. Discard unused portion of each syringe. Do not mix with other preparations.