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FRAGMIN®
Pharmacia & Upjohn
Dalteparin Sodium
Anticoagulant - Antithrombotic
 
Action And Clinical Pharmacology: Dalteparin is an antithrombotic agent. Dalteparin sodium (low molecular weight heparin sodium) has an average molecular weight of 5 000.

Dalteparin is produced through controlled nitrous acid de-polymerization of sodium heparin from porcine intestinal mucosa. It is composed of strongly acidic sulfated polysaccharide chains with an average molecular weight of 5 000 and about 90% of the material within the range 2 000 to 9 000. Dalteparin is composed of molecules with and without a specially characterized pentasaccharide, the antithrombin binding site, that is essential for high affinity binding to the plasma protein antithrombin (ATIII).

Dalteparin acts antithrombotically mainly by accelerating the rate of the neutralization of certain activated coagulation factors by ATIII but other mechanisms may also be involved. Dalteparin potentiates preferentially the inhibition of coagulation factor Xa and only slightly affects other hemostatic mechanisms such as clotting time and the antithrombotic effect of dalteparin is well correlated to the inhibition of factor Xa.

Heparin and dalteparin dosages cannot be measured directly in the blood stream. Rather their effect on clotting mechanisms is a function of the dosage. Heparin dosage is monitored by both prolongation of APTT, and by anti-Xa activity. For dalteparin however, only extremely high doses lead to noticeable increases in the APTT, therefore measurement of APTT can be used only as an indicator of overdosage. In the case of dalteparin, anti-Xa activity of plasma is used both as an estimate of clotting activity, and as a basis to determine dosage. Dalteparin potency is described in international anti-Xa units (IU).

The specific activity of dalteparin on factor Xa (by measurement of anti-factor Xa IU/mg) is 130, and its specific activity on factor IIa (by measurement of anti-factor IIa IU/mg) is 58. The ratio of anti-Xa/anti-IIa activity for dalteparin is 2.2 (for unfractionated heparin the anti-Xa/anti-IIa is equal to 1). The antithrombotic activity is comparable to heparin while the bleeding effect is reduced.

The % inhibition of thrombin generation by dalteparin compared with unfractionated heparin, is 38% in platelet poor plasma and 73% in platelet rich plasma. The % of antithrombotic activity of dalteparin compared with unfractionated heparin is 47%.

Dalteparin has a smaller effect on platelet function and platelet adhesion than heparin, and thus has only a small effect on primary hemostasis. Heparin treatment depletes the pool of platelet factor 4, while dalteparin has much less of an effect.

Heparin administration releases lipoprotein lipase from tissue sites into the circulation, depleting the pool of these enzymes, which leads to increased plasma triglyceride levels and altered lipid metabolism. Dalteparin has been shown to have a substantially reduced effect on lipid metabolism.

Some studies have shown that dalteparin has less of an effect than heparin on platelet function and adhesion and less disturbance on primary hemostasis. Also, at low doses, dalteparin has been found to depress ATIII levels to a lesser extent than does heparin.

Pharmacokinetics: Dalteparin has a much longer half-life than standard heparin. The half-life after i.v. injection is 2 hours and after s.c. injection, 3 to 4 hours. The bioavailability after s.c. injection is approximately 90% and the pharmacokinetics are non-dose dependent. The plasma concentration of dalteparin following s.c. administration is easily predicted since there is a direct relationship between the administered dose and the anti-Xa activity in plasma (measured as area under the activity curve). The volume of distribution is found to be the plasma volume, approximately 3 L, and the AUCs show good dose dependency. Because of the high bioavailability of dalteparin administered s.c., other pharmacokinetic parameters are similar, regardless of route of administration. Depending on the level of anticoagulation required, the therapeutic plasma level of dalteparin used has been 0.2 to 1 anti-Xa units/mL.

Animal studies using radioactively labelled drug have shown that the distribution of dalteparin is similar, whether the dose is administered i.v. or s.c. After 4 hours about 20% is seen in the urine, with the major organs for the remainder being the liver, gastrointestinal tract and kidney. After 72 hours, 70% of a radioactive dalteparin dose has been excreted. Less dalteparin is found in the liver than standard heparin; the kidneys are the major site of dalteparin metabolism. Dalteparin, in contrast to heparin, is not cleared by a saturable mechanism; low doses are expressed in plasma and increasing the dose does not modify its clearance.

Indications And Clinical Uses: Thromboprophylaxis in conjunction with surgery.

Treatment of acute deep venous thrombosis.

Unstable coronary artery disease (UCAD), i.e., unstable angina and non-Q-wave myocardial infarction.

Prevention of clotting in the extracorporeal system during hemodialysis and hemofiltration in connection with acute renal failure or chronic renal insufficiency.

Contra-Indications: Dalteparin should not be administered i.m.

Hypersensitivity to dalteparin or other low molecular weight heparins and/or heparins e.g., history of confirmed or suspected immunologically mediated heparin induced thrombocytopenia (delayed onset severe thrombocytopenia); acute gastroduodenal ulcer and cerebral hemorrhage; septic endocarditis (endocarditis lenta, subacute endocarditis); injuries to and operations on the central nervous system, eyes and ears; uncontrollable active bleeding; major blood clotting disorders; severe untreated hypertension; diabetic or hemorrhagic retinopathy; other diseases involving an increased risk of hemorrhage; for the treatment of acute DVT and UCAD where repeated high dosages of dalteparin are required, spinal/ epidural anesthesia is contraindicated due to an increased risk of bleeding.

Manufacturers' Warnings In Clinical States: Dalteparin should be used with care in patients with hepatic insufficiency, renal insufficiency or a history of gastrointestinal ulceration.

Determination of anti-factor Xa levels in plasma is the only method available for monitoring dalteparin activity. Routine clotting assays are unsuitable for monitoring its anticoagulant activity. Only at very high plasma dalteparin levels is APTT prolongation observed.

Thromboprophylaxis in Conjunction with Surgery Only: There have been cases of intra-spinal hematomas with the concurrent use of low molecular weight heparins and spinal/epidural anesthesia resulting in long-term or permanent paralysis. The risk of these events may be higher with the use of postoperative indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis: nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other drugs and diseases affecting coagulation. The risk also appears to be increased by traumatic or repeated epidural or spinal procedure. Dalteparin should only be used concurrently with spinal/epidural anesthesia when the therapeutic benefits to the patients outweigh the possible risks. Careful vigilance for neurological signs is recommended with rapid diagnosis and treatment, if signs occur (see also Adverse Effects).

When a higher dose (5 000 IU s.c.) of dalteparin is administered for thromboprophylaxis in conjunction with surgery, no spinal/epidural invasion should be performed for at least 12 hours following the last dose of dalteparin and the next dose should be held until at least 12 hours after the anesthetic procedure. Alternatively, when a lower dose (2 500 IU s.c.) of dalteparin is administered, the dose can be initiated 1 to 2 hours prior to surgery. Dalteparin injection should be given after spinal/epidural anesthesia and only if the anesthesiologist considers the spinal/epidural puncture as uncomplicated. If a second dose is required on the same day (for general surgery associated with other risk factors and elective hip surgery), it should be administered 8 to 12 hours after the surgery. Indwelling catheters should not be removed or manipulated for at least 10 to 12 hours following the last dose of dalteparin.

Dalteparin dosage should be carefully monitored in patients with severely impaired renal function. The main route of elimination is via the kidney. In clinical trials with patients with impaired renal function, the T1/2 for anti-Xa activity was 6.3 to 7 hours, much longer than for healthy volunteers.

Except under special circumstances, dalteparin should not be used when abortion is imminent or threatened. It may be used in such cases only when, in the opinion of the physician, the increased risk of bleeding is outweighed by the risk of thrombosis and thromboembolism.

Pregnancy and Lactation: Clinical experience of use in pregnant women is limited. No increased incidence of fetal damage has been detected in animal experiments.

The 25 000 IU/mL multidose vial containing benzyl alcohol is not recommended to be used during pregnancy. Benzyl alcohol may cross the placenta.

No information is available as to whether dalteparin passes into breast milk. Mothers receiving dalteparin should avoid breast-feeding.

Children: To date there are no trials in children to support the use of dalteparin. The benefits of treatment should, therefore, be weighed against the risks.

Use in Knee Surgery: The risk of bleeding in knee surgery patients receiving low molecular weight heparins may be greater than in other orthopedic surgical procedures. It should be noted that hemarthrosis is a serious complication of knee surgery. The frequency of bleeding events observed with dalteparin in orthopedic surgery patients is derived from clinical trials in hip replacement surgery patients. The physician should weigh the potential risks with the potential benefits to the patient in determining whether to administer a low molecular weight heparin in this patient population.

Use in Unstable Coronary Artery Disease: When thrombolytic treatment is considered appropriate in patients with unstable angina and non-Q-wave myocardial infarction, concomitant use of an anticoagulant such as dalteparin may increase the risk of bleeding.

Precautions: Dalteparin cannot be used interchangeably (unit for unit) with unfractionated heparin (UFH) or other low molecular weight heparins (LMWHs) as they differ in their manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosages. Special attention and compliance with instructions for use of each specific product is required during any change in treatment.

Biochemical Monitoring: Dalteparin has only a moderate prolonging effect on clotting time assays such as APTT or thrombin time. For laboratory monitoring of effect, anti-Xa methods are recommended. Prolongation of APTT during hemodialysis and treatment of acute deep venous thrombosis should only be used as a criterion of overdose. Dose increases aimed at prolonging APTT could cause overdosing and bleeding.

When dalteparin is administered s.c., the individual patient's antifactor Xa activity level will not remain within the range that would be expected with unfractionated heparin by continuous i.v. infusion throughout the entire dosing interval. The peak plasma antifactor Xa level occurs approximately 4 hours after s.c. administration (see Table I). For the twice daily dosing regimen (100 IU/kg/12 hours), the steady state level is attained after 2 to 4 injections (24 to 48 hours). Dalteparin should be administered as directed in the Dosage section.

Patient Monitoring: As with all antithrombotic agents, there is a risk of systemic bleeding with dalteparin administration.

Care should be taken with dalteparin use in high dose treatment of newly operated patients. After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain and periodic measurements of hemoglobin, and antifactor Xa determinations. Bleeding complications may be considered major if hemoglobin is decreased by 2 g/dL or if a transfusion of 2 or more units has been required.

With normal prophylactic doses, dalteparin does not modify global clotting tests of activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin clotting time (TT). Therefore, treatment can not be monitored with these tests.

Platelets: Platelet counts should be determined prior to the start of treatment with dalteparin and, subsequently, twice weekly for the duration of treatment.

Caution is recommended when administering dalteparin to patients with congenital or drug induced thrombocytopenia, or platelet defects.

In patients who have a history of heparin-induced thrombocytopenia (HIT), the risk of this occurrence for the individual patient in response to the low molecular weight heparins cannot be estimated, but would be expected to be increased relative to the general populations (see also Contraindications).

Prior to instituting dalteparin, an in vitro test for antiplatelet antibody in presence of dalteparin for instance, a platelet aggregation test should be performed. There are limitations to this test. It may, nevertheless, be used as a guide. A positive result contraindicates dalteparin. With a negative result, treatment with dalteparin may be instituted, but patients must be monitored with particular care to include platelet counts at least once daily.

During dalteparin administration, special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100 000/µL). A positive or unknown result of in vitro tests for antiplatelet antibody in the presence of dalteparin or other low molecular weight heparins and/or heparins would contraindicate dalteparin.

Hemodialysis: Patients undergoing chronic hemodialysis with dalteparin normally require only a few dose adjustments and therefore only occasional monitoring of anti-Xa levels is required. Patients undergoing acute hemodialysis have a narrower therapeutic interval and should be subjected to comprehensive monitoring of anti-Xa levels.

Selection of General Surgery Patients: Risk factors associated with postoperative venous thromboembolism following general surgery include history of venous thromboembolism, varicose veins, obesity, heart failure, malignancy, previous long bone fracture of a lower limb, bed rest for more than 5 days prior to surgery, predicted duration of surgery of more than 30 minutes, age 60 years or above.

Cardiovascular: See also Warnings and Contraindications.

Geriatrics: Age is highly correlated to thrombosis risk and as the proportion of patients aged over 65 is high in the dalteparin documentation, there is a large body of clinical experience in the treatment of elderly patients. No dose reduction or increased bleeding has been noted in the clinical studies with dalteparin with respect to elderly patients.

Drug Interactions: As dalteparin can cause a rise in liver transaminases, this should be considered when liver function tests are assessed.

Concomitant medication with effect on hemostasis, such as ASA, NSAIDs, vitamin-K antagonists and dextran may enhance the anticoagulant effect of dalteparin. However, unless specifically contraindicated, patients with UCAD (unstable angina and non-Q-wave myocardial infarction) should receive ASA.

For information concerning the antidote in cases of excess, see Overdose: Symptoms and Treatment.

Adverse Reactions: Bleeding: Injection site hematomas are a common side effect with heparin. These occurred less often with dalteparin in the clinical trials, and are of minor clinical importance but are still the most common side effect of the drug, occurring at a frequency of about 5% with lower (prophylaxis) doses to less than 10% with higher (treatment) doses.

Other bleeding side effects are rare. In the clinical trials with dalteparin, bleeding occurred at low frequency which did not differ from that for heparin overall. Dalteparin patients with altered APTT values are at bleeding risk, indicating a plasma anti-Xa activity of about 2 U/mL. Other risk factors associated with bleeding for heparin are: a serious concurrent illness, chronic heavy consumption of alcohol, use of platelet inhibiting drugs, renal failure, age and female sex. These risk factors should be expected to apply for dalteparin, too. Bleeding may range from minor local hematomas to major hemorrhagic events. Often the first sign of bleeding may be epistaxis, hematuria, or melena. Bleeding may be from any site and may be difficult to detect, i.e., retroperitoneal bleeds. Bleeding may also occur from surgical sites. Petechiae or easy bruising may precede frank hemorrhage.

Skeletal: A similar weak osteopenic effect was observed for dalteparin and heparin in a 6-month dog study. Since this symptom has been reported as an adverse effect after long-term treatment with heparin in high doses, the risk of osteoporosis cannot be ruled out. Caution should be used for patients on long-term therapy.

Liver: Transient slight to moderate elevation of liver transaminases (AST, ALT) has been observed for dalteparin. This observation has not been correlated to any long-term effect on liver function.

Hypersensitivity: Mild, nonimmunological thrombocytopenia is common but usually reversible during treatment. Skin necrosis and allergic reactions are rare. Dalteparin therapy should be discontinued in patients showing local or systemic allergic responses. Few cases of anaphylactoid reactions have been observed, as well as a few cases of the severe immunologically mediated thrombocytopenia associated with arterial and/or venous thrombosis or thromboembolism.

Lipid Metabolism: Increases in lipolytic activity and lipoprotein lipase can be expected during dalteparin therapy, although lipid metabolism is disturbed to a much greater extent by heparin than by dalteparin.

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 dalteparin is usually sufficient. Dalteparin should be discontinued in cases of major bleeding. Protamine sulfate may be administered in more serious cases with special caution.

The anticoagulant effect induced by dalteparin is inhibited by protamine. Prolongation of the coagulation time can be neutralized by protamine. Anti-Xa is neutralized by protamine to about 25 to 50%.

One mg protamine inhibits the effect of 100 anti-Xa international units of dalteparin sodium. Please refer to the product monograph for protamine sulfate injection for dosage and directions.

One mg protamine inhibits the effect of 100 anti-Xa international units of dalteparin.

Dosage And Administration: Dalteparin may be given by s.c. injection or by intermittent or continuous i.v. infusion, depending upon the circumstances. Because of the long half-life, high bioavailability, low incidence of side effects, and ease of administration of dalteparin, s.c. administration may be the route of choice.

Thromboprophylaxis in Conjunction with Surgery: The dose required for adequate prophylaxis without increased bleeding varies depending on the risk factors involved.

General Surgery with Associated Risk of Thromboembolic Complications: 2 500 IU administered s.c. 1 to 2 hours before the operation, and thereafter 2 500 IU s.c. each morning until the patient is mobilized, in general 5 to 7 days or longer.

General Surgery Associated with Other Risk Factors and Elective Hip Surgery: 5 000 IU is given s.c. the evening before the operation and 5 000 IU s.c. the following evenings. Treatment is continued until the patient is mobilized, in general 5 to 7 days or longer. As an alternative 2 500 IU is given s.c. 1 to 2 hours before operation and 2 500 IU s.c. 8 to 12 hours later. On the following days 5 000 IU is given s.c. each morning.

Treatment of Acute Deep Venous Thrombosis: The following dosage is recommended: 200 IU/kg body weight given s.c. once daily. The expected plasma anti-Xa levels during s.c. treatment would be <0.3 IU anti-Xa/mL before injection and <1.7 IU anti-Xa/mL 3 to 4 hours after injection. In order to individualize the dose, a functional anti-Xa assay should be performed 3 to 4 hours post-injection. The single daily dose should not exceed 18 000 IU.

For patients with increased risk of bleeding, a dose of 100 IU/kg body weight given s.c. twice daily or 100 lU/kg body weight administered over a period of 12 hours as continuous i.v. infusion, can be used. The expected plasma anti-Xa levels during s.c. treatment would be >0.1 IU anti-Xa/mL before injection and <1.0 IU anti-Xa/mL 3 to 4 hours after injection.

Normally concomitant treatment with vitamin-K antagonists is started immediately. Treatment with dalteparin should be continued until the levels of the prothrombin complex factors (FII, FVII, FIX, FX) have decreased to a therapeutic level, in general for approximately 5 days.

Unstable Coronary Artery Disease (Unstable Angina and Non-Q-Wave Myocardial Infarction): 120 IU/kg body weight given s.c. twice daily with a maximum dose of 10 000 IU/12 hours. The expected plasma anti-Xa levels during s.c. treatment would be >0.1 IU anti-Xa/mL before injection and <1.6 IU anti-Xa/mL 3 to 4 hours after injection. These levels were obtained from another patient population. Treatment should be continued for up to 6 days. Concomitant therapy with ASA is recommended.

Anticoagulation for Hemodialysis and Hemofiltration: Chronic Renal Failure, Patients with No Known Bleeding Risk: Hemodialysis and hemofiltration for a maximum of 4 hours. Dose as below or only i.v. bolus injection of 5 000 IU. Hemodialysis and hemofiltration for more than 4 hours: i.v. bolus injection of 30 to 40 IU/kg body weight followed by i.v. infusion of 10 to 15 IU/kg body weight per hour. This dose normally produces plasma levels lying within the range of 0.5 to 1.0 IU anti-Xa/mL.

Acute Renal Failure, Patients with High Bleeding Risk: I.V. bolus injection of 5 to 10 IU/kg body weight, followed by i.v. infusion of 4 to 5 IU/kg body weight per hour. Plasma level should lie within the range of 0.2 to 0.4 IU anti-Xa/mL.

Dilution: Dalteparin solution for injection may be mixed with isotonic sodium chloride and isotonic glucose infusion solutions in glass infusion bottles and plastic containers. Post-dilution concentration: 20 IU/mL. See Table II.

As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitation, discoloration and leakage prior to administration, whenever solution and container permit.

The infusion rate is 10 mL/hour. The solution should be used within 24 hours.



Availability And Storage: Potency is described in International anti-Xa units (IU). One unit (anti-Xa) of dalteparin sodium, average molecular weight 5 000, corresponds to the activity of one unit of the 1st International Standard for Low Molecular Weight Heparin with respect to inhibition of coagulation Factor Xa in plasma utilizing the chromogenic peptide substrate S-2765 (N-a-Benzyloxycarbonyl-D-arginyl-glycyl-arginine-pNA.2HCl).

Ampuls: 2 500 IU/mL: Each mL of solution for injection contains: dalteparin sodium 2 500 IU (anti-Xa). Nonmedicinal ingredients: hydrochloric acid, sodium chloride, sodium hydroxide and water for injection. Packages of 10“4 mL ampuls.

10 000 IU/mL: Each mL of solution for injection contains: dalteparin sodium 10 000 IU (anti-Xa). Nonmedicinal ingredients: hydrochloric acid, sodium chloride, sodium hydroxide and water for injection. Packages of 10“1 mL ampuls.

Prefilled Syringes: 2 500 IU: Each single dose syringe contains: dalteparin sodium 2 500 IU (anti-Xa). Nonmedicinal ingredients: hydrochloric acid, sodium chloride, sodium hydroxide and water for injection. Prefilled syringes of 0.2 mL, packages of 10.

5 000 IU: Each single dose syringe contains: dalteparin sodium 5 000 IU (anti-Xa). Nonmedicinal ingredients: hydrochloric acid, sodium chloride, sodium hydroxide and water for injection. Prefilled syringes of 0.2 mL, packages of 10.

Vials: Each mL of solution for injection contains: dalteparin sodium 25 000 IU (anti-Xa). Nonmedicinal ingredients: benzyl alcohol, hydrochloric acid, sodium chloride, sodium hydroxide and water for injection. Multidose vials of 3.8 mL.

Store at room temperature (15 to 30°C). The 25 000 IU/mL multidose vial must be used within 2 weeks after initial penetration.