Dalteparin

Pronunciation

(dal TE pa rin)

U.S. Brand Names

Fragmin®

Generic Available

Canadian Brand Names

Fragmin®

Use

Prevention of deep vein thrombosis which may lead to pulmonary embolism, in patients requiring abdominal surgery who are at risk for thromboembolism complications (eg, patients >40 years of age, obesity, patients with malignancy, history of deep vein thrombosis or pulmonary embolism, and surgical procedures requiring general anesthesia and lasting >30 minutes); prevention of DVT in patients undergoing hip-replacement surgery; patients immobile during an acute illness; acute treatment of unstable angina or non-Q-wave myocardial infarction; prevention of ischemic complications in patients on concurrent aspirin therapy

Use - Unlabeled/Investigational

Active treatment of deep vein thrombosis

Pregnancy Risk Factor

Pregnancy Implications

Multiple-dose vials contain benzyl alcohol (avoid in pregnant women due to association with fetal syndrome in premature infants).

Lactation

Excretion in breast milk unknown/use caution

Contraindications

Hypersensitivity to dalteparin or any component of the formulation; thrombocytopenia associated with a positive in vitro test for antiplatelet antibodies in the presence of dalteparin; hypersensitivity to heparin or pork products; patients with active major bleeding; patients with unstable angina or non-Q-wave MI undergoing regional anesthesia; not for I.M. or I.V. use

Warnings/Precautions

Patients with recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) are at risk of spinal or epidural hematoma and subsequent paralysis. Consider risk versus benefit prior to neuraxial anesthesia. Risk is increased by concomitant agents which may alter hemostasis, as well as traumatic or repeated epidural or spinal puncture. Patient should be observed closely for bleeding if dalteparin is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia.

Not to be used interchangeably (unit for unit) with heparin or any other low molecular weight heparins. Use with caution in patients with known hypersensitivity to methylparaben or propylparaben. Use with caution in patients with history of heparin-induced thrombocytopenia. Monitor platelet count closely. Rare thrombocytopenia may occur. Consider discontinuation of dalteparin in any patient developing significant thrombocytopenia. Monitor patient closely for signs or symptoms of bleeding. Certain patients are at increased risk of bleeding. Risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; or use shortly after brain, spinal, or ophthalmology surgery; in patient treated concomitantly with platelet inhibitors; recent GI bleeding; thrombocytopenia or platelet defects; severe liver disease; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures.

Use with caution in patients with severe renal failure (has not been studied). Safety and efficacy in pediatric patients have not been established. Rare cases of thrombocytopenia with thrombosis have occurred. Multidose vials contain benzyl alcohol and should not be used in pregnant women. Heparin can cause hyperkalemia by affecting aldosterone. Similar reactions could occur with LMWHs. Monitor for hyperkalemia.

Adverse Reactions

1% to 10%:

Hematologic: Bleeding (3% to 5%), wound hematoma (0.1% to 3%)

Local: Pain at injection site (up to 12%), injection site hematoma (0.2% to 7%)

<1% (Limited to important or life-threatening): Thrombocytopenia (including heparin-induced thrombocytopenia), allergic reaction (fever, pruritus, rash, injections site reaction, bullous eruption), anaphylactoid reaction, operative site bleeding, gastrointestinal bleeding, skin necrosis. Spinal or epidural hematomas can occur following neuraxial anesthesia or spinal puncture, resulting in paralysis. Risk is increased in patients with indwelling epidural catheters or concomitant use of other drugs affecting hemostasis.

Drug Interactions

Drugs which affect platelet function (eg, aspirin, NSAIDs, dipyridamole, ticlopidine, clopidogrel) may potentiate the risk of hemorrhage.

Thrombolytic agents increase the risk of hemorrhage.

Warfarin: Risk of bleeding may be increased during concurrent therapy. Dalteparin is commonly continued during the initiation of warfarin therapy to assure anticoagulation and to protect against possible transient hypercoagulability.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, garlic, ginseng (all have additional antiplatelet activity).

Stability

Store at temperatures 20°C to 25°C (68°F to 77°F).

Mechanism of Action

Low molecular weight heparin analog with a molecular weight of 4000-6000 daltons; the commercial product contains 3% to 15% heparin with a molecular weight <3000 daltons, 65% to 78% with a molecular weight of 3000-8000 daltons and 14% to 26% with a molecular weight >8000 daltons; while dalteparin has been shown to inhibit both factor Xa and factor IIa (thrombin), the antithrombotic effect of dalteparin is characterized by a higher ratio of antifactor Xa to antifactor IIa activity (ratio = 4)

Pharmacodynamics/Kinetics

Onset of action: 1-2 hours

Duration: >12 hours

Half-life elimination (route dependent): 2-5 hours

Time to peak, serum: 4 hours

Dosage

Adults: SubQ:

Abdominal surgery:

Low-to-moderate DVT risk: 2500 int. units 1-2 hours prior to surgery, then once daily for 5-10 days postoperatively

High DVT risk: 5000 int. units 1-2 hours prior to surgery and then once daily for 5-10 days postoperatively

Patients undergoing total hip surgery: Note: Three treatment options are currently available. Dose is given for 5-10 days, although up to 14 days of treatment have been tolerated in clinical trials:

Postoperative start:

Initial: 2500 int. units 4-8 hours * after surgery

Maintenance: 5000 int. units once daily; start at least 6 hours after postsurgical dose

Preoperative (starting day of surgery):

Initial: 2500 int. units within 2 hours before surgery

Adjustment: 2500 int. units 4-8 hours * after surgery

Maintenance: 5000 int. units once daily; start at least 6 hours after postsurgical dose

Preoperative (starting evening prior to surgery):

Initial: 5000 int. units 10-14 hours before surgery

Adjustment: 5000 int. units 4-8 hours * after surgery

Maintenance: 5000 int. units once daily, allowing 24 hours between doses.

*Dose may be delayed if hemostasis is not yet achieved.

Unstable angina or non-Q-wave myocardial infarction: 120 int. units/kg body weight (maximum dose: 10,000 int. units) every 12 hours for 5-8 days with concurrent aspirin therapy. Discontinue dalteparin once patient is clinically stable.

Immobility during acute illness: 5000 int. units once daily

Dosing adjustment in renal impairment: Half-life is increased in patients with chronic renal failure, use with caution, accumulation can be expected; specific dosage adjustments have not been recommended

Dosing adjustment in hepatic impairment: Use with caution in patients with hepatic insufficiency; specific dosage adjustments have not been recommended

Administration

For deep SubQ injection only. May be injected in a U-shape to the area surrounding the navel, the upper outer side of the thigh, or the upper outer quadrangle of the buttock. Apply pressure to injection site; do not massage. Use thumb and forefinger to lift a fold of skin when injecting dalteparin to the navel area or thigh. Insert needle at a 45- to 90-degree angle. The entire length of needle should be inserted. Do not expel air bubble from fixed-dose syringe prior to injection. Air bubble (and extra solution, if applicable) may be expelled from graduated syringes.

Administration once daily beginning prior to surgery and continuing 5-10 days after surgery prevents deep vein thrombosis in patients at risk for thromboembolic complications. For unstable angina or non-Q-wave myocardial infarction, dalteparin is administered every 12 hours until the patient is stable (5-8 days).

Monitoring Parameters

Periodic CBC including platelet count; stool occult blood tests; monitoring of PT and PTT is not necessary

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug can only be administered by injection. You may have a tendency to bleed easily while taking this drug (brush teeth with soft brush, use waxed dental floss, use electric razor, avoid scissors or sharp knives and potentially harmful activities). Report unusual fever; unusual bleeding or bruising (bleeding gums, nosebleed, blood in urine, dark stool); pain in joints or back; severe head pain; skin rash; or redness, swelling, or pain at injection site. Breast-feeding precaution: Consult prescriber if breast-feeding.

Additional Information

Multidose vial contains 14 mg/mL benzyl alcohol.

Anesthesia and Critical Care Concerns/Other Considerations

Many critically-ill and surgery patients require preventive measures for venous thromboembolism. LMWHs compare favorably to unfractionated heparin in the prevention and treatment of venous thromboembolism. LMWHs are associated with less thrombocytopenia, compared to heparin, and do not require routine therapeutic monitoring.

Obesity/Renal Dysfunction: There is no consensus for adjusting/correcting the weight-based dosage of LMWH for patients who are morbidly obese. Monitoring of antifactor Xa concentration 4 hours after injection may be warranted. Patients who have a reduction in calculated creatinine clearance are at risk of accumulated anticoagulant effect when they are treated with certain LMWHs. All LMWHs may not behave the same in patients with renal dysfunction. Some clinicians monitor anti-Xa levels for patients with Clcr<30 mL/minute.

Cardiovascular Considerations

Low molecular weight heparins (LMWHs) compare favorably to unfractionated heparin (UFH) in the prevention and treatment of venous thromboembolism. LMWHs are associated with less thrombocytopenia, compared to heparin, and do not require routine therapeutic monitoring. In patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI), the 2002 ACC/AHA guidelines recommend anticoagulation with subcutaneous LMWH or intravenous UFH be added to antiplatelet therapy with aspirin and/or clopidogrel. Enoxaparin is preferable to UFH as an anticoagulant unless CABG is planned within 24 hours (Class IIa recommendation; level of evidence: A). In patients with ST-segment elevation myocardial infarction, most studies are limited to small numbers of patients treated with dalteparin or enoxaparin. Control groups (placebo, UFH), dosing, primary endpoints (composite ones), and bleeding definitions vary. In general, the studies suggest equivalent or superior outcomes with these LMWHs and less major bleeding. Preliminary results of a larger trial comparing prehospital dosing of enoxaparin (30 mg I.V. bolus; 1 mg/kg SubQ twice daily for a maximum of 7 days) versus UFH in patients receiving tenecteplase suggests a higher incidence of major bleeding and intracranial hemorrhage in the enoxaparin group (Wallentin L, 2002). Almost all cases of intracranial hemorrhage were confined to patients >75 years of age. Another ongoing trial will address this safety issue.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

None reported

Dosage Forms

Injection, solution [multidose vial]: Antifactor Xa 10,000 int. units per 1 mL (9.5 mL) [contains benzyl alcohol]; antifactor Xa 25,000 units per 1 mL (3.8 mL) [contains benzyl alcohol]

Injection, solution [preservative free; prefilled syringe]: Antifactor Xa 2500 int. units per 0.2 mL (0.2 mL); antifactor Xa 5000 int. units per 0.2 mL (0.2 mL); antifactor Xa 7500 int. units per 0.3 mL (0.3 mL); antifactor Xa 10,000 int. units per 1 mL (1 mL)

References

Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)," J Am Coll Cardiol , 2002, 40(7):1366-74. Available at: http://www.acc.org/clinical/guidelines/unstable/incorporated/index.htm. Accessed May 20, 2003.

Frostfeldt G, Ahlberg G, Gustafsson G, et al, "Low Molecular Weight Heparin (Dalteparin) as Adjunctive Treatment of Thrombolysis in Acute Myocardial Infarction - A Pilot Study: Biochemical Markers in Acute Coronary Syndromes (BIOMACS II), J Am Coll Cardiol , 1999, 33(3):627-33.

"Invasive Compared With Noninvasive Treatment in Unstable Coronary-Artery Disease: FRISC II Prospective Randomised Multicentre Study. Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease Investigators," Lancet , 1999, 354(9180):708-15.

Klein W, Buchwald A, Hillis SE, et al, "Comparison of Low Molecular-Weight Heparin With Unfractionated Heparin Acutely and With Placebo for 6 Weeks in the Management of Unstable Coronary Artery Disease. Fragmin in Unstable Coronary Artery Disease Study," Circulation , 1997, 96(1):61-8.

Kontny F, Dale, J Abildgaard U, et al, "Randomized Trial of Low Molecular Weight Heparin (Dalteparin) in Prevention of Left Ventricular Thrombus Formation and Arterial Embolism After Acute Anterior Myocardial Infarction: The Fragmin in Acute Myocardial Infarction (FRAMI) Study," J Am Coll Cardiol , 1997, 30(4):962-9.

Long-Term Low-Molecular-Mass Heparin in Unstable Coronary-Artery Disease: FRISC II Prospective Randomised Multicentre Study. Fragmin and Fast Revascularization During Instability in Coronary Artery Disease Investigators," Lancet , 1999, 354(9180):701-7.

"Low-Molecular-Weight Heparin During Instability in Coronary Artery Disease, Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group," Lancet , 1996, 347(9001):561-8.

Nagge J, Crowther M, and Hirsh J, "Is Impaired Renal Function a Contraindication to the Use of Low-Molecular Weight Heparin?" Arch Intern Med , 2002, 162(22):2605-9.

Wallentin L, "ASSENT 3 PLUS," [Paper presented at] American Heart Association 75th Scientific Sessions, November 17-20, 2002; Chicago, Ill.

Wong GC, Giugliano RP, and Antman EM, "Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention," JAMA , 2003, 289(3):331-42.

Zed PJ, Tisdale JE, and Borzak S, "Low-Molecular-Weight Heparins in the Management of Acute Coronary Syndromes," Arch Intern Med , 1999, 159(16):1849-57.

International Brand Names

Boxol® (ES); Fragmin® (AT, AU, BE, BG, CA, CH, CL, CO, CZ, DE, DK, ES, FI, GB, HK, HR, HU, IL, IT, JP, LU, NL, NO, NZ, PL, PT, RO, RU, SE, SG, SI, TR, YU, ZA); Fragmine® (FR)

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