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Dalteparin Sodium (Fragmin): Drug Monograph

    Brand Names
    • Fragmin
    Drug Class
    • Low molecular weight heparin
    Indications
    • Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction
    • Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery or medical patients with severely restricted mobility during acute illness
    • Extended treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in patients with cancer.
    • Limitations of use:  not indicated for the acute treatment of VTE.
    Dosing

    (Adult):

    General Notes: Dalteparin sodium is administered by subcutaneous (Sub-Q) injection.  It must not be administered by intramuscular injection.

    • DVT prophylaxis in abdominal surgery
      • 2500 IU Sub-Q once daily or 5000 IU Sub-Q once daily or 2500 IU Sub-Q followed by 2500 IU Sub-Q 12 hours later and then 5000 IU Sub-Q once daily x 5-10 days postoperatively.
    • DVT prophylaxis in total hip replacement surgery:
      • Preoperative start - day of surgery:  2500 IU Sub-Q 2 hours before surgery followed by 2500 IU Sub-Q 4 to 8 hours after surgery, then 5000 IU Sub-Q once daily.
      • Preoperative start - evening before surgery:  5000 IU Sub-Q 10-14 hours before surgery starts, followed by 5000 IU Sub-Q 4 to 8 hours after surgery.
      • Postoperatively:  start - 2500 IU Sub-Q 4 to 8 hours after surgery, then 5000 IU Sub-Q once daily.
    • Extended treatment of VTE in patients with cancer:
      • Month 1:  200 IU/kg Sub-Q once daily (to max dose of 18,000 IU) x 30 days.
      • Months 2-6:  150 IU/kg Sub-Q once daily (to max dose of 18,000). 
      • Note:
        • Monitor platelet counts as risk for heparin-induced thrombocytopenia (HIT) increases with dose and duration of use.
    • Unstable angina and non-Q-wave MI
      • 120 IU/kg subcutaneous (to max dose of 10,000 IU) every 12 hours along with aspirin therapy (75-165 mg every day) until clinically stabilized, usually for 5-8 days.

    (Pediatrics):

    • None
    Renal Dosing
    • For cancer patients being treated for VTE and whose CrCl <30 mL/min: 
      • Consider monitoring anti-Xa levels to determine the appropriate dose.
      • Target anti-Xa range is 0.5-1.5 IU/mL.
      • Perform sampling 4-6 hours after dosing and only after the patient has received 3-4 doses.
    Hepatic Dosing
    • None
    Dosage Forms
    • Single-dose prefilled syringe:  2,500 IU/0.2mL, 5,000 IU/0.2mL, 7500 IU/0.3mL, 10,000 IU/0.4 mL, 12,500 IU/0.5mL, 15,000 IU/0.6mL, 18,000 IU/0.72mL.
    • Single-dose graduated syringe:  10,000 IU/1mL.
    • Multiple dose vial: 95,000/3.8mL
    Black Box Warnings
    • Epidural or spinal hematomas.  May result in long-term or permanent paralysis.  Consider these risks. 
    • Factors that can increase the risk of developing epidural or spinal hematomas include:  use of indwelling epidural catheters; concomitant use of other drugs that affect hemostatis, such as NSAIDs, platelet inhibitors, and other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery.
    • Monitor patients frequently for signs and symptoms of neurological impairment.
    Contraindications
    • Active major bleeding
    • History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis
    • Hypersensitivity to dalteparin sodium
    • In patients undergoing Epidural/Neuraxial anesthesia, do not administer dalteparin sodium:
    • As a treatment for unstable angina and non-Q-wave MI
    • For prolonged VTE prophylaxis
    • Hypersensitivity to heparin or pork products
    Warnings
    • Use caution in conditions with increased risk of hemorrhage
    • Monitor thrombocytopenia of any degree closely, especially with longer use
    • Multiple-dose formulations contain benzyl alcohol
    • Periodic blood counts recommended
    Adverse Reactions
    • Hematoma at the injection site
    • Risk for bleeding varies with the indication and may increase with higher doses
    • Thrombocytopenia
    • Elevations of serum transaminases
    Overdose
    • Overdose may lead to hemorrhagic complications.
    • Complications may generally be stopped by slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of dalteparin sodium given.
    • Take particular care to avoid overdosage with protamine sulfate.
    Antidote
    • Protamine sulfate (1% solution), though may not be as effective at neutralizing all of the dalteparin since some of the medication is still in the subcutaneous tissue.
    Drug Interactions
    • Use dalteparin sodium with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents.
    Special Populations
    • Pregnancy: Pregnancy Category B
    • Labor and Delivery: None
    • Nursing Mothers: Dalteparin is minimally excreted in human milk.  Clinical implications, if any, of a small amount of anticoagulant activity on a nursing infant are unknown. 
    • Renal Impairment: CrCl <30 mL/min;  monitor anti-Xa levels to determine the appropriate dose.
    • Hepatic Impairment: None
    • Pediatric Patients: Safety and effectiveness in pediatric patients have not been established.
    • Geriatric Patients: No overall differences in effectiveness observed between older subjects and younger subjects.  Give careful attention to dosing intervals and concomitant medications in geriatric patients, particularly in those with low body weight and those predisposed to decreased renal function.
    Pregnancy Rating
    • Category B
    Breastfeeding
    • Dalteparin is minimally excreted in human milk.  Clinical implications, if any, of a small amount of anticoagulant activity on a nursing infant are unknown.
    Chemical Structure
    • Scientific Name:  Strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups).
    • Molecular Weight:  Average molecular weight of 5000; about 90% of the material within the range 2000-9000.  Molecular weight distribution is:
      • <3000 daltons                             3.0-15%
      • 3000 to 8000 daltons             65.0-78.0%
      • >8000 daltons                    14.0-26.0%
    Mechanism of Action
    • Dalteparin is a low molecular weight heparin with antithrombotic properties.
    • It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin.
    • In humans, dalteparin potentiates preferentially the inhibition of coagulation Factor Xa, while only slightly affecting the activated partial thromboplastin time (APTT).
    Pharmacodynamics
    • Doses of dalteparin injection of up to 10,000 anti-Factor Xa IU administered subcutaneously as a single dose or two 5000 IU doses 12 hours apart to healthy subjects did not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT), or APTT.
    • Subcutaneous administration of doses of 5000 IU twice daily for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.
    Pharmacokinetics
    • Absorption:
      • Mean peak levels of plasma anti-Factor Xa activity following single subcutaneous doses of 2500, 5000, and 10,000 IU were attained in about 4 hours in most subjects.
      • Absolute bioavailability in healthy volunteers, measured as the anti-Factor Xa activity, was 87 ± 6%.  Increasing the dose from 2500 to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was greater than proportional by about one-third.
      • Peak anti-Factor Xa activity increased more of less linearly with dose over the same dose range.  There appeared to be no appreciable accumulation of anti-Factor Xa activity with twice daily dosing of 100 IU/kg subcutaneously for up to 7 days.
      • The mean disposition half-lives were 1.47 ± 0.3 and 2.5 ± 0.3 hours.
      • Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively.  Longer apparent terminal half-lives (3 to 5 hours) are observed following subcutaneous dosing, possible due to delayed absorption.
    • Distribution: The volume of distribution is ~ 40 to 60 mL/kg.
    • Metabolism:  None
    • Elimination:  Renally
      • In patients with chronic renal insufficiency requiring hemodialysis, the mean terminal half-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU dalteparin was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers; therefore, greater accumulation can be expected in these patients
    Pharmacogenetics
    • None
    Counseling Points
    • Inform patients of the instructions for injecting dalteparin sodium if their therapy is to continue after discharge  from the hospitals.
    • Inform patients that it may take them longer than usual to stop bleeding.
    • Inform patients that they may bruise and/or bleed more easily when they are treated with dalteparin sodium. They should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician.
    • Inform patients to tell their physicians and dentists they are taking dalteparin sodium and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.
    • Inform patients to tell their physicians and dentists of all medications they are taking, including those obtained with a prescription, such as aspirin or other NSAIDs.
    • If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants inform the patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur, the patient should contact his or her physician immediately.
    • Inform patients that the use of aspirin and other NSAIDs may enhance the risk of hemorrhage.  Discontinue their use prior to dalteparin therapy whenever possible.  If co-administration is essential, the patient's clinical and laboratory status should be closely monitored.
    References
    • Dalteparin sodium (Fragmin).  Product Insert.  Eisai Inc.  Woodcliff Lake, NJ.  2010.

MESH Terms & Keywords

  • Dalteparin Sodium, Fragmin, Low Molecular Weight, Heparin