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Dalteparin (Systemic)


VA CLASSIFICATION
Primary: BL111

Commonly used brand name(s): Fragmin.

Another commonly used name is
tedelparin .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticoagulant—

antithrombotic—
Note: Dalteparin is one of a group of substances known as low molecular weight heparins (LMWHs).



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
The use of low molecular weight heparins (LMWHs) has several advantages compared to heparin. Improved bioavailability at low doses when administered subcutaneously, a longer plasma half-life, and a more predictable anticoagulant response allow for simpler dosing without laboratory monitoring {31} {45}. Studies in animals show that with doses of equivalent antithrombotic effect, LMWHs produce less bleeding than standard heparin {31} {45}. The clinical importance of this observation is uncertain, but may allow the use of higher anticoagulant doses of LMWHs, thereby improving efficacy without compromising safety {31} {45}. The potential advantage of reduced bleeding has been demonstrated in studies in patients receiving high doses for the treatment of venous thrombosis {31} {45} {54} {55}. However, in studies using prophylactic doses, no difference in bleeding has been demonstrated {31} {45} {56} {57}. This contrasting effect may be due to inappropriate dosage regimens in early studies, and the difficulty of measuring hemorrhagic tendencies in humans {19}. LMWHs are associated with a lower incidence of heparin-induced thrombocytopenia, possibly due to reduced effects on platelet function and binding {31} {45} {68}. These advantages must be weighed against the higher cost of the LMWHs, although the simpler dosing regimens used with LMWHs may allow home treatment in selected patients, thereby reducing overall costs and improving patient satisfaction {31} {42} {43} {44}.

Meta-analyses of randomized, controlled trials comparing various LMWHs to unfractionated heparin in the treatment of deep venous thrombosis (DVT) have shown a trend toward greater efficacy, fewer major hemorrhages, and reduced total mortality with the use of LMWHs {45} {46} {47}.

Unfractionated heparin is routinely used during hemodialysis to prevent thrombosis in the extracorporeal system {17} {22}. However, increased risks of bleeding and, with long-term use, complications such as osteoporosis and altered lipid metabolism make it a less-than-ideal agent for this purpose {17} {21} {22}. Dalteparin may have a lower risk of osteoporosis and a reduced stimulation of lipolytic activity, making it an advantageous alternative to heparin in this setting {24} {38} {41}.

Accepted

Angina pectoris, unstable (treatment) and
Myocardial infarction, non–Q-wave (treatment)—Dalteparin is indicated for the treatment of unstable angina pectoris and non–Q-wave myocardial infarction for the prevention of ischemic complications in patients on concurrent aspirin therapy{01}.

Thromboembolism, pulmonary (prophylaxis); and
Thrombosis, deep venous (prophylaxis)—Dalteparin is indicated for prevention of deep venous thrombosis (DVT), which may lead to pulmonary embolism, in patients undergoing abdominal or hip surgery who are at risk for thromboembolic complications {01} {02} {03} {04} {05} {06} {07} {08} {09} {10}{81}.
—Patients at risk include patients who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes, or patients who have additional risk factors such as malignancy or a history of DVT or pulmonary embolism {01}.

Note: The use of LMWHs for the above indications has received grade A recommendations (supported by the highest level of evidence) from the Fourth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy {11}. The recommendations are based on the results of studies not only with dalteparin, but with other LMWHs also.


[Thrombosis, deep venous (treatment)]—Dalteparin is used in the treatment of DVT. It has been shown to be as safe and effective as unfractionated heparin when administered subcutaneously or by continuous intravenous infusion {02} {13} {14} {15} {16}.

[Thrombosis of the extracorporeal system during hemodialysis (prophylaxis) ]—Dalteparin, given as either a single intravenous injection prior to dialysis, or as a continuous intravenous infusion during dialysis, is used to prevent thrombosis in the extracorporeal system during hemodialysis {02} {17} {18} {19} {20} {21} {22} {23}.

Acceptance not established
Low molecular weight heparins have been used to prevent venous thromboembolism in patients who have had an ischemic stroke and have lower extremity weakness {11}. Pooled data indicate that the incidence of leg DVT is 42% in these patients {11}. Dalteparin has been shown to significantly reduce the incidence of DVT when compared with placebo in one small study {12}. However, another placebo-controlled study failed to show a difference, although the dosing regimens used in the studies were not comparable {58}. The Fourth ACCP Consensus Conference on Antithrombotic Therapy considers both low-dose unfractionated heparin and LMWH effective in this setting and gives the indication a grade A recommendation {11}. The optimal prophylactic regimen for dalteparin has not yet been determined.
There have been reports of the use of dalteparin for other conditions, including:

   • long-term anticoagulant therapy following an acute DVT in patients unable to take oral anticoagulants {24};
   • prevention of venous thromboembolism following an acute anterior wall myocardial infarction {25};
   • maintaining femoropopliteal graft patency {26};
   • an alternative to unfractionated heparin in patients with heparin-induced thrombocytopenia (HIT) {27} {28};
   • treatment of disseminated intravascular coagulation {29}; and
   • treatment of proliferative glomerulonephritis {30}
These reports were either case reports or single studies; therefore, the utility of dalteparin in these situations still requires confirmation with larger follow-up studies. It should be noted that LMWHs are not indicated for the treatment of HIT because of their potential cross-reactivity with heparin, but may have utility in patients who have a negative platelet aggregation test for the selected LMWH {27} {28} {68} {69}.

In addition, the Fourth ACCP Consensus Conference on Antithrombotic Therapy has stated that LMWHs may be used to prevent venous thromboembolism in patients undergoing total knee replacement (a grade A recommendation), patients with acute spinal cord injury (a grade B recommendation, supported by the second highest level of evidence), patients with multiple trauma (a grade C recommendation, supported by the lowest levels of evidence), and in general medical patients with clinical risk factors such as congestive heart failure and/or chest infections (a grade A recommendation) {11}. However, dalteparin has not been studied in any of these conditions, and its safety and efficacy for these uses are unknown. Until studies are available, use of dalteparin in these conditions can only be determined on a case-by-case basis {11}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Obtained by nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa {01} {02}.
Molecular weight—
    90% of the material is between 2000 and 9000 daltons (average 5000 daltons) {01} {02}

Mechanism of action/Effect:

Dalteparin's antithrombotic properties are achieved by enhancing the inhibition of coagulation factor Xa and thrombin (factor IIa) by binding to antithrombin III (ATIII) {01} {31}. Unlike heparin, however, dalteparin preferentially potentiates the inhibition of coagulation factor Xa {01} {02}. It is less able to inhibit thrombin because the inactivation of thrombin requires a minimum chain length of 18 saccharides; this chain length is found in only 25 to 50% of low molecular weight heparin molecules {02} {31}. While the ratio of anti-factor Xa activity to anti-factor IIa activity for heparin is 1:1, the ratio for dalteparin is 2.2:1 {02}. Dalteparin does not significantly affect clotting tests such as prothrombin time (PT), thrombin time (TT), or activated partial thromboplastin time (APTT) {01} {02}.


Other actions/effects:

Compared to heparin, dalteparin binds less to endothelial cells {02} {31} {45}. Heparin's binding to these cells affects both lipid metabolism and platelet function {02}. Dalteparin, therefore, produces no significant changes in platelet aggregation, fibrinolysis, platelet factor 4, or lipoprotein lipase {01} {02}.

Absorption:

Approximately 90% bioavailable following subcutaneous injection, measured as anti-factor Xa activity {01} {02}.

Protein binding:

Very low (< 10%). The much lower protein binding compared to heparin contributes to dalteparin's greater bioavailability and more predictable anticoagulant response. {31} {45}

Half-life:

Elimination, apparent, based on anti-factor Xa activity—3 to 5 hours after subcutaneous administration; approximately 2 hours following intravenous injection {01} {02}. May be increased to approximately 6 to 7 hours in patients with impaired renal function {02}.

Time to peak concentration:

Approximately 4 hours following subcutaneous injection {01}.

Peak serum concentration

Dose-related. After single subcutaneous doses of 2500, 5000, and 10,000 International Units (IU), peak concentrations of plasma anti-factor Xa activity were 0.19 ± 0.04, 0.41 ± 0.07, and 0.82 ± 0.10 IU/mL, respectively. {01}

Therapeutic plasma concentration

As anti-factor Xa activity—0.2 to 1 IU/mL {02}.

Elimination:
    Renal {01} {02}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients with known hypersensitivity to heparin or to pork products may be sensitive to dalteparin also {01}.

Carcinogenicity

No long-term animal studies have been performed with dalteparin to determine its carcinogenic potential {01}.

Mutagenicity

Dalteparin was not mutagenic in the in vitro Ames test, the mouse lymphoma cell forward mutation test, the human lymphocyte chromosomal aberration test, and the in vivo mouse micronucleus test. {01}

Pregnancy/Reproduction
Fertility—
In studies of rats, subcutaneous doses up to 1200 International Units per kg of body weight (IU/kg) did not affect fertility {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

Heparin is considered to be the anticoagulant of choice during pregnancy since it does not cross the placenta {32}. There is also evidence that dalteparin does not cross the placenta {33} {34}. The advantages of dalteparin over heparin during pregnancy include the potential for once-daily administration, a lower incidence of heparin-induced thrombocytopenia, and possibly a lower risk of heparin-induced osteoporosis {32}. However, until adequate clinical studies comparing the use of dalteparin to heparin during pregnancy are performed, there is insufficient evidence to support the routine use of dalteparin {32}.

Studies in pregnant rats and rabbits given intravenous doses of dalteparin up to 2400 IU/kg and 4800 IU/kg, respectively, showed no evidence of harm to the fetus {01}.

FDA Pregnancy Category B {01}.

Note: The 25,000-IU-per-mL multi-dose vial contains benzyl alcohol, which is not recommended for use during pregnancy since benzyl alcohol may cross the placenta {02}.


Breast-feeding

It is not known whether dalteparin is distributed into breast milk. However, problems in humans have not been documented. {01} {02}

Pediatrics

No information is available on the relationship of age to the effects of dalteparin in pediatric patients. Safety and efficacy have not been established. {01}

Note: The 25,000-IU-per-mL multi-dose vial contains benzyl alcohol, which is not recommended for use in neonates.



Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of dalteparin in the elderly.

Pharmacokinetic differences requiring dose reductions have not been noted in elderly subjects. Clinical studies performed in elderly patients have not shown an increase in bleeding. {02} {35}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
In addition to the interactions listed below, the possibility should be considered that multiple effects leading to further impairment of blood clotting and/or increased risk of bleeding may occur if dalteparin is administered to a patient receiving any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage {36}.

Anticoagulants, coumarin- or indandione-derivative, or
Platelet aggregation inhibitors (see Appendix II ) such as:
» Anti-inflammatory drugs, nonsteroidal (NSAIDs)
» Aspirin
Dextran
» Ticlopidine {59}    (increased risk of bleeding must be considered)

{01}{02}
Thrombolytic agents, such as:
Alteplase (rt-PA)
Anistreplase (APSAC)
Streptokinase
Urokinase    (concurrent or sequential use may increase the risk of bleeding; however, unfractionated heparin is used concurrently with thrombolytic therapy in patients with acute myocardial infarction, and may be continued post-thrombolysis to prevent further thromboembolism; experience with the use of low molecular weight heparin in this setting is limited; careful monitoring of the patient is recommended if dalteparin is used under these circumstances)

{59}{60}{61}{74}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT])    (serum values may be increased during dalteparin therapy and are reversible; the usefulness of these enzymes in the differential diagnosis of myocardial infarction, pulmonary embolism, or liver disease may, therefore, be decreased )

{01}{02}
Free fatty acids and
Triglycerides    (initially, plasma triglyceride concentrations may decrease, with a resulting increase in plasma free fatty acids, due to stimulation of lipolytic activity by release of lipoprotein lipase from tissue sites. However, release of lipoprotein lipase is not as pronounced as that seen with heparin {37}. The subsequent increase in plasma triglyceride concentrations that is seen with long-term heparin use due to depletion of lipoprotein lipase has not been seen with dalteparin {21}. Since the increase in triglyceride concentrations is a particular problem in uremic patients who require chronic hemodialysis and the long-term use of heparin, dalteparin may be advantageous in this population due to its reduced stimulation of lipolytic activity {38})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Bleeding, major, active    (may be exacerbated)

{01}{02}
» Hypertension, severe, uncontrolled    (increased risk of cerebral hemorrhage)

{01}{02}
» Stroke, hemorrhagic or
» Stroke, ischemic, large {62}    (increased risk of uncontrollable hemorrhage; cardioembolic strokes have a risk of secondary hemorrhagic transformation, with large infarcts [i.e., deficits involving the entire middle cerebral distribution] especially prone to worsening {63}; some clinicians recommend waiting 7 days before initiating anticoagulant therapy in patients with large infarcts {64})

{01}{02}
» Thrombocytopenia associated with positive in vitro tests for antiplatelet antibody in the presence of dalteparin or
» Thrombocytopenia, dalteparin- or heparin-induced, history of    (risk of recurrence)

{01}{02}
Risk-benefit should be considered when the following medical problems exist
Any medical procedure or condition in which the risk of bleeding or hemorrhage is present, such as:
» Anesthesia, epidural or spinal
(risk of epidural or spinal hematoma, which can result in long-term or permanent paralysis; this risk is increased with the use of indwelling epidural catheters or by the concomitant use of medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs, platelet inhibitors, or other anticoagulants; the risk also may be increased by traumatic or repeated epidural or spinal puncture. See General Dosing Information for guidelines regarding the use of regional anesthesia in patients receiving perioperative dalteparin.) {01}
» Bleeding disorders, congenital or acquired {01} {02}
» Endocarditis, bacterial {01} {02}
» Hepatic function impairment, severe {01} {02}
» Platelet defects {01} {02}
» Renal function impairment, severe {01} {02}
» Retinopathy, diabetic or hypertensive {01} {02}
» Surgery, brain, ophthalmological, or spinal, recent {01} {02}
» Ulcers, other lesions, or recent bleeding of the gastrointestinal tract, active {01} {02}
Sensitivity to dalteparin or to heparin {01} {02}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Anti-factor Xa activity    (monitoring of plasma anti-factor Xa activity is considered optional {75} when dalteparin is used therapeutically, and is recommended in patients undergoing acute hemodialysis, with recommended plasma concentrations as follows: {02} {40}    • Treatment of deep venous thrombosis—

• Subcutaneous, > 0.3 International Units anti-factor Xa activity per mL (IU/mL) before injection and < 1.5 IU/mL 3 to 4 hours after injection;


• Intravenous, 0.5 to 1 IU/mL

   • Acute hemodialysis—0.2 to 0.4 IU/mL
)


Note: No special monitoring is needed when dalteparin is used prophylactically {01} {02} {40}. Routine clotting assays such as activated partial thromboplastin time (APTT), prothrombin time (PT), or thrombin time (TT) are unsuitable for monitoring dalteparin's anticoagulant activity since dalteparin does not significantly affect these tests {01} {02} {40}; increased doses intended to prolong the APTT could cause overdosing and bleeding {02}. Prolongation of the APTT should only be used as a criterion of overdose {02}.


Blood counts, complete (CBC), including:
Hematocrit
Hemoglobin
» Platelet count    (recommended prior to the initiation of therapy, then twice weekly for the duration of therapy to detect occult bleeding or any degree of thrombocytopenia )

{01}{02}
Blood pressure measurement    (recommended periodically during therapy; an unexplained drop in blood pressure may signal occult bleeding)

{01}
» Neurologic status {01}    (monitor for signs and symptoms of neurological impairment such as paresthesias, leg weakness, sensory loss, motor deficit, or bowel/bladder dysfunction, which may indicate a potential epidural or spinal hematoma {79}; if neurologic compromise is noted, urgent intervention is necessary, including radiographic confirmation and decompressive laminectomy; good or partial recovery is more likely if surgery is performed within 8 hours of the development of paraplegia {66} {79} {80})


» Platelet aggregation test    (recommended prior to the initiation of therapy in patients who have congenital, or a history of drug-induced, thrombocytopenia or platelet defects; if the result is negative, dalteparin therapy may be instituted, with daily monitoring of the platelet count; however, if the result is positive, dalteparin should not be given)

{02}
Stool tests for occult blood    (should be performed at regular intervals during therapy)

{01}


Side/Adverse Effects

Note: The occurrence of hemorrhage may be increased with higher doses {01}. Also, other risk factors may be associated with hemorrhage, including a serious concurrent illness, chronic heavy consumption of alcohol, use of platelet inhibiting drugs, renal failure, and female sex {02}.
Osteoporosis is associated with the use of long-term, high-dose heparin {31}. Dalteparin has been shown to have a weak osteopenic effect in dogs {02}. However, the effect does not appear to be as great as that seen with heparin; therefore, the risk of heparin-induced osteoporosis may be lower with dalteparin {24} {41}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hematoma at injection site (deep, dark purple bruise, pain, or swelling at place of injection){01}{02}

Incidence less frequent
    
Hemorrhage{01}{02} {52}(bleeding gums; coughing up blood; difficulty in breathing or swallowing; dizziness; headache; increased menstrual flow or vaginal bleeding; nosebleeds; paralysis; prolonged bleeding from cuts; red or dark brown urine; red or black, tarry stools; shortness of breath; unexplained pain, swelling, or discomfort, especially in the chest, abdomen, joints, or muscles; unusual bruising; vomiting of blood or coffee ground–like material; weakness)

Incidence rare
    
Allergic reaction (fever; skin rash, hives, or itching){01}{02}
    
anaphylactoid reaction (bluish discoloration, flushing, or redness of skin; coughing; difficulty in swallowing; dizziness or feeling faint, severe; skin rash, hives [may include giant urticaria], or itching; swelling of eyelids, face, or lips; tightness in chest, troubled breathing, and/or wheezing){01}{02}
    
epidural or spinal hematoma (back pain; bowel/bladder dysfunction; leg weakness; numbness; paralysis; paresthesias)—back pain is not a typical presentation but some patients may experience this symptom{01}{79}
    
skin necrosis (blue-green to black skin discoloration; pain, redness, or sloughing of skin at place of injection){01}{02}
    
thrombocytopenia (bleeding from mucous membranes; rash consisting of pinpoint, purple-red spots, often beginning on the legs; unusual bruising){01}{02}
Note: If an epidural or spinal hematoma is suspected, urgent intervention is necessary, including radiographic confirmation and decompressive laminectomy. Good or partial recovery is more likely if surgery is performed within 8 hours of the development of paraplegia. {66} {79} {80}
The syndrome of thrombocytopenia with thrombosis is a well-known complication of unfractionated heparin therapy {67}. Low molecular weight heparins (LMWHs) are associated with a lower incidence of heparin-induced thrombocytopenia {31} {45} {68}. However, there have been case reports of this complication with LMWHs {70} {71} {72} {73}. Clinicians should be aware of the possible occurrence of thromboembolic events with the use of LMWHs, and should monitor the platelet count appropriately {70} {71} {72} {73} {74}.





Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Pain at injection site{01}





Overdose
For specific information on the agents used in the management of dalteparin overdose, see the Protamine (Systemic) monograph.

For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute effects
    
Bleeding complications or hemorrhage{01} {52}(bleeding gums; coughing up blood; difficulty in breathing or swallowing; dizziness; headache; increased menstrual flow or vaginal bleeding; nosebleeds; paralysis; prolonged bleeding from cuts; red or dark brown urine; red or black, tarry stools; shortness of breath; unexplained pain, swelling, or discomfort, especially in the chest, abdomen, joints, or muscles; unusual bruising; vomiting of blood or coffee ground–like material; weakness)


Treatment of overdose
Specific treatment—Administration of protamine, a heparin antagonist, is required. One mg of protamine sulfate (1% solution) per 100 anti-factor Xa International Units (IU) of dalteparin is given as a slow intravenous injection. If the activated partial thromboplastin time (APTT) measured 2 to 4 hours after the first injection remains prolonged, a second injection of 0.5 mg protamine sulfate per 100 anti-factor Xa IU of dalteparin may be administered. However, the APTT may remain more prolonged with dalteparin than with conventional heparin, despite the additional dosing of protamine. In all cases, the anti-factor Xa activity is only neutralized to about 25 to 50%. {01} {02}

Protamine sulfate should be administered with great care to avoid an overdose. Severe hypotensive and anaphylactoid reactions, possibly fatal, may occur with protamine sulfate. It should be administered only when resuscitation techniques and treatment of anaphylactic shock are readily available. {01}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Dalteparin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to dalteparin, heparin, or pork products
Other medications, especially platelet aggregation inhibitors, such as aspirin, nonsteroidal anti-inflammatory drugs, and ticlopidine
Other medical problems, especially bleeding, major, active; bleeding disorders; endocarditis, bacterial; hepatic function impairment, severe; hypertension, severe, uncontrolled; platelet defects; renal function impairment, severe; retinopathy, diabetic or hypertensive; stroke, hemorrhagic or ischemic; surgery, recent; thrombocytopenia; and ulcers, other lesions, or recent bleeding of the gastrointestinal tract

Proper use of this medication
» Proper injection technique

» Safe handling and disposal of syringe

» Proper dosing
Missed dose: Using as soon as possible; not using if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Need to inform all physicians and dentists that this medicine is being used

» Notifying physician immediately if signs and symptoms of bleeding or epidural/spinal hematoma occur


Side/adverse effects
Signs and symptoms of potential side effects, especially hematoma at injection site, hemorrhage, allergic reaction, anaphylactoid reaction, epidural/spinal hematoma, skin necrosis, and thrombocytopenia


General Dosing Information
Dalteparin cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins {01}.

Dalteparin is administered by deep subcutaneous injection. It must not be injected intramuscularly. {01} {02}

Injection technique: The patient should be sitting or lying down during the injection. Injection sites include a U-shaped area around the navel, the upper outer side of the thigh, or the upper outer quadrant of the buttock. The site should be varied daily. When giving the injection around the navel or the thigh, a fold of skin must be lifted up with thumb and forefinger, and the entire length of the needle should be inserted at a 45- to 90-degree angle. {01} {02}

If a thromboembolic event occurs during dalteparin prophylaxis, dalteparin should be discontinued and appropriate therapy initiated {01}.

Guidelines regarding the use of regional anesthesia in patients receiving perioperative dalteparin {66} {80}
Preoperative dalteparin—A single-dose spinal anesthetic may be the safest neuraxial technique. Needle placement should occur at least 10 to 12 hours after the last dose of dalteparin. Subsequent dosing should be delayed for at least 2 hours after needle placement. The presence of blood during needle placement may justify a delay in the start of postoperative prophylaxis.

Postoperative dalteparin—Patients may safely undergo single-dose and continuous catheter techniques. With a continuous technique, the epidural catheter should be left indwelling overnight and removed the following day, and the first dose of dalteparin should be given 2 hours after catheter removal. Postoperative prophylaxis in the presence of an indwelling catheter must be administered carefully and with close surveillance of the patient's neurologic status. An opioid and/or dilute local anesthetic solution is recommended in these patients to allow intermittent assessment of neurologic function.

The timing of catheter removal is extremely important. Removal should be delayed for at least 10 to 12 hours after a dose of dalteparin. Subsequent dosing should not occur for at least 2 hours following catheter removal.


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


DALTEPARIN SODIUM INJECTION

Usual adult dose
Angina pectoris, unstable (treatment) or
Myocardial infarction, non–Q-wave (treatment)
Subcutaneous, 120 International Units (IU) per kg of body weight, but not more than 10,000 IU every 12 hours with concurrent aspirin (75 to 165 mg daily) until the patient is clinically stabilized. Concurrent aspirin therapy is recommended except when contraindicated.{01}{48}

Note: In clinical trials, the usual duration of treatment was 5 to 8 days{01}.


Thromboembolism, pulmonary (prophylaxis) and
Thrombosis, deep venous (prophylaxis)
Abdominal surgery associated with a risk of thromboembolic complications: Subcutaneous, 2500 IU initially, given one to two hours prior to abdominal surgery, then repeated once a day for five to ten days following surgery, until the patient is mobile {01} {02} {03} {04} {05}.

Abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder : Subcutaneous, 5000 IU given the evening before the operation, then repeated once a day every evening for five to ten days following surgery, until the patient is mobile {01}{02} {08} {49}. Alternatively, in patients with malignancy 2500 IU given one to two hours prior to surgery and again twelve hours later, followed by 5000 IU each morning for five to ten days following surgery, until the patient is mobile{01}{02} {06} {07}.

Hip replacement surgery: Subcutaneous   • Postoperative Start— 2500 IU 4 to 8 hours after surgery, allow a minimum of 6 hours between this dose and the dose given on postoperative day 1. Adjust the timing of the dose on postoperative day 1 accordingly. Postoperative period dose is 5000 IU daily.{81}
   • Preoperative Start— Day of surgery: 2500 IU within 2 hours before surgery , allow a minimum of 6 hours between this dose and the dose given on postoperative day 1. Adjust the timing of the dose on postoperative day 1 accordingly. 2500 IU is administered 4 to 8 hours after surgery and 5000 IU is administered daily during the postoperative period.{81}
   • Preoperative Start—Evening before surgery: 5000 IU administered 10 to 14 hours before surgery. Allow approximately 24 hours between doses. 5000 IU is given 4 to 8 hours after surgery, and the postoperative dose is 5000 IU daily.{81}


Note: Up to 14 days of treatment was well tolerated in controlled clinical trials, where the average duration of treatment was 5 to 10 days postoperatively{01}{81}.


[Thrombosis, deep venous (treatment)]
Subcutaneous, 200 IU per kg of body weight once a day {13} {75} {76}, or 100 IU per kg of body weight two times a day {02} {51}. Alternatively, it may be administered at a dose of 200 IU per kg of body weight given as a continuous intravenous infusion over twenty-four hours (i.e., 8.33 IU per kg of body weight per hour) {02}. Treatment may {75} be guided by monitoring anti-factor Xa activity {02}. Concomitant treatment with a vitamin K antagonist, such as warfarin, should begin at the same time, and dalteparin should be discontinued when the vitamin K antagonist reaches a full therapeutic effect, usually after five or six days of therapy {02} {59} {77}.

[Thrombosis of the extracorporeal system during hemodialysis (prophylaxis)]


Chronic renal failure in patients with no known bleeding risk:
Dialysis lasting up to four hours—Intravenous, 5000 IU, as a single injection into the arterial line at the start of dialysis; or dosed as for dialysis procedures of more than four hours" duration {02} {17} {18} {22}.

Dialysis lasting more than four hours—Intravenous loading dose, 30 to 40 IU per kg of body weight followed by a continuous intravenous infusion of 10 to 15 IU per kg of body weight per hour {02} {21}.



Acute renal failure in patients with a high bleeding risk:
Intravenous loading dose, 5 to 10 IU per kg of body weight, followed by a continuous intravenous infusion of 4 to 5 IU per kg of body weight per hour. Therapy should be guided by monitoring anti-factor Xa activity. {02}



Usual pediatric dose
Safety and efficacy have not been established {01} {02}. A case report described the use of dalteparin in a neonate who developed a proximal deep vein thrombosis following balloon valvuloplasty for pulmonary stenosis. Dalteparin was administered subcutaneously at a dose of 100 IU per kg of body weight two times a day for two days, followed by 200 IU per kg of body weight once a day for twelve weeks (administered by the infant's mother at home). No problems were reported during treatment. {78}

Note: The 10,000- and 25,000-IU-per-mL multi-dose vials contain benzyl alcohol, which is not recommended for use in neonates.


Strength(s) usually available
U.S.—


2500 anti-factor Xa IU (16 mg dalteparin sodium) per 0.2 mL (Rx) [Fragmin (in single unit-dose syringes)]


5000 anti-factor Xa IU (32 mg dalteparin sodium) per 0.2 mL (Rx) [Fragmin (in single unit-dose syringes)]


10,000 anti-factor Xa IU (64 mg dalteparin sodium) per mL (Rx) [Fragmin (in 9.5 mL multiple-dose vials) ( benzyl alcohol 14 mg per mL)]

Canada—


2500 anti-factor Xa IU (16 mg dalteparin sodium) per 0.2 mL (Rx) [Fragmin (in single unit-dose syringes)]{50}


5000 anti-factor Xa IU (32 mg dalteparin sodium) per 0.2 mL (Rx) [Fragmin (in single unit-dose syringes)]{50}


2500 anti-factor Xa IU (16 mg dalteparin sodium) per mL (Rx) [Fragmin ( in 4-mL ampuls)]{50}


10,000 anti-factor Xa IU (64 mg dalteparin sodium) per mL (Rx) [Fragmin (in 1-mL ampuls)]{02}


25,000 anti-factor Xa IU (160 mg dalteparin sodium) per mL (Rx) [Fragmin (in 3.8-mL multi-dose vials) (benzyl alcohol 14 mg per mL)]{02}

Packaging and storage:
Store at controlled room temperature, between 20 and 25 °C (68 and 77 °F) {01}.

Preparation of dosage form:
For a continuous intravenous infusion, dalteparin may be diluted in 0.9% sodium chloride injection or 5% dextrose injection in glass or plastic containers {50}. The recommended postdilution concentration is 20 IU per mL, which can be prepared by adding 2500 IU to 125 mL or 10,000 IU to 500 mL of solution {50}. The solution should be used within 24 hours {50}.

Stability:
The 25,000-IU-per-mL multi-dose vial must be used within two weeks after initial penetration {02}.

Incompatibilities:
Dalteparin sodium injection should not be mixed with other injections or infusions unless compatibility has been established {01}.

Additional information:
The 10,000- and 25,000-IU-per-mL multi-dose vials contain benzyl alcohol, which is not recommended for use in neonates. A fatal syndrome consisting of metabolic acidosis, central nervous system depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhage has been associated with the administration of benzyl alcohol to neonates.



Developed: 01/06/1996
Revised: 12/18/2000



References
  1. Product Information: Fragmin®, dalteparin. Pharmacia & Upjohn Company, Kalamazoo, MI, USA,1999. Revised May 1999
  1. Fragmin product monograph (Pharmacia—Canada), Rev 11/94, Rec 4/95; Rev 4/97, Rec 6/97.
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  1. Product Information: Fragmin®, dalteparin sodium. Pharmacia & Upjohn, Kalamazoo, MI (PI revised 8/2000) PI reviewed 12/2000.

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