Dalteparin

Mechanism of Action

Dalteparin is a low molecular weight heparin (LMWH) with antithrombotic properties. This LMWH enhances the activity of antithrombin III and leads to the inhibition of several blood coagulation factors, including factor Xa and thrombin, in a dose-dependent manner. Factor Xa plays a crucial role in the blood clotting cascade, leading to thrombin formation and, ultimately, clot development. Compared to UFH, dalteparin has a more pronounced effect on factor Xa. Dalteparin has an inhibitory ratio of anti-Xa:anti-IIa is 2.7:1 compared to 1:1 for UFH.[8] Activated partial thromboplastin time (aPTT) and thrombin time (TT) increase more with UFH than dalteparin. Dalteparin does not significantly impact plasma antithrombin levels, platelet counts, or the fibrinolytic system. Additionally, dalteparin is less lipolytic when compared to UFH. Anti-Xa activity levels are correlated with the dose per kg/total body weight.[9][10][1][4] 

Pharmacokinetics

Dalteparin has a first-order, one-compartment pharmacokinetic profile.[11]

Absorption: Dalteparin is primarily absorbed subcutaneously. In healthy volunteers, the absolute bioavailability measured as anti-Factor Xa activity was 87±6%. The plasma half-life ranges from 2.4 to 4 hours after subcutaneous and 2 hours after intravenous (IV) dosing.

Distribution: The approximate volume of distribution for anti-Factor Xa activity of dalteparin was about 40 to 60 mL/kg.

Metabolization: Dalteparin undergoes hepatic metabolism, primarily through desulfation or depolymerization.

Excretion: LMWHs, including dalteparin, rely more on renal clearance than unfractionated heparin (UFH). Approximately 3% of an active dose of dalteparin is eliminated renally as active fragments. In patients with renal insufficiency, accumulation may occur.

Special Populations

Pregnant patients: Dalteparin does not cross the placenta and is generally considered safe in pregnancy. If needed during pregnancy, preservative-free formula should be used. Dosage requirements may change during pregnancy due to volume distribution differences, and the glomerular filtration rate increases as the pregnancy progresses.[12] 

Pediatric patients: With increasing age, the clearance corrected for body weight decreases while the elimination of half-life increases.

Administration

Dalteparin is available in subcutaneous single-dose syringes, vials, and ampoules for subcutaneous and IV use. Subcutaneous injections are typically given once or twice daily. Medical guidelines suggest that the appropriate dalteparin dose should be determined based on total body weight (TBW). A fixed-dose is based on total body weight (TBW) with predictable dose-response curves.[11][13]

Dosage Forms and Strengths 

The injectable solution, single-dose prefilled syringe

• 2,500 IU/0.2 mL

• 5,000 IU/0.2 mL

• 7,500 IU/0.3 mL

• 12,500 IU/0.5 mL

• 15,000 IU/0.6 mL

• 18,000 IU/0.72 mL

Injection, single-dose graduated syringe

• 10,000 IU/mL

Injection, multiple-dose vials

• 95,000 IU/3.8 mL (25,000 IU/mL)

A missed dose should be administered as soon as possible. However, if the next dose is due, skip the missed dose and continue with the next scheduled dose; do not double the dose.

Specific Populations 

Lactation considerations: Limited data are available. No adverse effects have been reported on breastfed infants. Regarding the impact on milk production, no data is unavailable.[14] 

Pediatric patients: For pediatric patients on dalteparin, adverse reactions were usually consistent with adults. Preservative-free forms of dalteparin should be used in neonates and infants—formulations preserved with benzyl alcohol cause gasping syndrome in preterm infants with low birth weight. Additional adverse reactions related to benzyl alcohol are neurological changes, intracranial hemorrhage, hematological changes, seizures, skin deterioration, renal and hepatic failure, low blood pressure, bradycardia, and cardiovascular demise.[15][16]

Preterm and low-birth-weight infants may be at an increased risk for these adverse reactions due to their limited ability to metabolize benzyl alcohol. 

Older patients: No difference is apparent in efficacy in older compared to younger patients during trials of dalteparin. The risk of bleeding can increase with age. A study evaluating the safety profile of LMWHs in the geriatric population found that the safety profile was equivalent to non-vitamin K antagonist oral anticoagulants (NOACs), but the efficacy was lower. LMWHs only accumulated significantly in patients with reduced renal function. The results of a study with COVID-19 patients with a mean age of 67 showed lower in-hospital mortality with moderate doses of LMWHs that was evident compared to prophylactic doses.[7] 

Adverse Effects

Adverse Effects

Overall, dalteparin is well tolerated. The risk of hemorrhage is similar to that of UFH. LMWHs are not recommended in patients with heparin-induced thrombocytopenia due to the cross-reaction in plasma from UFH-associated antiplatelet antibodies. The FDA's most common adverse effects (>1%) are as follows: bleeding, type 1 thrombocytopenia, hematoma at the injection site, pain at the injection site, and transient elevation of transaminases.[17]

Drug-Drug Interactions

Defibrotide is contraindicated due to the pharmacodynamic activity of dalteparin and the risk of hemorrhage. Mifepristone use is also contraindicated due to an increased risk of serious bleeding when used for the termination of pregnancy. Dalteparin should be used with caution in patients taking oral anticoagulants and/or platelet inhibitors due to the increased risk of bleeding. Patients taking aspirin, dipyridamole, vitamin K antagonists, and NSAIDs may need to take precautions, as dalteparin can increase the anticoagulant effects of these medications. Antihistamines, cardiac glycosides, tetracyclines, or ascorbic acid may reduce the effectiveness of dalteparin.[4][18]

Contraindications

Contraindications

FDA contraindications are as follows:

• Active major bleeding
• History of heparin-induced thrombocytopenia/with thrombosis
• Hypersensitivity to dalteparin
• Do not administer in patients undergoing epidural/neuraxial anesthesia
• Hypersensitivity to heparin or pork products. 

Dalteparin should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia (HIT). Thrombocytopenia should be closely monitored. LMWH has a lower risk than UFH but can also trigger platelet activation by HIT antibodies.[19]   

Box Warning

Epidural or spinal hematomas can occur in patients receiving LMWH or heparinoids and who are concurrently receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas can lead to permanent or long-term paralysis. Clinicians should carefully consider these risks when administering spinal procedures to these patients. Several factors contribute to the increased risk of epidural or spinal hematomas in these patients. These include indwelling epidural catheter use, concurrent use of other drugs that affect coagulation, history of spinal deformity or spinal surgery, and repeated epidural or spinal punctures. The preferred timing of dalteparin administration after neuraxial procedures is unknown. Patients should be frequently monitored for neurological impairment; urgent treatment may be necessary. Risks and benefits must be weighed before using dalteparin after neuraxial procedures for VTE prophylaxis.[20]   

Precautions

Dalteparin may increase the risk of bruising and bleeding; periodic complete blood counts, platelet counts, and stool occult blood tests may be recommended. If patients taking dalteparin notice bruising, bleeding, black, tarry stools, blood in urine or stool, or pinpoint red spots on the skin, they should alert the prescribing clinicians. Patients on dalteparin should also avoid picking their noses and be careful when brushing their teeth, flossing, and using toothpicks. The patients should also avoid contact sports and the use of sharp tools.

Warnings

Dalteparin injection is not intended for intramuscular administration. Dalteparin is not interchangeable, unit for unit, with unfractionated heparin or other LMWHs.

Monitoring

During treatment with dalteparin, periodic complete blood counts, including platelet count and stool occult blood tests, are indicated. No special monitoring of blood clotting times, such as activated partial thromboplastin Time (aPTT), is necessary. When given at recommended prophylaxis doses, routine coagulation tests such as prothrombin time (PT) and aPTT are not sensitive enough to measure dalteparin activity accurately and, therefore, are unsuitable for monitoring. However, patients with renal insufficiency are susceptible to potential over- or undertreatment as dalteparin is renally excreted. Therefore, therapeutic drug monitoring, specifically by measuring anti-Xa activity, may be necessary. Additionally, monitoring of transaminase levels is advisable.

Toxicity

Dalteparin causes less hepatic and renal deposition than UFH. Overdosage and toxicity symptoms of dalteparin include unusual bleeding, blood in urine, black, tarry stools, easy bruising, red blood in stools, and vomit that is bloody or looks like coffee grounds.  The FDA states that overdosage may lead to hemorrhagic complications. This can be managed by slow IV injection of protamine sulfate with 1 mg of protamine sulfate for every 100 anti-Xa IU dalteparin. 

Carcinogenic Effects

According to the results of long-term animal studies, dalteparin sodium has unknown potential to cause cancer. However, the medication is non-mutagenic in multiple tests, including the in vitro Ames Test, mouse lymphoma cell forward mutation test, human lymphocyte chromosomal aberration test, and the in vivo mouse micronucleus test. Furthermore, subcutaneous doses of dalteparin sodium up to 1200 IU/kg did not affect male and female fertility or reproductive performance.

Teratogenic Effects

No evidence of impaired fertility or harm to fetuses was found in reproduction studies with dalteparin sodium in pregnant rats and rabbits at IV doses up to 2400 and 4800 IU/kg, respectively. However, no adequate studies have been conducted on pregnant women. Use during pregnancy should be limited to cases where the medication is necessary.

Enhancing Healthcare Team Outcomes

Dalteparin is an anticoagulant administered subcutaneously to prevent and treat VTE. Patients undergoing treatment should maintain regular appointments with their clinicians to monitor blood counts, transaminases, and therapeutic drug levels, ensuring the desired anticoagulant effects. Symptoms of overdose, such as unusual bleeding, blood in urine, black or tarry stools, easy bruising, red blood in stools, or bloody vomit resembling coffee grounds, warrant immediate medical attention. In cases of overdosage, an IV injection of protamine sulfate can be administered. Admitted patients should have a care team, including clinicians, pharmacists, and lab technicians, collaborating to prevent subtherapeutic effects or overdosage.