Dalteparin - Dosage, Indications, Contraindications, and Side Effects

Overview

Dalteparin is a low molecular-weight Heparin (LMWH) used in the prevention or treatment of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE). It has a rapid onset of action compared to oral anticoagulants such as Warfarin and differs significantly from other LMWHs in terms of plasma half-life, or molecular weight. Dalteparin was initially approved by the United States Food and Drug Administration (USFDA) in 1994 for adults, and on May 16th, 2019, it was approved to minimize the frequency of symptomatic venous thromboembolism in pediatric patients above one month of age.

Information About the Drug to the Patient:

What Is Venous Thromboembolism?

“Venous” means veins, “thrombo” means blood clot, and embolism is a particle in the blood circulation that causes obstruction. Venous thromboembolism (VTE) is a condition in which a blood clot blocks blood flow. Veins carry blood from the extremities to the heart, so when there is an obstruction, the blood gets collected behind the blockage resulting in inflammation and a lack of oxygen and nutrients to the cells. VTE can lead to two different kinds of conditions such as deep vein thrombosis (DVT) (blood clots formed in one or more deep veins in the body, usually in the leg) and pulmonary embolism (PE) (a blood clot that blocks the blood flow to an artery in the lung).

What Is Dalteparin?

Dalteparin is an anticoagulant medicine (blood thinner) administered mainly to prevent certain conditions such as deep vein thrombosis and pulmonary embolism. It is also used in the management and prevention of DVT or PE in children above one month of age and in adults with DVT or PE with cancer. It acts by reducing the clotting ability of the blood.

How Does Dalteparin Work?

Dalteparin is a form of Heparin that works by increasing the inhibition of Factor Xa and thrombin by antithrombin (ATIII), thus preventing clot formation. Due to the inactivation of factor Xa, there is only a slight increase in activated partial thromboplastin time (APTT) in comparison to unfractionated Heparin. It acts immediately on blood coagulation in order to block the conversion of fibrinogen to fibrin.

How Should Dalteparin Be Taken?

Dalteparin is available as an injection and is administered by a healthcare professional subcutaneously (under the skin). For adults, it is given once daily or twice, depending on the condition. For children, it is administered twice a day. The treatment duration depends on the condition and the response to the medication.

• Dateparin is given for five to eight days for patients with angina and heart attacks.

• Up to six months to treat and prevent DVT in patients with cancer.

• Dalteparin is given for 12 to 14 days to prevent DVT in people on bed rest.

• To prevent DVT after surgery, Dalteparin is given on the day of surgery and for five to ten days following the surgery.

What Are Some of the Important Instructions About Dalteparin?

• It may take longer to stop bleeding for patients under treatment with Dalteparin; patients must be more cautious as they may bleed or bruise more easily.

• If any unusual bleeding, bruising, or dark spots are noticed under the skin, the doctor must be informed immediately.

• Pregnant women, neonates, and infants are associated with risks as Dalteparin may contain benzyl alcohol as a preservative.

What Must the Patient Inform the Doctor, Before Taking Dalteparin?

• Patients must inform the doctor before any surgery, before taking any new medicine, or before dental appointments regarding the treatment with Dalteparin.

• If the patient is allergic to Dalteparin, Heparin, or any other ingredients in the medicine, the doctor must be informed before starting the treatment.

• In case of patients experiencing heavy bleeding anywhere in the body that cannot be stopped, bleeding disorders, ulcers in the stomach or intestine, diabetes, high blood pressure, and liver or kidney diseases.

• Female patients must notify the doctor if they are pregnant, breastfeeding, or planning to become pregnant before using Dalteparin.

• The doctor must be informed if the patient is taking any over-the-counter medicines, herbal or vitamin supplements, or any other medications before starting the treatment with Dalteparin.

What Are the Side Effects of Dalteparin?

Some of the side effects of Dalteparin include;

• Pain, redness, and bruising at the site of injection.

• Bleeding from the nose.

• Blood in the urine.

• Dizziness.

• Rash or dark red spots under the skin.

• Difficulty in breathing or swallowing.

• Excessive menstrual bleeding.

• Vomiting or spitting blood.

• Bloody or tarry stools.

• Swelling of the face, eyes, tongue, lips, and throat.

Information About the Drug to the Doctors:

Description

Dalteparin injection is a sterile, low molecular-weight Heparin available in the form of pre-filled syringes and multiple-dose vials. It is produced through controlled nitrous acid depolymerization of sodium Heparin obtained from porcine intestinal mucosa, followed by a chromatographic purification process. Each pre-filled syringe contains either 2500, 5000, 7500,10,000,12500, 15000, 0r 18,000 anti-Xa International Units of Dalteparin sodium. The pre-filled syringe also contains water for injection and sodium chloride to maintain physiological ionic strength and is free of preservatives, whereas each multiple-dose vial contains 14 mg of benzyl alcohol as a preservative along with water for injection.

What Are the Indications of Dalteparin?

The indications of Dalteparin include:

• Prophylaxis of complications of unstable angina and myocardial infarction (non-Q-wave) when concomitantly administered with Aspirin.

• As prophylaxis of deep vein thrombosis (DVT) in patients who are at risk of thromboembolic complications and undergoing hip replacement surgery, or abdominal surgery.

• Patients with severely restricted mobility due to acute illness.

• Extended treatment of symptomatic venous thromboembolism to lower its recurrence in adult patients with cancer.

• Treatment of symptomatic venous thromboembolism to lower its recurrence in pediatric patients above one month of age.

What Are the Contraindications of Dalteparin?

Contraindications of Dalteparin include:

• Acute treatment of venous thromboembolism (VTE) or as a prolonged VTE prophylaxis.

• As a treatment for unstable angina and non-Q wave myocardial infarction.

• Patients with a history of allergic reactions such as rash, pruritus, etc., or hypersensitivity to Dalteparin sodium, Heparin, or pork products.

• Patients associated with active major bleeding.

• Patients undergoing treatment with epidural or neuraxial anesthesia.

• The patient is a known case of Heparin-induced thrombocytopenia or Heparin-induced thrombocytopenia with thrombosis.

What Are the Adverse Reactions of Dalteparin?

The most commonly reported adverse reactions include:

• Hematoma at the site of injection.

• Increased liver function test.

• Thrombocytopenia.

• Major hemorrhage.

• Wound hematoma.

• Pain at the site of injection.

• Hematuria.

• Spinal hematoma.

• Epidural hematoma.

• Intracranial hemorrhage.

• Anaphylactoid reactions.

• Excessive menstrual bleeding.

• Bloody or tarry stools.

Dosage and Administration

The recommended dose of Dalteparin is as follows:

• As a preventive measure for ischemic complications of unstable angina and myocardial infarction, Dalteparin is recommended subcutaneously at a dose of 120 International Units per kilogram (IU/kg), but not exceeding 10000 IU every 12 hours for five to eight days along with oral Aspirin of about 75 to 165 mg (milligrams) once a day.

• In patients for an extended treatment of symptomatic venous thromboembolism to lower its recurrence in adult patients with cancer Dalteparin is recommended subcutaneously at a dose of 200 IU/kg once a day, for 30 days, and the total daily dose must not be more than 18,000 IU.

• Dalteparin is recommended subcutaneously from the second month onwards up to six months, at a dose of 150 IU/kg once a day, and the total daily dose must not be more than 18,000 IU.

• As a prophylactic treatment for deep vein thrombosis, for patients undergoing hip replacement surgery, administration of Dalteparin 5000 IU ten to 14 hours before surgery, 2500 IU within two hours before surgery, and 2500 IU four to eight hours after the surgery is recommended. 5000 IU of Dalteparin is recommended for five to ten days during the postoperative period.

• For patients undergoing abdominal surgery, 2500 IU of Dalteparin is administered subcutaneously one to two hours prior to the surgery, followed by one dose daily postoperatively for five to ten days.

• For patients with an increased risk of thromboembolic complications such as malignant disorders, Dalteparin is recommended at a dose of 5000 IU subcutaneously followed by one dose daily postoperatively for five to ten days, or 2500 IU can be administered one to two hours before surgery subcutaneously and 2500 IU after 12 hours followed by 5000 IU one dose daily postoperatively for five to ten days.

• In the treatment of symptomatic venous thromboembolism in pediatric patients, Dalteparin is recommended depending on the age of the child as follows:

1. Four weeks - below two years: 150 IU/kg twice a day.

2. Two to eight years: 125 IU/kg twice a day.

3. Eight to 17 years - 100 IU/kg twice a day.

• Dose reductions must be done in cases of thrombocytopenia in adult patients with cancer or renal insufficiency.

Warnings and Precautions:

• Treatment with Dalteparin is associated with a risk of hemorrhage, including epidural or spinal hematoma. The risk is higher with the concomitant use of non-steroidal anti-inflammatory drugs, epidural catheters, or in individuals with a spinal deformity or a history of spinal surgery.

• Dalteparin may cause Heparin-induced thrombocytopenia.

• Dalteparin must be used with extreme caution in patients with severe uncontrolled hypertension, severe liver or kidney insufficiency, increased risk of hemorrhage, congenital or acquired bleeding disorders, etc., as bleeding can occur at any site during the treatment.

• Regular monitoring of complete blood count, platelet count, blood chemistry, and stool occult blood loss must be advised during the treatment with Dalteparin.

• Benzyl alcohol is present as a preservative which has a potential risk of causing adverse reactions in neonates and infants. Hence preservative-free Dalteparin can be used in neonates and infants.

What Are the Pharmacological Aspects of Dalteparin?

Mechanism of Action:

Dalteparin is a low molecular-weight Heparin having antithrombotic properties. It acts by improving the inhibition of factor Xa and thrombin by antithrombin while slightly affecting the clotting time (activated partial thromboplastin time). It acts mainly by increasing the rate of neutralization of activated coagulation factors while only slightly affecting the other hemostatic mechanisms.

Pharmacokinetics:

• On administration of Dalteparin, maximum levels of anti-Xa activities were noticed after four hours in most of the subjects. Gradual increase in dose from 2500 IU to 10,000 IU led to an overall linear increase in the activity of anti-Xa by an average of 33 percent.

• After administering the drug for seven days at a dose of 100 IU/kg showed no anti-Xa activity.

• The mean volume of distribution was around 40 to 60 ml/kg.

• Following a single dose of 30 IU/kg, the clearance was estimated to be 24.6 ml/kg/hr/, and at a dose of 120 IU/kg, the clearance was around 15.6 ml/kg/hr. The half-life is estimated to be 1.47 hours at a dose of 30 IU/kg and 2.5 hours at a dose of 120 IU/kg.

• Following a subcutaneous administration, the apparent half-life was around three to five hours, which was probably due to a delay in absorption.

• In those with chronic kidney disease, the terminal half-life following a single dose administered intravenously is around 5.7 hours.

Pharmacodynamics:

Dalteparin injection administered subcutaneously up to 10000 IU anti-Xa as a single dose or two doses of 5000 IU 12 hours apart to healthy subjects did not exhibit any significant changes in fibrinolysis, platelet aggregation, or clotting tests such as APTT, prothrombin time (PT), or thrombin time (TT). Administration of 5000 IU twice daily for seven consecutive days to patients undergoing abdominal surgery did not show significant changes in platelet factor4, lipoprotein lipase, or APTT.

What Are the Drug Interactions of Dalteparin?

Dalteparin can interact with drugs such as;

• Mifepristone.

• Defibrotide.

• Antithrombin alfa.

• Azithromycin.

• Caplacizumab.

• Ceftriaxone.

• Clarithromycin.

• Enoxaparin.

• Estradiol.

• Heparin.

• Phenobarbital.

• Ramipril.

• Roxithromycin.

• Sulfamethoxazole, etc.

Clinical Studies:

• Studies on the prophylactic use of Dalteparin in ischemic heart diseases: A double-blind, randomized clinical trial was conducted in patients with ischemic heart disease who were randomly assigned to receive either 120 IU/kg of Dalteparin or placebo, which were administered every 12 hours. All the patients were on Aspirin at a dose of 75 mg once a day and beta-blockers. The majority of the participants were white males aged around 68 years. The results were myocardial infarction or fatal, needing Heparin intravenously or nitroglycerin and revascularization. Combined incidence after a week of treatment was 9.3 percent in the group receiving Dalteparin versus 7.6 percent in those receiving Heparin.

• Studies on the prophylaxis of deep vein thrombosis for patients undergoing hip replacement surgery: This was an open-label study where in groups were randomly assigned to receive either Dalteparin 5000 IU subcutaneously administered once daily and the comparative group received oral Warfarin sodium. The study was conducted for five to nine days on a majority of white female patients with a mean age of 63 years. Deep vein thrombosis was found to be significantly lower in those subjects receiving Dalteparin in comparison to those receiving Warfarin.

• In another blind study, 5000 IU was administered subcutaneously once daily following hip surgery versus 5000 IU of Heparin administered subcutaneously for nine days. The occurrence of pulmonary embolism and deep vein thrombosis was significantly lower in the group receiving Dalteparin.

• A study was performed on patients with a risk of thromboembolic complications as prophylaxis of DVT following abdominal surgery. The mean age of the subjects participating was 64 years, and most of them were females. It was observed that the use of Dalteparin 2500 IU was superior to Heparin or placebo in reducing the risk of developing deep vein thrombosis.

Nonclinical Toxicology:

Carcinogenicity studies regarding Dalteparin have not been performed in long-term animal studies; Dalteparin was not mutagenic in the in vitro Ames test and Dalteparin administered up to 1200 IU/kg did not show any significant effects on fertility or reproductive capacity of males and female rats.

Use of Dalteparin in Specific Populations:

• Pregnancy: There may be a risk to the mother associated with untreated venous thromboembolism in pregnancy and potential risks for the infant when Dalteparin is used in pregnancy. The available data have not reported an association between Dalteparin and adverse developmental outcomes in the fetus or pregnant women. However, Dalteparin must be used in pregnancy only if clearly required.

• Lactation: Limited data is available indicating the presence of small amounts of Dalteparin in human milk. However, no adverse effects have been reported. No data is available concerning Dalteparin on milk production. The benefits of breastfeeding must be considered along with the mother’s requirement for Dalteparin for the underlying condition and any potential side effects on the breastfed infant.

• Pediatric Use: The safety and effectiveness of Dalteparin have been established in pediatric patients above one month of age for the treatment of symptomatic VTE. Preservative-free Dalteparin must be used in neonates and infants as serious adverse reactions were reported in benzyl alcohol-preserved medications.

• Geriatric Use: No overall differences were observed between elderly individuals and younger subjects with respect to the effectiveness of Dalteparin. However, research suggests the risk of bleeding may increase with age; hence caution must be exercised in dosing intervals and concomitant medications in elderly patients, especially in those with low body weight and predisposed to reduced renal function.