Dalteparin Side Effects

Some side effects of dalteparin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

For the Consumer

Applies to dalteparin: subcutaneous solution

Get emergency medical help if you have any of these signs of an allergic reaction while taking dalteparin: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using dalteparin and call your doctor at once if you have a serious side effect such as:

• unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;

• easy bruising, purple or red pinpoint spots under your skin;

• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

• black or bloody stools, coughing up blood or vomit that looks like coffee grounds;

• numbness, tingling, or muscle weakness (especially in your legs and feet);

• loss of movement in any part of your body;

• sudden weakness, severe headache, confusion, or problems with speech, vision, or balance; or

• trouble breathing.

Less serious side effects include pain, redness, or swelling where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

For Healthcare Professionals

Applies to dalteparin: subcutaneous solution

General

Bleeding or hemorrhagic complications may occur at any site in the body. However, in general the incidence of bleeding has been low. Hematoma at the injection site is the most commonly reported bleeding complication, and the incidence of bleeding may increase with doses above 2500 intl units per day.

Any unexplained decrease in blood pressure and/or hematocrit should prompt consideration of a possible hemorrhagic event.

Protamine may be used to neutralize the hemorrhagic effects of dalteparin. Protamine should be given in a dose of 1 mg protamine per 100 anti-Xa units of dalteparin.

A well controlled multicenter study (Kakkar et al, 1993) evaluated the prevention of venous thromboembolism after major abdominal surgery. The total number of patients with major bleeding episodes was not significantly different (3.6% versus 4.8%, p=0.10) with dalteparin 2500 intl units once a day versus 5000 intl units unfractionated heparin twice a day. However, the incidence of wound related hematomas was significantly greater in the heparin group (1.4% versus 2.7%).

In another study (Bergqvist et al, 1986) 5000 intl units of dalteparin once a day compared to 5000 intl units of unfractionated heparin two times a day led to significantly more hemorrhagic complications (4.6% versus 11.6%). There was no difference in the reduction of deep vein thrombosis between the two treatment groups. The higher dosage of dalteparin may have led to more bleeding problems.

The manufacturer states in the dalteparin package labeling that the incidence of bleeding may increase with higher doses. The number of postoperational transfusions required in patients receiving 2500 intl units versus 5000 intl units per day was 5.7% (n=459) and 15.9% (n=508) of patients, respectively.

Kakkar and colleagues noted that compared to non-bleeders, patients who bleed with the use of dalteparin were older (mean age 64 years), more likely to be male, to have a malignancy, or to be taking nonsteroidal anti-inflammatory agents, including aspirin.

Hematologic

Hematologic side effects have included thrombocytopenia (up to 13.6%), thrombocytosis, thrombosis, and hypochromic anemia. Thrombocytopenia has occurred more frequently in patients treated with unfractionated heparin than with low molecular weight heparin. The manufacturer reports platelet counts of less than 100,000/mm3 and less than 50,000/mm3 in less than 1% of dalteparin-treated patients from initial clinical trials supporting non-cancer indications. The true incidence of dalteparin-induced thrombocytopenia is not known.

Hematologic side effects have also included a case of hematoma with subsequent compartment syndrome in the thigh of a patient receiving dalteparin for angina.

Patients undergoing spinal/epidural anesthesia or puncture and anticoagulation or who are scheduled to be anticoagulated with low molecular weight heparins or heparinoids are at risk for long-term or permanent paralysis due to epidural or spinal hematoma. The risk of these events is increased by the use of indwelling epidural catheters or by concomitant use of platelet inhibitors, other anticoagulants, or drugs that affect hemostasis.

A well-controlled clinical trial (Warkentin, et al) evaluated the frequency of heparin-induced thrombocytopenia in 665 patients receiving a low molecular weight heparin or unfractionated heparin for postsurgical prophylaxis of deep vein thrombosis. Heparin-induced thrombocytopenia was defined as a decrease in platelet count below 150,000 m2 that began 5 or more days after the start of the study drug and a positive in vitro test for antibodies. Heparin-induced thrombocytopenia occurred in 2.7% of patients receiving low molecular weight heparin. The incidence of thrombosis was significantly higher in those patients with heparin-induced thrombocytopenia (88.9% versus 17.8%). Heparin-dependent IgG antibodies occurred more frequently in those receiving unfractionated heparin versus low molecular weight heparin (7.8% versus 2.2%, respectively).

One small study (Ramakrishan, et al) reported that the incidence of cross-reactivity between unfractionated heparin and dalteparin in patients with heparin-induced thrombocytopenia was 40% (6/15 patients). Seven of the remaining 9 patients who did not demonstrate in vitro cross reactivity were successfully treated with dalteparin. Due to the extensive cross-reactivity, low molecular weight heparins are not indicated for treatment of heparin-induced thrombocytopenia. However, many studies have shown this can be done successfully.

Patients previously exposed to unfractionated heparin or a low-molecular-weight heparin appear to be more susceptible to developing heparin-induced thrombocytopenia (HIT) and HIT-related thromboembolic complications (e.g., transient ischemic attack, stroke) than those who were never exposed.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated, prothrombotic reaction that occurs in 0.5% to 5% of patients treated with unfractionated heparin and in less than 1% of patients treated with a low molecular weight heparin (LMWH). The decrease in platelet count associated with HIT usually begins 5 to 14 days after starting heparin. However, patients with a previous exposure to heparin may have an abrupt decrease in platelets upon restarting heparin. Patients with LMWH-induced HIT exhibit a longer delay in the onset of symptoms compared with those who develop it from unfractionated heparin. Following discontinuation, platelet counts begin to recover within 4 days, but may take more than 2 weeks in patients with high-titer HIT antibodies. Thrombocytopenia is caused by heparin-dependent IgG antibodies that bind to a specific platelet protein, platelet factor 4 (PF4). The heparin-PF4-IgG immune complex binds to platelets causing platelet activation. The activated platelets cause release of platelet-derived procoagulant microparticles, which accelerate coagulation reactions and generates thrombin. LMWHs have a high cross-reactivity with circulating heparin-PF4-IgG immune complex. Factors associated with a higher risk for developing HIT-associated thrombosis include women, nonwhites, severity of thrombocytopenia, and lower body weight. Complications associated with HIT include exacerbation of venous thromboembolism, arterial or venous thrombosis, limb gangrene, stroke, and skin necrosis. The antibodies that cause HIT will usually disappear after approximately 3 months; therefore, use of unfractionated heparin or LMWH may be considered in a patient with a history of HIT if the antibody test is negative.

Hepatic

Albada and colleagues noted increases in serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) from 17 units/L to 24.5 units/L and 22.5 units/L to 45 units/L, respectively, in those receiving dalteparin up to 10 days for treatment of acute venous thromboembolism. Liver functions tests tend to reach a maximum within the first week of therapy and then usually return to normal.

The manufacturer has reported asymptomatic increases in hepatic transaminase levels (SGOT/AST and SGPT/ALT) greater than 3 times the upper limit of normal in 4.7% and 4.2%, respectively, of patients with non-cancer indications.

Hepatic side effects of dalteparin and other low molecular weight heparins have included asymptomatic transient elevations in liver function tests that usually are reversible and clinically insignificant.

Local

Local side effects of subcutaneous injections include pain, erythema, and hematoma formation. Rarely patients may experience painful, red induration and necrotic ulcerations at the injection site. Skin necrosis distant from the injection site has also been reported.

The most commonly reported side effect is hematoma at the injection site. Pain at the injection site may be dose-related, occurring more frequently with doses above 2500 intl units per day. One study found that pain at the injection site was significantly greater with unfractionated heparin (5000 intl units two times a day) versus dalteparin (5000 intl units once a day).

Skin necrosis has occurred with low molecular weight heparin and may be due to toxic epidermal necrolysis.

Hypersensitivity

Hypersensitivity side effects have rarely included rash, fever, pruritus, bullous eruption and skin necrosis. Anaphylactic reactions have been reported.

Musculoskeletal

A patient suffered severe osteoporosis after using high dose unfractionated heparin for one year for recurrent deep vein thrombosis and pulmonary embolism. The patient was switched to 15,000 units of low molecular weight heparin daily and remained free from thromboembolism or osteoporosis. This uncontrolled, preliminary report suggests low molecular weight heparins may not cause osteoporosis.

Musculoskeletal side effects have included a case report suggesting that low molecular weight heparins may prevent osteoporosis during prolonged use. Unfractionated heparin may aggravate or cause osteoporosis.

Dermatologic

Dermatologic side effects have included alopecia and rare cases of skin necrosis. At least one case of acute generalized exanthematous pustulosis has been reported after administration of dalteparin. Following discontinuation, symptoms resolved within 2 weeks.

Alopecia related to the use of dalteparin has been reported. Cases have involved female patients ranging in age from 9 years to 75 years. The 9 year old patient required anticoagulation for a cardiac disease while the other patients were anticoagulated during dialysis for chronic renal failure. In each case, the withdrawal of dalteparin resulted in a return to normal hair growth.

Genitourinary

Genitourinary side effects including at least one case of priapism associated with dalteparin therapy have been reported.

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