Fragmin Side Effects

Please note - some side effects for Fragmin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Fragmin - for the Consumer

Fragmin

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Fragmin:

Pain, swelling, redness, or bruising at the injection site.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); unusual bruising or bleeding.

Store Fragmin at room temperature, between 66 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Keep Fragmin out of the reach of children and away from pets.

Fragmin Side Effects - for the Professional

Fragmin

Hemorrhage

The incidence of hemorrhagic complications during treatment with Fragmin Injection has been low. The most commonly reported side effect is hematoma at the injection site. The incidence of bleeding may increase with higher doses; however, in abdominal surgery patients with malignancy, no significant increase in bleeding was observed when comparing Fragmin 5000 IU to either Fragmin 2500 IU or low dose heparin.

In a trial comparing Fragmin 5000 IU once daily to Fragmin 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding events was 4.6% and 3.6%, respectively (n.s.). In a trial comparing Fragmin 5000 IU once daily to heparin 5000 U twice daily, the incidence of bleeding events was 3.2% and 2.7%, respectively (n.s.) in the malignancy subgroup.

Unstable Angina and Non-Q-Wave Myocardial Infarction

Table 8 summarizes major bleeding events that occurred with Fragmin, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

Hip Replacement Surgery

Table 9 summarizes: 1) all major bleeding events and, 2) other bleeding events possibly or probably related to treatment with Fragmin (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.

Six of the patients treated with Fragmin experienced seven major bleeding events. Two of the events were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial hemorrhage nor died of bleeding complications.

In the third hip replacement surgery clinical trial, the incidence of major bleeding events was similar in all three treatment groups: 3.6% (18/496) for patients who started Fragmin before surgery; 2.5% (12/487) for patients who started Fragmin after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.

Abdominal Surgery

Table 10 summarizes bleeding events that occurred in clinical trials which studied Fragmin 2500 and 5000 IU administered once daily to abdominal surgery patients.

Medical Patients with Severely Restricted Mobility During Acute Illness

Table 11 summarizes major bleeding events that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.

Three of the major bleeding events that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with Fragmin and one in the group receiving placebo). Two deaths occurred after Day 21: one patient in the placebo group died from a subarachnoid hemorrhage that started on Day 55, and one patient died on day 71 (two months after receiving the last dose of Fragmin) from a subdural hematoma.

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

Table 12 summarizes the number of patients with bleeding events that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding eventwas considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.

At the end of the six-month study, a total of 46 (13.6%) patients in the Fragmin arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the Fragmin arm at Day 71) was fatal.

Thrombocytopenia

See WARNINGS, Thrombocytopenia.

Other

Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bulleous eruption) have occurred rarely. A few cases of anaphylactoid reactions have been reported.

Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with Fragmin and reported at a rate of at least 2% in the group treated with Fragmin, was reported in 4.5% of patients treated with Fragmin 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with Fragmin 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.

Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete). Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Skin necrosis has occurred rarely. There have been isolated cases of alopecia reported that improved on drug discontinuation.

Side Effects by Body System

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.

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date, and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This information does not endorse drugs, diagnose patients, or recommend therapy. This drug information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug of drug combination is safe, effective, or appropriate for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of information provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse, or pharmacist.