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.

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:

Mild bleeding, bruising, irritation, pain, redness, or swelling at the injection site.

Seek medical attention right away if any of these SEVERE side effects occur when using Fragmin:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody, black, or tarry stools; dark red spots under the skin; difficulty walking; fainting; fever; pink or red urine; severe or persistent dizziness or weakness; tingling, numbness (especially in the legs and feet), and muscle weakness; unusual bruising or bleeding; vomit that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Fragmin Side Effects - for the Professional

Fragmin

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not accurately reflect the rates observed in practice.

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 risk for bleeding varies with the indication and may increase with higher doses.

Unstable Angina and Non-Q-Wave Myocardial Infarction

Table 5 summarizes major bleeding reactions that occurred with Fragmin, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

1  Treatment was administered for 5 to 8 days. 2  Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 U subcutaneously every 12 hours for 5 to 8 days. 3  Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently. 4  Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) a transfusion was required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding.
Table 5
Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction
Indication	Dosing Regimen
Unstable Angina and Non-Q-Wave MI	Fragmin 120 IU/kg/12 hr subcutaneous1 n (%)	Heparin2 intravenous and subcutaneous2 n (%)	Placebo every 12 hr subcutaneous n (%)
Major Bleeding Reactions3,4	15/1497 (1.0)	7/731 (1.0)	4/760 (0.5)

Hip Replacement Surgery

Table 6 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with Fragmin (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.

1  Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5. 2  Includes three treated patients who did not undergo a surgical procedure. 3  A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of ≥ 2 g/dL or transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage. 4  Includes two treated patients who did not undergo a surgical procedure. 5  Occurred at a rate of at least 2% in the group treated with Fragmin 5000 IU once daily.
Table 6
Bleeding Reactions Following Hip Replacement Surgery
Indication	Fragmin vs Warfarin Sodium		Fragmin vs Heparin
	Dosing Regimen		Dosing Regimen
Hip Replacement Surgery	Fragmin2 5000 IU once daily subcutaneous n (%)	Warfarin Sodium1 oral n (%)	Fragmin4 5000 IU once daily subcutaneous n (%)	Heparin 5000 U three times a day subcutaneous n (%)
Major Bleeding Reactions3	7/274 (2.6)	1/279 (0.4)	0	3/69 (4.3)
Other Bleeding Reactions5 Hematuria	8/274 (2.9)	5/279 (1.8)	0	0
Wound Hematoma	6/274 (2.2)	0	0	0
Injection Site Hematoma	3/274 (1.1)	NA	2/69 (2.9)	7/69 (10.1)

Six of the patients treated with Fragmin experienced seven major bleeding reactions. Two of the reactions 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 or died of bleeding complications.

In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions 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 7 summarizes bleeding reactions that occurred in clinical trials which studied Fragmin 2500 and 5000 IU administered once daily to abdominal surgery patients.

Table 7
Bleeding Reactions Following Abdominal Surgery
Indication	Fragmin vs Placebo		Fragmin vs Fragmin
	Dosing Regimen		Dosing Regimen
Abdominal Surgery	Fragmin 2500 IU once daily subcutaneous n (%)	Placebo once daily subcutaneous n (%)	Fragmin 2500 IU once daily subcutaneous n (%)	Fragmin 5000 IU once daily subcutaneous n (%)
Postoperative Transfusions	14/182 (7.7)	13/182 (7.1)	89/1025 (8.7)	125/1033 (12.1)
Wound Hematoma	2/79 (2.5)	2/77 (2.6)	1/1030 (0.1)	4/1039 (0.4)
Reoperation Due to Bleeding	1/79 (1.3)	1/78 (1.3)	2/1030 (0.2)	13/1038 (1.3)
Injection Site Hematoma	8/172 (4.7)	2/174 (1.1)	36/1026 (3.5)	57/1035 (5.5)
Indication	Fragmin vs Heparin
	Dosing Regimen
Abdominal Surgery	Fragmin 2500 IU once daily subcutaneous n (%)	Heparin 5000 U twice daily subcutaneous n (%)	Fragmin 5000 IU once daily subcutaneous n (%)	Heparin 5000 U twice daily subcutaneous n (%)
Postoperative Transfusions	26/459 (5.7)	36/454 (7.9)	81/508 (15.9)	63/498 (12.7)
Wound Hematoma	16/467 (3.4)	18/467 (3.9)	12/508 (2.4)	6/498 (1.2)
Reoperation Due to Bleeding	2/392 (0.5)	3/392 (0.8)	4/508 (0.8)	2/498 (0.4)
Injection Site Hematoma	1/466 (0.2)	5/464 (1.1)	36/506 (7.1)	47/493 (9.5)

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

Medical Patients with Severely Restricted Mobility During Acute Illness

Table 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.

1  A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) intraocular, spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of ≥ 2 units of blood products; 4) required significant medical or surgical intervention; or 5) led to death.
Table 8
Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness
Indication	Dosing Regimen
Medical Patients with Severely Restricted Mobility	Fragmin 5000 IU once daily subcutaneous n (%)	Placebo once daily subcutaneous n (%)
Major Bleeding Reactions1 at Day 14	8/1848 (0.4)	0/1833 (0)
Major Bleeding Reactions1 at Day 21	9/1848 (0.5)	3/1833 (0.2)

Three of the major bleeding reactions 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).

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was 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.

1  Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that occurred at different time intervals were counted once in each interval in which the event occurred.
Table 9
Bleeding Reactions (Major and Any) (As treated population)1
Study period	Fragmin 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5 months			OAC Fragmin 200 IU/kg (max 18,000 IU) subcutaneous once daily x 5-7 days and OAC for 6 months (target INR 2-3)
	Number at risk	Patients with Major Bleeding n (%)	Patients with Any Bleeding n (%)	Number at risk	Patients with Major Bleeding n (%)	Patients with Any Bleeding n (%)
Total during study	338	19 (5.6)	46 (13.6)	335	12 (3.6)	62 (18.5)
Week 1	338	4 (1.2)	15 (4.4)	335	4 (1.2)	12 (3.6)
Weeks 2-4	332	9 (2.7)	17 (5.1)	321	1 (0.3)	12 (3.7)
Weeks 5-28	297	9 (3.0)	26 (8.8)	267	8 (3.0)	40 (15.0)

Thrombocytopenia

[See Warnings and Precautions (5.2)]

Elevations of Serum Transaminases

In Fragmin clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with Fragmin.

In the Fragmin clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with Fragmin for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.

Other

Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been reported.

Local Reactions: 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.

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of Fragmin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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). [see Boxed Warning]

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

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Side Effects by Body System - for Healthcare Professionals

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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