The following serious adverse reactions are described in more detail in other sections of the prescribing information.
- Risk of Hemorrhage including Spinal/Epidural Hematoma [see WARNINGS AND PRECAUTIONS]
- Thrombocytopenia [see WARNINGS AND PRECAUTIONS]
- Benzyl Alcohol preservative Risk to Premature Infants [see WARNINGS AND PRECAUTIONS]
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.
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.
Table 5 : Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction
|Unstable Angina and Non-Q-Wave MI||FRAGMIN 120 IU/kg/12 hr subcutaneous1
|Heparin2 intravenous and subcutaneous2
|Placebo every 12 hr subcutaneous
|Major Bleeding Reactions3,4||15/1497 (1.0)||7/731 (1.0)||4/760 (0.5)|
|1Treatment was administered for 5 to 8 days.
2Heparin 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.
3Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently.
4Bleeding 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.
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.
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)|
|1Warfarin 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.
2Includes three treated patients who did not undergo a surgical procedure.
3A 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.
4Includes two treated patients who did not undergo a surgical procedure.
5Occurred at a rate of at least 2% in the group treated with FRAGMIN 5000 IU once daily.
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.
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 (11)||36/1026 (3.5)||57/1035 (5.5)|
|Indication||FRAGMIN vs Heparin|
|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 (11)||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.
Table 8 : Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness
|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)|
|1A 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.|
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.
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)|
|1Patients 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.|
[see WARNINGS AND PRECAUTIONS]
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 (NCICTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.
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.
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.