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Fragmin (Dalteparin Sodium) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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 (%)
  Heparin 2
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
  FRAGMIN 2
5000 IU once daily subcutaneous
n (%)
  Warfarin
Sodium1 oral
n (%)
  FRAGMIN 4
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.



REPORTS OF SUSPECTED FRAGMIN SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Fragmin. The information is not vetted and should not be considered as verified clinical evidence.

Possible Fragmin side effects / adverse reactions in 44 year old female

Reported by a health professional (non-physician/pharmacist) from United Kingdom on 2011-10-04

Patient: 44 year old female

Reactions: Wrong Technique in Drug Usage Process, Injury Associated With Device

Suspect drug(s):
Fragmin



Possible Fragmin side effects / adverse reactions in 76 year old female

Reported by a health professional (non-physician/pharmacist) from France on 2011-10-05

Patient: 76 year old female

Reactions: Confusional State, Disturbance in Attention

Adverse event resulted in: hospitalization

Suspect drug(s):
Pariet (Rabeprazole Sodium) Gastro-Resistant Tablet
    Dosage: 10 mg, 1 x/day
    Start date: 2011-08-24
    End date: 2011-09-13

Topalgic LP (Tramadol Hydrochloride) Prolonged-Release Tablet
    Dosage: 150 mg, 2x/day, oral
    Administration route: Oral
    Start date: 2011-08-24
    End date: 2011-09-12

Primperan TAB
    Dosage: 1 df, 3x/dav, oral
    Administration route: Oral
    Start date: 2011-08-24
    End date: 2011-09-13

Mianserin Hydrochloride (Mianserin Hydrochloride)
    Dosage: 10 mg, 1x/day, oral
    Administration route: Oral
    Start date: 2011-09-09
    End date: 2011-09-12

Fragmin
    Dosage: 5000 iu, 1 x/day, intravenous
    Start date: 2011-08-24



Possible Fragmin side effects / adverse reactions in 76 year old female

Reported by a health professional (non-physician/pharmacist) from France on 2011-10-11

Patient: 76 year old female

Reactions: Confusional State, Disturbance in Attention

Adverse event resulted in: hospitalization

Suspect drug(s):
Tramadol HCL
    Dosage: 150 mg, 2x/day, oral
    Administration route: Oral
    Start date: 2011-08-24
    End date: 2011-09-12

Rabeprazole Sodium
    Dosage: 10 mg, 1x/day
    Start date: 2011-08-24
    End date: 2011-09-13

Mianserin Hydrochloride (Mianserin Hydrochloride)
    Dosage: 10 mg, 1x/day, oral
    Administration route: Oral
    Start date: 2011-09-09
    End date: 2011-09-12

Metoclopramide
    Dosage: 1 df, 3x/day, oral
    Administration route: Oral
    Start date: 2011-08-24
    End date: 2011-09-13

Fragmin
    Dosage: 5000 iu anti xa/0.2ml, 1x/day, intravenous
    Start date: 2011-08-24



See index of all Fragmin side effect reports >>

Drug label data at the top of this Page last updated: 2014-03-21

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