A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Fragmin Side Effects, and Drug Interactions - Dalteparin
Fragmin Side Effects, and Drug Interactions - Dalteparin
SIDE EFFECTS
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 study 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 study comparing FRAGMIN 5000 IU once daily to heparin
5000 IU twice daily, the incidence
of bleeding events was 3.2% and 2.7%, respectively (n.s.) in the
malignancy subgroup.
Abdominal Surgery
Table 5 summarizes bleeding
events that occurred in clinical
trials which studied FRAGMIN 2500 and 5000 IU administered once
daily to abdominal surgery patients.
Table 5
Bleeding Events in Abdominal Surgery
|
Indication
Abdominal Surgery
|
FRAGMIN vs Heparin
|
FRAGMIN vs Placebo
|
FRAGMIN vs FRAGMIN
|
|
Dosing Regimen
|
Dosing Regimen
|
Dosing Regimen
|
|
FRAGMIN
|
Heparin
|
FRAGMIN
|
Heparin
|
FRAGMIN
|
Placebo
|
FRAGMIN
|
FRAGMIN
|
|
2500 IU
qd s.c.
|
5000 U bid s.c.
|
5000 IU
qd s.c.
|
5000 U
bid s.c.
|
2500 IU
qd s.c.
|
qd s.c.
|
2500 IU
qd s.c.
|
5000 IU
qd s.c.
|
|
Postoperative
Transfusions
|
26/ 459
(5.7%)
|
36/ 454
(7.9%)
|
81/ 508
(15.9%)
|
63/ 498
(12.7%)
|
14/ 182
(7.7%)
|
13/ 182
(7.1%)
|
89/ 1025
(8.7%)
|
125/ 1033
(12.1%)
|
|
Wound Hematoma
|
16/ 467
(3.4%)
|
18/ 467
(3.9%)
|
12/ 508
(2.4%)
|
6/ 498
(1.2%)
|
2/ 79
(2.5%)
|
2/ 77
(2.6%)
|
1/ 1030
(0.1%)
|
4/ 1039
(0.4%)
|
|
Reoperation due to
Bleeding
|
2/ 392
(0.5%)
|
3/ 392
(0.8%)
|
4/ 508
(0.8%)
|
2/ 498
(0.4%)
|
1/ 79
(1.3%)
|
1/ 78
(1.3%)
|
2/ 1030
(0.2%)
|
13/ 1038
(1.3%)
|
|
Injection Site
Hematoma
|
1/ 466
(0.2%)
|
5/ 464
(1.1%)
|
36/ 506
(7.1%)
|
47/ 493
(9.5%)
|
8/ 172
(4.7%)
|
2/ 174
(1.1%)
|
36/ 1026
(3.5%)
|
57/ 1035
(5.5%)
|
Hip Replacement Surgery
Table 6 summarizes:
- all major bleeding
events and
- other bleeding
events possibly or probably related to treatment
with FRAGMIN, warfarin, or heparin
in clinical trials
of hip replacement
surgery.
Table 6
Bleeding Events in Hip Replacement Surgery
|
Indication
|
FRAGMIN vs Warfarin Sodium
|
FRAGMIN vs Heparin
|
|
Dosing Regimen
|
Dosing Regimen
|
|
Hip Replacement
Surgery
|
FRAGMIN
5000 IU qd s.c.
(n = 2742 )
|
Warfarin Sodium1
Oral
(n = 279)
|
FRAGMIN
5000 IU qd s.c.
(n = 694)
|
Heparin
5000 U tid such
(n = 69)
|
|
Major Bleeding Events 3
|
7/ 274 (2.6%)
|
1/ 279 (0.4%)
|
0
|
3/ 69 (4.3%)
|
|
Other Bleeding Events 5 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%)
|
- 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:
- hemorrhage caused a significant
clinical event,
- it was associated with a hemoglobin
decrease of ³2
g/dL or transfusion
of 2 or more units of blood
products,
- it resulted in reoperation due to bleeding,
or
- 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.
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.
Thrombocytopenia: (See WARNINGS:
Thrombocytopenia.)
Other
Allergic Reactions: Allergic reactions (i.e., pruritus,
rash, fever, injection
site reaction,
bullous eruption) and
skin necrosis have occurred
rarely. A few cases of anaphylactoid reactions have been reported.
Local Reactions: Pain at 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 qd vs 11.8% of patients treated with heparin
5000 U bid 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 qd vs 13% of patients treated
with heparin 5000 U
tid.
Ongoing Safety Surveillance: Since first international
market introduction in 1985, there have been 5 reports of epidural
or spinal hematoma formation
with concurrent use of dalteparin sodium
and spinal/epidural anethesia or spinal
puncture. No cases have been
reported in the United States since approval in 1994. Four of the
5 patients had post-operative indwelling epidural
catheters placed for analgesia
or received additional drugs affecting hemostasis. The hematomas
caused long-term or permanent paralysis in four of the cases (one
complete, three partial paralyses). The fifth patient
experienced temporary paraplegia
but made a full recovery. Because these events were reported voluntarily
from a population
of unknown size, estimates of frequency
cannot be made.
DRUG INTERACTIONS
Drug Interactions
FRAGMIN should be used with care in patients receiving oral
anticoagulants and/or platelet
inhibitors because of increased risk
of bleeding.
Laboratory Tests
Periodic routine complete blood
counts, including platelet
count, and stool occult
blood tests are recommended
during the course of treatment with FRAGMIN. No
special monitoring of blood
clotting times (e.g.,
APTT) is needed.
When administered at recommended prophylaxis
doses, routine coagulation tests such
as Prothrombin Time (PT) and Activated Partial Thromboplastin Time
(APTT) are relatively insensitive measures of FRAGMIN activity
and, therefore, unsuitable for monitoring.
Drug/Laboratory Test Interactions
Elevations of Serum Transaminases: Asymptomatic increases
in transaminase
levels (SGOT/AST and SGPT/ALT) greater than three times the upper
limit of normal
of the laboratory
reference range have been
reported in 1.7 and 4.3%, respectively, of patients during treatment
with FRAGMIN. Similar significant
increases in transaminase
levels have also been observed in patients treated with heparin
and other low molecular weight
heparins. Such elevations are fully reversible
and are rarely associated with increases in bilirubin. Since transaminase
determinations are important in the differential diagnosis of myocardial
infarction, liver disease
and pulmonary emboli,
elevations that might be caused by drugs like FRAGMIN should be
interpreted with caution.
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