DALTEPARIN SODIUM
DESCRIPTION:
FRAGMIN Injection contains dalteparin sodium, which is a sterile, low molecular
weight heparin. Each syringe contains 2500 (16 mg dalteparin sodium) or 5000 (32
mg dalteparin sodium) anti- Factor Xa International units in 0.2 mL (with
reference to the W.H.O. First International Low Molecular Weight Heparin
Reference Standard). Each syringe also contains water for injection and sodium
chloride, when required, to maintain physiologic ionic strength. The pH of the
injection is 5.0 to 7.5. FRAGMIN is preservative free and intended for use only
as a single dose injection.
Dalteparin sodium is produced through controlled nitrous acid depolymerization
of sodium heparin from porcine intestinal mucosa followed by a chromatographic
purification process. It is composed of strongly acidic sulphated polysaccharide
chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end
groups) with an average molecular weight of 5000 and about 90+ACU- of the material
within the range 2000-9000. The molecular weight distribution is:
+ADw-3000 daltons 3.0-15.0+ACU-
3000 to 8000 daltons 65.0-78.0+ACU-
+AD4-8000 daltons 14.0-26.0+ACU-
ACTIONS/CLINICAL PHARMACOLOGY:
Dalteparin is a low molecular weight heparin with antithrombotic properties. It
acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. In
man, dalteparin potentiates preferentially the inhibition of coagulation Factor
Xa, while only slightly affecting clotting time, e.g., activated partial
thromboplastin time (APTT).
PHARMACODYNAMICS:
Doses of FRAGMIN Injection of up to 10,000 anti- Factor Xa IU administered
subcutaneously as a single dose or two 5,000 IU doses 12 hours apart to healthy
subjects do not produce a significant change in platelet aggregation,
fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin
time (TT) or APTT. Subcutaneous administration of doses of 5,000 IU b.i.d. of
FRAGMIN for seven consecutive days to patients undergoing abdominal surgery did
not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.
PHARMACOKINETICS:
Mean peak levels of plasma anti-Factor Xa activity following single subcutaneous
doses of 2,500, 5,000 and 10,000 IU were 0.19 0.04, 0.41 0.07 and 0.82
0.10 IU/mL, respectively, and were attained in about 4 hours in most
subjects. Absolute bioavailability in healthy volunteers, measured as the anti-
Factor Xa activity, was 87 6+ACU-. Increasing the dose from 2,500 to 10,000 IU
resulted in an overall increase in anti-Factor Xa AUC that was greater than
proportional by about one-third.
Peak anti-Factor Xa activity increased more or less linearly with dose over the
same dose range. There appeared to be no appreciable accumulation of anti-Factor
Xa activity with twice-daily dosing of 100 IU/kg subcutaneously for up to 7
days.
The volume of distribution for dalteparin anti- Factor Xa activity was 40 to 60
mL/kg. The mean plasma clearances of dalteparin anti-Factor Xa activity in
normal volunteers following single intravenous bolus doses of 30 and 120 anti-
Factor Xa IU/kg were 24.6 5.4 and 15.6 2.4 mL/hr/kg, respectively. The
corresponding mean disposition half-lives are 1. 47 0.3 and 2.5 0.3 hr.
Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were
2.1 0.3 and 2.3 0.4 hrs, respectively. Longer apparent terminal half-
lives (3 to 5 hrs) are observed following subcutaneous dosing, possibly due to
delayed absorption. In patients with chronic renal insufficiency requiring
hemodialysis, the mean terminal half-life of anti-Factor Xa activity following a
single intravenous dose of 5,000 IU FRAGMIN was 5.7 2.0 hrs, i.e.
considerably longer than values observed in healthy volunteers, therefore,
greater accumulation can be expected in these patients.
CLINICAL STUDIES:
FRAGMIN Injection, administered once-daily beginning prior to surgery and
continuing for 5 to 10 days after surgery, has been shown to prevent deep vein
thrombosis (DVT) in patients at risk for thromboembolic complications (see
INDICATIONS and DOSAGE AND ADMINISTRATION). Data from two double-blind
randomized controlled clinical trials performed in patients undergoing major
abdominal surgery, summarized in the following tables, show that FRAGMIN 2500 IU
was superior to placebo and similar to heparin in preventing DVT (see Tables 1
and 2).
TABLE 1
ABDOMINAL SURGERY
TREATMENT GROUP
FRAGMIN PLACEBO
DOSING REGIMEN 2500 IU qd qd
NUMBER OF PATIENTS TREATED 102 102
TREATMENT FAILURES
Total Thromboembolic Events (+ACU-) 4/91 (4.4)(+ACo-) 16/91 (17.6)
Proximal DVT (+ACU-) 0/91 (0) 5/91 (5.5)
Distal DVT (+ACU-) 4/91 (4.4) 11/91 (12.1)
PE (+ACU-) 0/91 (0) 2/91 (2.2)(+ACoAKg-)
+ACo- P-value versus placebo +AD0- 0.008
+ACoAKg- Both patients also had DVT, 1 proximal and 1 distal
TABLE 2
ABDOMINAL SURGERY
TREATMENT GROUP
FRAGMIN HEPARIN
DOSING REGIMEN 2500 IU qd 5000 IU bid
NUMBER OF PATIENTS TREATED 195 196
TREATMENT FAILURES
Total Thromboembolic Events (+ACU-) 7/178 (3.9)(+ACo-) 7/174 (4.0)
Proximal DVT (+ACU-) 3/178 (1.7) 4/174 (2.3)
Distal DVT (+ACU-) 3/178 (1.7) 3/174 (1.7)
PE (+ACU-) 1/178 (0.6) 0/174 (0)
+ACo- P-value versus heparin +AD0- 0.74
Data from a double-blind randomized controlled clinical trial show that FRAGMIN
5000 IU once daily is more effective than FRAGMIN 2500 IU once-daily in
preventing DVT in patients undergoing abdominal surgery with malignancy (see
Table 3).
TABLE 3
ABDOMINAL SURGERY PATIENTS WITH MALIGNANCY
INTENT TO TREAT
FRAGMIN FRAGMIN
DOSING REGIMEN 2500 IU qd 5000 IU qd
NUMBER OF PATIENTS TREATED 696 679
TREATMENT FAILURES
Total Thromboembolic Events (+ACU-) 99/656 (15.1)+ACo- 60/645 (9.3)
Proximal DVT (+ACU-) 18/657 (2.7) 14/646 (2.2)
Distal DVT (+ACU-) 80/657 (12.2) 41/646 (6.3)
PE (+ACU-)
Fatal 1/674 (0.1) 1/669 (0.1)
Non-fatal 2 4
+ACo- P+AD0- 0.001
INDICATIONS AND USAGE:
FRAGMIN Injection is indicated for prophylaxis against deep vein thrombosis,
which may lead to pulmonary embolism, in patients undergoing abdominal surgery
who are at risk for thromboembolic complications.
Patients at risk include patients who are over 40 years of age, obese,
undergoing surgery under general anesthesia lasting longer than 30 minutes or
who have additional risk factors such as malignancy or a history of deep vein
thrombosis or pulmonary embolism.
CONTRAINDICATIONS:
FRAGMIN Injection is contraindicated in patients with known hypersensitivity to
the drug, active major bleeding, or thrombocytopenia associated with positive in
vitro tests for anti-platelet antibody in the presence of FRAGMIN.
Patients with known hypersensitivity to heparin or pork products should not be
treated with FRAGMIN.
WARNINGS:
FRAGMIN Injection is not intended for intramuscular administration.
FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated
heparin or other low molecular weight heparins.
FRAGMIN SHOULD BE USED WITH EXTREME CAUTION IN PATIENTS WITH HISTORY OF HEPARIN-
INDUCED THROMBOCYTOPENIA.
HEMORRHAGE:
FRAGMIN, like other anticoagulants, should be used with extreme caution in
patients who have an increased risk of hemorrhage, such as those with severe
uncontrolled hypertension, bacterial endocarditis, congenital or acquired
bleeding disorders, active ulceration and angiodysplastic gastrointestinal
disease, hemorrhagic stroke or shortly after brain, spinal or ophthalmological
surgery.
As with other anticoagulants, bleeding can occur at any site during therapy with
FRAGMIN. An unexpected drop in hematocrit or blood pressure should lead to a
search for a bleeding site.
THROMBOCYTOPENIA:
Thrombocytopenia with platelet counts of +ADw-50,000/mm(raised to the power of 3)
and +ADw-100,000/mm(raised to the power of 3) occurred in +ADw-1+ACU- and +ADw-1+ACU-, respectively,
of patients undergoing abdominal surgery.
Thrombocytopenia of any degree should be monitored closely. Heparin-induced
thrombocytopenia can occur with the administration of FRAGMIN. The incidence of
this complication is unknown at present.
PRECAUTIONS:
GENERAL:
FRAGMIN Injection should not be mixed with other injections or infusions unless
specific compatibility data are available that support such mixing.
FRAGMIN should be used with caution in patients with bleeding diathesis,
thrombocytopenia or platelet defects+ADs- severe liver or kidney insufficiency,
hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding.
If a thromboembolic event should occur despite dalteparin prophylaxis, FRAGMIN
should be discontinued and appropriate therapy initiated.
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.
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+ACU-, 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.
CARCINOGENICITY, MUTAGENESIS, IMPAIRMENT OF FERTILITY:
Dalteparin sodium has not been tested for its carcinogenic potential in long-
term animal studies. It was not mutagenic in the In Vitro Ames Test, mouse
lymphoma cell forward mutation test and human lymphocyte chromosomal aberration
test and in the In Vivo mouse micronucleus test. Dalteparin sodium at
subcutaneous doses up to 1,200 IU/kg (7080 IU/m(squared)) did not affect the
fertility or reproductive performance of male and female rats.
PREGNANCY: PREGNANCY CATEGORY B.
TERATOGENIC EFFECTS:
Reproduction studies with dalteparin sodium at intravenous doses up to 2400
IU/kg (14160 IU/m(squared)) in pregnant rats and 4800 IU/kg (40800
IU/m(squared)) in pregnant rabbits did not produce any evidence of impaired
fertility or harm to the fetuses. There are, however, no adequate and well-
controlled studies in pregnant women. Because animal reproduction studies are
not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
NURSING MOTHERS:
It is not known whether dalteparin sodium is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when FRAGMIN
is administered to a nursing mother.
Pediatric Use:
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
FRAGMIN should be used with care in patients receiving oral anticoagulants
and/or platelet inhibitors because of increased risk of bleeding.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
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+ADs-
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+ACU- and 3.6+ACU-, 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+ACU-
and 2.7+ACU-, respectively (n.s.) in the malignancy subgroup.
The following table summarizes adverse bleeding events that occurred in clinical
trials which studied FRAGMIN 2500 and 5000 IU administered once daily to
abdominal surgery patients.
FRAGMIN vs. Heparin(+ACo-) FRAGMIN vs. Placebo FRAGMIN vs. FRAGMIN
FRAGMIN Heparin FRAGMIN Heparin FRAGMIN Placebo FRAGMIN FRAGMIN
2500 IU/10000 IU/5000 IU/10000 IU/2500 IU/ 2500 IU/5000 IU/
24 hr 24 hr 24 hr 24 hr 24 hr 24 hr 24 hr
Post- 5.7+ACU- 7.9+ACU- 15.9+ACU- 12.7+ACU- 7.7+ACU- 7.1+ACU- 8.7+ACU- 12.1+ACU-
Operational (n+AD0-459) (n+AD0-454) (n+AD0-508) (n+AD0-498) (n+AD0-182) (n+AD0-182) (n+AD0-1025) (n+AD0-1033)
Transfusions
Wound 3.4+ACU- 3.9+ACU- 2.4+ACU- 1.2+ACU- 2.5+ACU- 2.6+ACU- 0.1+ACU- 0.4+ACU-
Hematoma (n+AD0-467) (n+AD0-467) (n+AD0-508) (n+AD0-498) (n+AD0-79) (n+AD0-77) (n+AD0-1030) (n+AD0-1039)
Reoperation 0.5+ACU- 0.8+ACU- 0.8+ACU- 0.4+ACU- 1.3+ACU- 1.3+ACU- 0.2+ACU- 1.3+ACU-
due to (n+AD0-392) (n+AD0-392) (n+AD0-508) (n+AD0-498) (n+AD0-79) (n+AD0-78) (n+AD0-1030) (n+AD0-1038)
Bleeding
Injection 0.2+ACU- 1.1+ACU- 7.1+ACU- 9.5+ACU- 4.7+ACU- 1.1+ACU- 3.5+ACU- 5.5+ACU-
Site
Hematoma (n+AD0-466) (n+AD0-464) (n+AD0-506) (n+AD0-493) (n+AD0-172) (n+AD0-174) (n+AD0-1026) (n+AD0-1035)
+ACo- FRAGMIN administered once-daily, heparin administered twice daily at a dose
of 5000 IU.
THROMBOCYTOPENIA:
During clinical trials with FRAGMIN in thromboprophylaxis, thrombocytopenia,
platelet counts of +ADw-50,000/mm(raised to the power of 3) and +ADw-100,000/mm(raised
to the power of 3) were reported in +ADw-1+ACU- and +ADw-1+ACU-, respectively, of patients given
FRAGMIN and +ADw-1+ACU- and 1+ACU- of patients given heparin.
OTHER:
Pain at injection site was seen in the following percentages of patients
involved in clinical trials: 0+ACU- for FRAGMIN 2500 IU qd vs 0.4+ACU- for heparin 5000
IU bid+ADs- 4.5+ACU- for FRAGMIN 5000 IU qd vs 11.8+ACU- for heparin 5000 IU bid+ADs- 0+ACU- for
FRAGMIN 2500 IU qd vs 0+ACU- for placebo and 1.1+ACU- for FRAGMIN 2500 IU qd vs 1.8+ACU- for
FRAGMIN 5000 IU qd.
Allergic reactions (i.e., pruritus, rash, fever, injection site reaction,
bulleous eruption) and skin necrosis have occurred rarely. A few cases of
anaphylactoid reactions have been reported.
OVERDOSAGE:
SYMPTOMS/TREATMENT:
An excessive dosage of FRAGMIN Injection may lead to hemorrhagic complications.
These may generally be stopped by the slow intravenous injection of protamine
sulfate (1+ACU- solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of
FRAGMIN given. A second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU
of FRAGMIN may be administered if the APTT measured 2 to 4 hours after the first
infusion remains prolonged. Even with these additional doses of protamine, the
APTT may remain more prolonged than would usually be found following
administration of conventional heparin. In all cases, the anti- Factor Xa
activity is never completely neutralized (maximum about 60 to 75+ACU-).
Particular care should be taken to avoid overdosage with protamine sulfate.
Administration of protamine sulfate can cause severe hypotensive and
anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis,
have been reported with protamine sulfate, it should be given only when
resuscitation techniques and treatment of anaphylactic shock are readily
available. For additional information, consult the labeling of Protamine Sulfate
Injection, USP, products. A single subcutaneous dose of 100,000 IU/kg of FRAGMIN
to mice caused a mortality of 8+ACU- (1/12) whereas 50,000 IU/kg was a non-lethal
dose. The observed sign was hematoma at the site of injection.
DOSAGE AND ADMINISTRATION:
In patients undergoing abdominal surgery with a risk of thromboembolic
complications, 2500 IU of FRAGMIN Injection should be administered
subcutaneously only, each day, starting 1 to 2 hours prior to surgery and
repeated once daily for 5 to 10 days postoperatively (refer to INDICATIONS).
In abdominal surgery associated with a high risk of thromboembolic
complications, such as malignant disorder, 5000 IU should be administered
subcutaneously only the evening before surgery and repeated once daily for 5 to
10 days postoperatively. Alternatively in patients with malignancy, the first
5000 IU dose can be administered as 2500 IU s.c. 1 to 2 hours prior to surgery
with an additional 2500 IU s.c. dose 12 hours later and then 5000 IU once daily
for 5 to 10 days.
Dosage adjustment and routine monitoring of coagulation parameters are not
required if the dosage and administration recommendations specified above are
followed.
ADMINISTRATION:
FRAGMIN is administered by subcutaneous injection. It must not be administered
by intramuscular injection.
Subcutaneous injection technique: Patients should be sitting or lying down and
FRAGMIN administered by deep subcutaneous injection. FRAGMIN may be injected in
a U-shape area around the navel, the upper outer side of the thigh or the upper
outer quadrangle of the buttock. The injection site should be varied daily. When
the area around the navel or the thigh is used, using the thumb and forefinger,
you must lift up a fold of skin while giving the injection. The entire length of
the needle should be inserted at a 45 to 90 degree angle.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.