Sorry, you need to enable JavaScript to visit this website.

FRAGMIN (dalteparin sodium)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of
Administration
Dosage Form / StrengthClinically
Relevant
Nonmedicinal
Ingredients
ParenteralSolution
Ampoule:
10 000 IU (anti-factor Xa)/1 mL;
Multi-Dose Vial:
25 000 IU (anti-factor Xa)/mL 3.8 mL
Single-Dose Vial:
2 500 IU (anti-factor Xa)/mL 4 mL

Prefilled syringe with safety needle device
2 500 IU (anti-factor Xa)/0.2 mL
3500 IU (anti-factor Xa)/0.28 mL
5 000 IU (anti-factor Xa)/0.2 mL
7 500 IU (anti-factor Xa)/0.3 mL
10 000 IU (anti-factor Xa)/0.4 mL
12 500 IU (anti-factor Xa)/0.5 mL
15 000 IU (anti-factor Xa)/0.6 mL
18 000 IU (anti-factor Xa)/0.72 mL

Benzyl alcohol in Multi-Dose vial only.

For a complete listing, see Dosage Forms,
Composition and Packaging section

Indications And Clinical Use

FRAGMIN (Dalteparin Sodium Injection) is indicated for:

  • Thromboprophylaxis in conjunction with surgery
  • Treatment of acute deep venous thrombosis
  • Unstable coronary artery disease (UCAD), i.e., unstable angina and non-Q-wave myocardial infarction
  • Prevention of clotting in the extracorporeal system during hemodialysis and hemofiltration in connection with acute renal failure or chronic renal insufficiency
  • Extended treatment of symptomatic venous thromboembolism to prevent recurrence of venous thromboembolism in patients with cancer
  • Reduction of deep vein thrombosis (DVT) in hospitalized patients with severely restricted mobility during acute illness. Decreased mortality due to thromboembolic events and complications has not been demonstrated

Contraindications

FRAGMIN should not be used in patients who have the following:

  • Hypersensitivity to FRAGMIN or any of its constituents, including benzyl alcohol (when using the 25,000 IU multi-dose vial) (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women), or to other low molecular weight heparins and/or heparin or pork products.
  • History of confirmed or suspected immunologically-mediated heparin-induced thrombocytopenia (delayed-onset severe thrombocytopenia), and/or in patients in whom an in vitro platelet-aggregation test in the presence of FRAGMIN is positive
  • Septic endocarditis (endocarditis lenta, acute or subacute endocarditis)
  • Uncontrollable active bleeding
  • Major blood clotting disorders
  • Acute gastroduodenal ulcer
  • Cerebral hemorrhage
  • Severe uncontrolled hypertension
  • Diabetic or hemorrhagic retinopathy
  • Other conditions or diseases involving an increased risk of hemorrhage
  • Injuries to and operations on the central nervous system, eyes, and ears
  • Spinal/epidural anesthesia is contraindicated where concomitant treatment with repeated high doses of FRAGMIN (100-120 IU/kg given twice daily or 200 IU/kg once daily, such as those needed to treat acute deep-vein thrombosis and unstable coronary artery disease) are required, due to an increased risk of bleeding

Warnings And Precautions

Special Warnings and Precautions
The multi-dose vial of FRAGMIN (25,000 IU/mL) contains benzyl alcohol (14 mg/mL) as a preservative. Benzyl alcohol has been associated with a potentially fatal “Gasping Syndrome” in neonates. Because benzyl alcohol may cross the placenta, FRAGMIN preserved with benzyl alcohol should not be used in pregnant women (see Special Populations, Pregnant Women).

General

FRAGMIN should NOT be administered intra-muscularly.

FRAGMIN CANNOT BE USED INTERCHANGEABLY (UNIT FOR UNIT) WITH UNFRACTIONATED HEPARIN (UFH) OR OTHER LOW MOLECULAR WEIGHT HEPARINS (LMWHs) AS THEY DIFFER IN THEIR MANUFACTURING PROCESS, MOLECULAR WEIGHT DISTRIBUTION, ANTI-Xa AND ANTI-IIa ACTIVITIES, UNITS AND DOSAGES. SPECIAL ATTENTION AND COMPLIANCE WITH INSTRUCTIONS FOR USE OF EACH SPECIFIC PRODUCT ARE REQUIRED DURING ANY CHANGE IN TREATMENT.

Cardiovascular

Use in Patients with Prosthetic Heart Valves: Cases of prosthetic valve thrombosis have been reported in these patients who have received low molecular weight heparins for thromboprophylaxis. Some of these patients were pregnant women in whom thrombosis led to maternal and/or fetal deaths. Pregnant women are at higher risk of thromboembolism (see WARNINGS AND PRECAUTIONS, Special populations, Pregnant Women).

Use in Unstable Coronary Artery Disease: When thrombolytic treatment is considered appropriate in patients with unstable angina and non-Q-wave myocardial infarction, concomitant use of an anticoagulant such as FRAGMIN may increase the risk of bleeding.

Gastrointestinal

FRAGMIN should be used with caution in patients with a history of gastrointestinal ulceration.

Hematologic

Hemorrhage: Bleeding may occur in conjunction with unfractionated heparin or low molecular weight heparin use. As with other anticoagulants, FRAGMIN should be used with extreme caution in patients at increased risk of hemorrhage. 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 (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Bleeding, Post-Marketing Adverse Drug Reactions).

Platelets/Thrombocytopenia: Platelet counts should be determined prior to the start of treatment with FRAGMIN and, subsequently, twice weekly for the duration of treatment. Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. Its incidence is unknown at present.

Caution is recommended when administering FRAGMIN to patients with congenital or drug induced thrombocytopenia or platelet defects.

During FRAGMIN administration, special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100 000/μL). A positive or unknown result obtained from in vitro tests for antiplatelet antibody in the presence of FRAGMIN or other low molecular weight heparins and/or heparins would contraindicate FRAGMIN.

Hepatic

FRAGMIN should be used with caution in patients with hepatic insufficiency, as these patients may have potentially higher risk of hemorrhage (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Liver).

Hyperkalemia

Heparin and low molecular weight Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium or taking potassium sparing drugs.Plasma potassium should be measured in patients at risk.

Osteoporosis

Long term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with dalteparin the risk of osteoporosis cannot be excluded (see TOXICOLOGY, Long-term Toxicity, Human Toxicology).

Peri-Operative Considerations

Spinal/Epidural Hematomas:

When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non- steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see CONTRAINDICATIONS and ADVERSE REACTIONS).

When a higher dose (5000 IU s.c.) of FRAGMIN is administered for thromboprophylaxis in conjunction with surgery, no spinal/epidural invasion should be performed for at least 12 hours following the last dose of FRAGMIN and the next dose should be held until at least 12 hours after the anaesthetic procedure. Alternatively, when a lower dose (2500 IU s.c.) of FRAGMIN is administered, the dose can be initiated 1 - 2 hours prior to surgery. FRAGMIN injection should be given after spinal/epidural anaesthesia and only if the anaesthesiologist considers the spinal/epidural puncture as uncomplicated. Indwelling catheters should not be removed or manipulated for at least 10 - 12 hours following the last dose of FRAGMIN.

In patients receiving higher therapeutic dalteparin doses (such as 100IU/kg -120 IU/kg every 12 hours or 200 IU/kg once daily), the interval for the insertion or removal of the epidural or spinal catheter should be a minimum of 24 hours. Extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction.

Use in Knee Surgery: The risk of bleeding in knee surgery patients receiving low molecular weight heparins may be greater than in other orthopedic surgical procedures. It should be noted that hemarthrosis is a serious complication of knee surgery. The frequency of bleeding events observed with FRAGMIN in orthopedic surgery patients is derived from clinical trials in hip replacement surgery patients. The physician should weigh the potential risks with the potential benefits to the patient in determining whether to administer a low molecular weight heparin in this patient population.

Selection of General Surgery Patients: Risk factors associated with postoperative venous thromboembolism following general surgery include history of venous thromboembolism, varicose veins, obesity, heart failure, malignancy, previous long bone fracture of a lower limb, bed rest for more than 5 days prior to surgery, predicted duration of surgery of more than 30 minutes, and age 60 years or above.

Renal

FRAGMIN should be used with caution in patients with renal insufficiency.

Patients with impaired renal function should be carefully monitored because the half-life for anti-Xa activity after administration of low molecular weight heparin may be prolonged in this patient population (see ACTION AND CLINICAL PHARMACOLOGY, and DOSAGE AND ADMINISTRATION, Use in Patients with Renal Impairment). Dose reduction should be considered in patients with severe renal impairment.

Meanwhile, emerging data from publications based on one study suggests that in critically ill patients with severe renal insufficiency, thromboprophylaxis with Fragmin at 5,000 IU once daily, does not appear to be associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding8, 13 (see ACTION AND CLINICAL PHARMACOLOGY – special populations and conditions, Renal Insufficiency).

Special Populations

Pregnant Women:

The multi-dose vial of FRAGMIN (25,000 IU/mL) contains benzyl alcohol (14 mg/mL) as a preservative. Benzyl alcohol has been associated with serious adverse events, including a potentially fatal “Gasping Syndrome” in neonates. Cases of Gasping Syndrome have been reported in neonates when benzyl alcohol has been administered in amounts of 99-404 mg/kg/day. Manifestations of the disease include: metabolic acidosis, respiratory distress, gasping respirations, central nervous system dysfunction, convulsions, intracranial hemorrhages, hypoactivity, hypotonia, cardiovascular collapse and death. Benzyl alcohol containing formulations must not be used in premature or newborn babies. Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys’ capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old. Other formulations without benzyl alcohol are available. Because benzyl alcohol may cross the placenta, FRAGMIN preserved with benzyl alcohol should not be used in pregnant women.

There are also postmarketing reports of prosthetic valve thrombosis in pregnant women with prosthetic heart valves while receiving low molecular weight heparins for thromboprophylaxis. These events led to maternal death or surgical interventions.

Pregnant women with prosthetic heart valves appear to be at exceedingly high risk of thromboembolism. An incidence of thromboembolism approaching 30% has been reported in these patients, in some cases even with apparent adequate anticoagulation at treatment doses of low molecular weight heparins or unfractionated heparin. Any attempt to anticoagulate such patients should normally only be undertaken by medical practitioners with documented expertise and experience in this clinical area.

Data from one single publication suggests that ante partum thromboprophylaxis is warranted in pregnant women with idiopathic thrombosis or symptomatic thrombophilia4 (see ACTION AND CLINICAL PHARMACOLOGY – special populations and conditions, Pregnant Women)

Teratogenic Effects: As with other low molecular weight heparins (LMWH), FRAGMIN should not be used in pregnant women unless the therapeutic benefits to the patients outweigh the possible risks. There have been reports of congenital anomalies in infants born to women who received LMWHs during pregnancy, including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia and cardiac defects. A causal relationship has not been established nor has the incidence been shown to be higher than in the general population.

Non-teratogenic Effects: There have been postmarketing reports of fetal death when pregnant women received low molecular weight heparins. Causality for these cases has not been established. Pregnant women receiving anticoagulants, including FRAGMIN, are at increased risk for bleeding. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women receiving FRAGMIN should be carefully monitored. Pregnant women and women of child-bearing potential should be informed of the potential hazard to the fetus and the mother if FRAGMIN is administered during pregnancy.

Nursing Women:

It is not known whether FRAGMIN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FRAGMIN is administered to nursing women.

Fertility:

Four animal studies were conducted with Heparin fragment Kabi 2165 (dalteparin sodium) in rats and rabbits32. No effects on fertility, copulation or peri- and postnatal development were noted in these studies.

Pediatrics:

The safety and effectiveness of FRAGMIN in children have not been established. There is currently available data but no recommendation on a posology can be made (see ACTION AND CLINICAL PHARMACOLOGY, Pediatric population).

Geriatrics:

Elderly patients receiving low molecular weight heparins are at increased risk of bleeding. Careful attention to dosing intervals and concomitant medications, especially anti-platelet preparations, is advised. Close monitoring of elderly patients with low body weight (e.g., <45 kg) and those predisposed to decreased renal function is recommended.

Patients with Extreme Body Weight:

Safety and efficacy of low molecular weight heparins in high weight (e.g., >120 kg) and low weight (e.g., <46 kg) patients have not been fully determined. Individualized clinical and laboratory monitoring are recommended in these patients.

However, data from one single publication suggests that in the thrombosis treatment setting, a weight-adjusted dose beyond the recommended maximum dose of 18000 International Units/day (the largest patient weighed 190 Kg and received a daily dose of 38000 IU) results in mean peak anti-Xa levels that are within the therapeutically acceptable range30 (see ACTION AND CLINICAL PHARMACOLOGY – special populations and conditions, Overweight Population)

Monitoring and Laboratory Tests

Monitoring FRAGMIN Activity: Determination of anti-factor Xa levels in plasma is the only method available for monitoring FRAGMIN activity. Routine clotting assays are unsuitable for monitoring its anticoagulant activity. Only at very high plasma FRAGMIN levels is activated partial thromboplastin time (APTT) prolongation observed. Prolongation of APTT during hemodialysis and treatment of acute deep venous thrombosis should only be used as a criterion of overdose. Dose increases aimed at prolonging APTT could cause overdosing and bleeding.

Measurement of peak anti-Xa levels at about 4 hours post-dose should be considered in patients at higher risk of bleeding and receiving FRAGMIN, such as the elderly, patients with renal impairment or the extremes of body weight, during pregnancy, or for children. At treatment doses of 100 IU/kg s.c. twice daily, peak anti-Xa levels should generally be maintained at no more than 1.0 IU/mL in these patients.

When FRAGMIN is administered subcutaneously, the individual patient’s anti-Xa activity level will not remain within the range that would be expected with unfractionated heparin by continuous i.v. infusion throughout the entire dosing interval. FRAGMIN should be administered as directed (see DOSAGE AND ADMINISTRATION).

DosageAnti-Xa levels (IU/mL) at peak 3 - 4 hours post s.c. injections* Mean ± SD
2500 IU0.20 ± 0.08
5000 IU0.49 ± 0.13
100 IU/kg0.61 ± 0.17
120 IU/kg 0.91 ± 0.32
200 IU/kg1.2 ± 0.43

* For 2500 IU and 5000 IU (given as single doses), peak levels were obtained from populations of healthy volunteers; for multiple doses of 100 IU/kg twice daily, 120 IU/kg twice daily and 200 IU/kg once daily, peak levels were obtained from patient populations treated for acute DVT.

At higher doses, increases in APTT may occur. With normal prophylactic doses, FRAGMIN does not modify global clotting tests of APTT, prothrombin time (PT) and thrombin clotting time (TT). Therefore, treatment cannot be monitored with these tests.

Liver Function Tests: Since FRAGMIN use may be associated with a rise in hepatic transaminases, this observation should be considered when liver function tests are assessed (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Liver).

As with all antithrombotic agents, there is a risk of systemic bleeding with dalteparin sodium administration. Care should be taken with dalteparin sodium use in newly operated patients. After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain, periodic measurements of hemoglobin, and anti-Xa determinations.

Adverse Reactions

Adverse Drug Reaction Overview

Clinically significant adverse reactions observed with use of FRAGMIN and other low molecular weight heparins include bleeding events and local reactions, with a low incidence of thrombocytopenia and allergic reactions.

Clinical Trial Adverse Drug Reactions

Bleeding

As with any antithrombotic treatment, hemorrhagic manifestations can occur. Injection site hematomas are a common side effect with FRAGMIN (dalteparin sodium), occurring at a frequency of less than 5% with lower (prophylaxis) doses and less than 10% with higher (treatment) doses.

The incidence of major hemorrhagic complications during FRAGMIN treatment has been low and generally did not differ from that observed with unfractionated heparin. Patients taking FRAGMIN are at risk for major bleeding complications when plasma anti-Xa levels approach 2.1 IU/mL. Other risk factors associated with bleeding on therapy with heparins include serious concurrent illness, chronic heavy consumption of alcohol, use of platelet inhibiting drugs, renal failure, age and, possibly, female gender. Petechiae or easy bruising may precede frank hemorrhage. Bleeding may range from minor local hematomas to major hemorrhage. The early signs of bleeding may include epistaxis, hematuria, or melena. Bleeding may occur at any site and be difficult to detect, for example, retroperitoneal bleeding. Bleeding may also occur at surgical sites. Major hemorrhage, including retroperitoneal or intracranial bleeding, has been reported in association with FRAGMIN use, in some cases leading to fatality. Spinal or epidural hematomas have been reported with the concurrent use of FRAGMIN and spinal/epidural anaesthesia.

Thromboprophylaxis in Conjunction with Surgery

The following table summarizes major bleeding events that occurred in pivotal trials of FRAGMIN for thromboprophylaxis in general surgery associated with thromboembolic complications.

Bleeding Events for Thromboprophylaxis in General Surgery Associated with Thromboembolic Complications
 FRAGMIN1
N=385
n (%)
Heparin2
N=265
n (%)
Placebo
N=108
n (%)
Major bleeding   
Wound or Perioperative11 (2.9)3 (1.1)4 (3.7)
Bleed10 (2.6)2 (0.8)4 (3.7)
Wound hematoma1 (0.3)1 (0.4)0 (0.0)

Treatment for at least 5-7 days

1
2500 IU s.c. 2 hours before surgery, then 2500 IU daily
2
Heparin 5000 IU s.c. 2 hours before surgery, then 12 hours later and once daily thereafter

The following table summarizes major bleeding events that occurred in pivotal trials of FRAGMIN for thromboprophylaxis in general surgery associated with other risk factors (e.g., malignancy) and trials of elective hip surgery.

Bleeding Events for Thromboprophylaxis in General Surgery Associated with Other Risk Factors and Elective Hip Surgery
 

General Surgery

Associated with Other Risk Factors*

Elective Hip Surgery

FRAGMIN vs Warfarin sodium**

FRAGMIN vs Heparin*

FRAGMIN1

N=543

n (%)

Heparin2

N=533

n (%)

FRAGMIN3

started before surgery

N=496

n (%)

FRAGMIN4

started after surgery

N=487

n (%)

Warfarin sodium5 N=489

n (%)

FRAGMIN1

N=69

n (%)

Heparin2

N=97

n (%)

Major bleeding

11 (2.0)

10 (1.9)

18 (3.6)

12 (2.5)

15 (3.1)

0 (0.0)

3 (4.3)

*
Treatment for at least 5-10 days
**
Treatment for 6 ± 2 days
1
5000 IU s.c. once daily after surgery with the initial dose given 8 hours before surgery; or 2500 IU 2 hours before surgery and 2500 IU 12 hours later, then 5000 IU once daily
2
Heparin 5000 IU s.c. 2 hours before surgery, 5000 IU s.c. evening of surgery, then 5000 IU s.c. twice daily; or 5000 IU s.c. three times daily
3
2500 IU s.c. 2 hours before surgery, 2500 IU s.c. at least 4 hours after surgery, then 5000 IU s.c. once daily
4
2500 IU s.c. at least 4 hours after surgery, then 5000 IU s.c. once daily
5
Warfarin sodium 10 mg evening of day of surgery, then dose adjustment to maintain an INR from 2.0 to 3.0

In a third hip replacement surgery clinical trial in which patients were randomized to FRAGMIN 2500 IU administered 2 hours before surgery, followed by 2500 IU at least 6 hours later and maintained on 5000 IU daily or warfarin 5-7.5 mg beginning the night before surgery, the incidence of major bleeding events was 2.6% (7/274) for patients treated with FRAGMIN and 0.4% (1/279) for patients treated with warfarin.

Treatment of Acute Deep Vein Thrombosis

In 3 pivotal studies of patients with deep vein thrombosis treated with FRAGMIN 100-120 IU/kg s.c. twice daily or 120-240 IU/kg continuous infusion over 12 hours vs. heparin 240 U/kg continuous infusion over 12 hours, 2/103 (1.9%) and 1/119 (0.8%) of patients treated with FRAGMIN and heparin, respectively, experienced major bleeding. The corresponding percentages from pivotal studies of patients treated with FRAGMIN 200 IU/kg given s.c. once daily vs. heparin given in a dose of 20,000-40,000 U/24 hour i.v. infusion were 4/328 (1.2%) and 5/353 (1.4%), respectively.

Unstable Angina and Non-Q-Wave Myocardial Infarction

The following table summarizes major bleeding events that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

Major Bleeding Events in Unstable Angina and Non-Q-Wave Myocardial Infarction
 

FRAGMIN

120 IU/kg/12 hr. s.c.1
N=1497

n (%)

Heparin

i.v. and s.c.2
N=731

n (%)

Placebo

q 12 hr. s.c.

N=760 n (%)

Major Bleeding Events3,4

15 (1.0%)

7 (1.0%)

4 (0.5%)

1
Treatment was administered for 5 to 8 days
2
Heparin i.v. infusion for at least 48 hours, APPT 1.5 to 2 times control, then 12,500 U s.c. 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 events 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

Extended Treatment of Symptomatic Venous Thromboembolism (VTE) to Prevent Recurrence of VTE in Patients with Cancer

The following table summarizes major bleeding events that occurred in the pivotal trial of FRAGMIN in patients with cancer treated for symptomatic VTE to prevent recurrence of VTE.

Bleeding Events for Extended Treatment of Symptomatic VTE to Prevent Recurrence of VTE in Patients with Cancer
 

FRAGMIN1

N=338

n (%)

Oral Anticoagulant2
 N=335

n (%)

p-value*

Major bleeding

19 (5.6)

12 (3.6)

0.270

1
FRAGMIN 200 IU/kg s.c. administered once daily for the first month, then approximately 150 IU/kg s.c.for months 2-6
2
FRAGMIN 200 IU/kg s.c. for >5 days plus oral anticoagulant for 6 months dose adjusted to an INR of 2.0-3.0
*
Fisher’s Exact Test

Deep Vein Thrombosis in Hospitalized Patients with Severely Restricted Mobility

The following table summarizes the adverse events from the clinical trial of hospitalized patients with severely restricted mobility during acute illness.

Adverse Events in Hospitalized Patients with Restricted Mobility
 

Dalteparin, N=1848

n (%)

Placebo, N=1833

n (%)

Mortality  

Day 14

8 (0.43)

7 (0.38)

Day 21

43 (2.35)

42 (2.32)

Day 90

107 (6.12)

103 (6.01)

Hemorrhage1  

Fatal, day 21

2 (0.11)

1 (0.05)

Major, day 14

8 (0.43)

0 (0.00)

Major, day 21

9 (0.49)

3 (0.16)

Minor, day 14

16 (0.87)

5 (0.27)

Minor, day 21

19 (1.03)

10 (0.55)

Thrombocytopenia  

Day 14

10 (0.54)

6 (0.33)

Day 21

10 (0.54)

8 (0.44)

1
A bleeding event was considered major if: 1) 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 events that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (2 patients in the group treated with FRAGMIN and 1 in the group receiving placebo). Two deaths occurred after Day 21: 1 patient in the placebo group died from a subarachnoid hemorrhage that started on Day 55, and 1 patient died on day 71 (2 months after receiving the last dose of FRAGMIN) from a subdural hematoma.

MedDRA System Organ Class

Adverse Drug Reactions

Frequency

Blood and lymphatic system

disorders

Mild, reversible non-immunological

thrombocytopenia

common

angioedema

rare

Hepato-biliary disorders

Transient elevation of liver

transaminases (ASAT, ALAT)*

common

Immune system disorders

anaphylactoid reactions**

rare

Skin and subcutaneous tissue

disorders

Skin rash, allergic reactions and skin

necrosis

rare

General disorders and

administration site conditions

Pain at injection site

Common

Injury, poisoning and procedural complications

  
*
Has not been correlated to any long-term effect on liver function
**
FRAGMIN therapy should be discontinued in patients showing local or systemic allergic responses.

Skeletal Effects
Use of low molecular weight heparins over extended periods has been reported to be associated with development of osteopenia.

Post-Marketing Adverse Reactions

In post-marketing experience, the following undesirable effects have been reported:

MedDRA System Organ

Class

Adverse Drug Reactions

Frequency

Blood and lymphatic system

disorders

Severe immunologically-mediated heparin-

induced thrombocytopenia (type II, with or without associated thrombotic complications), see WARNINGS AND PRECAUTIONS, Hematologic, Platelets/Thrombocytopenia,

rare

thrombocytopeniaunknown
thrombocytopeniaunknown

Immune system disorders

anaphylactic reactions

rare

Skin and subcutaneous
tissue disorders

 

skin necrosis
alopecia

very rare
common

rashunknown

General disorders and administration site
conditions

 

retroperitoneal hemorrhage*
gastrointestinal hemorrhage*
intracranial hemorrhage*
hemorrhage (bleeding at any site)

very rare
unknown
unknown

Injury, poisoning and

procedural complications

spinal or epidural hematoma

unknown

* occasionally leading to fatality

Pediatric population: The most common adverse events reported in patients who were <18 years of age were thrombocytopenia, haemorrhage, error in drug administration, thrombosis, and alopecia. The safety of long term dalteparin administration has not been established.

Drug Interactions

Drug-Drug Interactions

FRAGMIN should be used with caution in patients receiving oral anticoagulants, platelet inhibitors, non-steroidal anti-inflammatories, thrombolytic agents and dextran because of increased risk of bleeding. Acetylsalicylic acid (ASA), unless contraindicated, is recommended in patients treated for unstable angina or non-Q-wave myocardial infarctions (see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS).

Because NSAIDs and ASA analgesic/anti-inflammatory doses reduce production of vasodilatatory prostaglandins, and thereby renal blood flow and renal excretion, particular care should be taken when administering dalteparin concomitantly with NSAIDs or high dose ASA in patients with renal failure.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbs have not been established.

Drug-Lab tests Interactions

Interactions with lab tests have not been established

Drug-Lifestyle Interactions

Interactions with lifestyle have not been established.

Dosage And Administration

FRAGMIN may be given by subcutaneous (s.c.) injection or by intermittent or continuous intravenous (i.v.) infusion, depending upon the circumstances. FRAGMIN must NOT be administered intramuscularly (see WARNINGS AND PRECAUTIONS). Clinical trials conducted in support of clinical uses outlined below generally used subcutaneous dosing.

Dosing

Thromboprophylaxis in Conjunction with Surgery

The dose of FRAGMIN required for adequate prophylaxis without substantially increasing bleeding risk varies depending on patient risk factors.

General surgery with associated risk of thromboembolic complications: 2500 IU s.c. administered 1-2 hours before the operation, and thereafter 2500 IU s.c. each morning until the patient is mobilized, in general 5-7 days or longer.

General surgery associated with other risk factors (see WARNINGS AND PRECAUTIONS, Peri-Operative Considerations, Selection of General Surgery Patients): 5000 IU s.c. is given the evening before the operation and then 5000 IU s.c. the following evenings. Treatment is continued until the patient is mobilized, in general for 5-7 days or longer.

As an alternative, 2500 IU s.c. is given 1-2 hours before the operation, with 2500 IU s.c. given again no sooner than 4 hours after surgery, but at least 8 hours after the previous dose, provided primary hemostasis is obtained. Starting on the day after surgery, 5000 IU s.c. is given each morning, in general for 5-7 days or longer.

Elective hip surgery: 5000 IU s.c. is given the evening before the operation and then 5000 IU s.c. the following evenings. Treatment is continued until the patient is mobilized, in general for 5-7 days or longer.

As an alternative 2500 IU s.c. is given 1-2 hours before the operation and 2500 IU s.c. 4-8 hours after surgery, provided primary hemostasis is obtained. Starting on the day after surgery, 5000 IU s.c. is given each morning, in general for 5-7 days or longer.

The pre-operative dose may be omitted and an initial dose of 2500 IU s.c. administered 4-8 hours after the operation, provided primary hemostasis is obtained. Starting on the day after surgery, 5000 IU s.c. is given each morning, in general for 5-7 days or longer. Omission of the pre- operative dose may reduce risk of peri-operative bleeding, however increased risk of venous thromboembolic events is possible. This option is based on the results of the North American Fragmin Trial (NAFT), which excluded patients at high risk of bleeding, i.e., documented cerebral or gastrointestinal bleeding within 3 months prior to surgery, defective hemostasis, e.g., thrombocytopenia (<100 x 109/L), ongoing anticoagulant treatment.

Treatment of Acute Deep Vein Thrombosis
The following dosage is recommended: 200 IU/kg body weight given s.c. once daily. The expected plasma anti-Xa levels during subcutaneous treatment would be <0.3 IU anti-Xa/mL before injection and <1.7 IU anti-Xa/mL 3 - 4 hours after injection. In order to individualize the dose, a functional anti-Xa assay should be performed 3 - 4 hours post-injection. The single daily dose should not exceed 18 000 IU. The following weight intervals are recommended to be adapted to the single-dose prefilled syringes as in the table below.

Weight (kg)Dosage (IU)
46-5610 000
57-6812 500
 
69-8215 000
83 and above*18 000

For patients with increased risk of bleeding, a dose of 100 IU/kg body weight given s.c. twice daily or 100 IU/kg body weight administered over a period of 12 hours as continuous i.v. infusion, can be used. The expected plasma anti-Xa levels during subcutaneous treatment would be >0.1 IU anti-Xa/mL before injection and <1.0 IU anti-Xa/mL 3 - 4 hours after injection.

Normally concomitant treatment with vitamin-K antagonists is started immediately. Treatment with FRAGMIN should be continued until the levels of the prothrombin complex factors (FII, FVII, FIX, FX) have decreased to a therapeutic level, in general for approximately 5 days.

*For patient weighing (kg) 83 and above, data from one single publication suggests that in the thrombosis treatment setting, a weight-adjusted dose beyond the recommended maximum dose of 18000 International Units/day (the largest patient weighed 190 Kg and received a daily dose of 38000 IU) results in mean peak anti-Xa levels that are within the therapeutically acceptable range24 (see ACTION AND CLINICAL PHARMACOLOGY – special populations and conditions, Overweight Population)

Extended Treatment of Symptomatic Venous Thromboembolism (VTE) to Prevent Recurrence of VTE in Patients with Cancer

Month 1: 200 IU/kg body weight given s.c. once daily for the first 30 days of treatment. The total daily dose should not exceed 18,000 IU daily.

Months 2-6: Approximately 150 IU/kg given s.c. once daily using the table shown below.

Weight (kg)Dosage (IU)
≤567 500
57-6810 000
69-8212 500
83-9815 000
≥9918 000

Dose reductions for chemotherapy-induced thrombocytopenia: In the case of chemotherapy- induced thrombocytopenia with platelet counts <50,000/mm3, FRAGMIN should be interrupted until the platelet count recovers above 50,000/mm3. For platelet counts between 50,000 and 100,000/mm3, FRAGMIN should be reduced by 17% to 33% of the initial dose (allowing for dosage adjustment using the prefilled syringes), depending on the patient's weight (table below). Once the platelet count recovers to ≥ 100,000/mm3, FRAGMIN should be re-instituted at full dose.

Weight (kg)Scheduled Dose (IU)Reduced Dose (IU)Mean Dose Reduction (%)
≤567 500 5 00033
57-6810 0007 50025
69-8212 50010 00020
83-9815 00012 50017
≥9918 00015 00017

Unstable Coronary Artery Disease (Unstable Angina and Non-Q-Wave Myocardial Infarction)

120 IU/kg body weight given s.c. twice daily with a maximum dose of 10 000 IU/12 hours. The expected plasma anti-Xa levels during subcutaneous treatment would be >0.1 IU anti-Xa/mL before injection and <1.6 IU anti-Xa/mL 3 - 4 hours after injection. These levels were obtained from another patient population. Treatment should be continued for up to 6 days. Concomitant therapy with ASA is recommended.

Deep Vein Thrombosis in Hospitalized Patients with Severely Restricted Mobility

In hospitalized patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN is 5000 IU administered by s.c. injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.

Use in Patients with Renal Impairment

All patients with renal impairment treated with low molecular weight heparins should be monitored carefully.

Administration of low molecular weight heparins to patients with renal impairment has been shown to result in prolongation of anti-Xa activity, especially in those with severe renal impairment (creatinine clearance <30 mL/min), which may lead to an increased risk of bleeding. This effect has not yet been determined for FRAGMIN. Consideration of dosage adjustment in patients with severe renal impairment should be undertaken (see ACTION AND CLINICAL PHARMACOLOGY). However, emerging data from the literature suggests that in critically ill patients with severe renal insufficiency, thromboprophylaxis with Fragmin at 5,000 IU once daily, does not appear to be associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding8, 13 (see ACTION AND CLINICAL PHARMACOLOGY – special populations and conditions, Renal Insufficiency).

Anticoagulation for Hemodialysis and Hemofiltration

Chronic renal failure, patients with no other known bleeding risk: Hemodialysis and hemofiltration for a maximum of 4 hours: dose as below, or only i.v. bolus injection of 5000 IU. Hemodialysis and hemofiltration for more than 4 hours: i.v. bolus injection of 30 - 40 IU/kg body weight followed by i.v infusion of 10 - 15 IU/kg body weight per hour. This dose normally produces plasma levels lying within the range of 0.5 - 1.0 IU anti-Xa/mL.

Acute renal failure, patients with high bleeding risk: i.v. bolus injection of 5 - 10 IU/kg body weight, followed by i.v. infusion of 4 - 5 IU/kg body weight per hour. Plasma level should lie within the range of 0.2 - 0.4 IU anti-Xa/mL.

Dilution

FRAGMIN solution for injection may be mixed with isotonic sodium chloride or isotonic glucose infusion solutions in glass infusion bottles and plastic containers. Post-dilution concentration: 20 IU/mL.

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitation, discolouration and leakage prior to administration, whenever solution and container permit.

 1 mL 10 000 IU
Isotonic NaCl Infusion
(9 mg/mL)
500 mL
or 
Isotonic Glucose Infusion
(50 mg/mL)
500 mL

The infusion rate is 10 mL/hour. The solution should be used within 24 hours.

Overdosage

Accidental overdosage following administration of FRAGMIN may lead to hemorrhagic complications. FRAGMIN should be immediately discontinued, at least temporarily, in cases of significant excess dosage. In more serious cases, protamine should be administered.

The anticoagulant effect of FRAGMIN is inhibited by protamine. This effect may be largely neutralized by slow intravenous injection of protamine sulphate. The dose of protamine to be given should be 1 mg protamine per 100 anti-Xa IU of FRAGMIN administered. A second infusion of 0.5 mg protamine per 100 anti-Xa IU of FRAGMIN may be administered if the APTT measured 2 to 4 hours after the first infusion remains prolonged. However, even with higher doses of protamine, the APTT may remain prolonged to a greater extent than usually seen with unfractionated heparin. Anti-Xa activity is never completely neutralized (maximum about 60%).

Particular care should be taken to avoid overdosage with protamine sulphate. Administration of protamine sulphate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulphate, it should be given only when resuscitation equipment and treatment of anaphylactic shock are readily available. Refer to the protamine sulphate Product Monograph for further directions for use.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action And Clinical Pharmacology

Mechanism of Action

FRAGMIN is a low molecular weight heparin with antithrombotic properties.

Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa. It is composed of strongly acidic sulphated polysaccharide chains with a weight average molecular weight of 6000 Daltons and about 90% of the material within the range 2000-9000. Dalteparin sodium is composed of molecules with and without a specially characterized pentasaccharide, the antithrombin binding site that is essential for high affinity binding to the plasma protein antithrombin (AT III).

Pharmacodynamics

FRAGMIN acts by potentiating the activity of antithrombin III, inhibiting formation of both Factor Xa and thrombin. However, it preferentially potentiates inhibition of Factor Xa, resulting in only slight increases of clotting time, i.e., activated partial thromboplastin time (APTT).

Effects of unfractionated heparin are monitored by assessing APTT and anti-factor Xa (anti-Xa) activity. For FRAGMIN, however, only high doses lead to noticeable increases in the APTT; therefore, measurement of APTT can be used only as an indicator of overdosage. In the case of FRAGMIN, anti-Xa activity of plasma is used both as an estimate of clotting activity, and as a basis to determine dosage. FRAGMIN potency is described in international anti-Xa units (IU).

The specific activity of FRAGMIN on factor Xa (by measurement of anti-factor Xa IU/mg) is 130, and its specific activity on factor IIa (by measurement of anti-factor IIa IU/mg) is 58. The ratio of anti-Xa/anti-IIa activity for FRAGMIN is 2.2 (for unfractionated heparin the anti-Xa/anti-IIa is equal to 1).

Dalteparin sodium has a smaller effect on platelet function and platelet adhesion than heparin, and thus has only a small effect on primary hemostasis. Heparin treatment depletes the pool of platelet factor 4, while dalteparin sodium has much less of an effect.

Pharmacokinetics

Absorption: The half-life of FRAGMIN has been shown to be 2 hours after intravenous injection and 3-4 hours after subcutaneous injection. The bioavailability after subcutaneous injection is approximately 90% and the pharmacokinetics are not dose-dependent. The plasma concentration of FRAGMIN following subcutaneous administration correlates directly with the administered dose and anti-Xa activity in plasma, as measured by the area under the activity curve. For the twice daily dosing regimen (100 IU/kg/12 hours) of FRAGMIN, the steady state level is attained after 2-4 s.c. injections (24-48 hours).

Distribution: The volume of distribution was found to be approximately 3 litres.

Animal studies using radioactively labelled drug have shown that the distribution of FRAGMIN is similar, whether the dose is administered intravenously or subcutaneously (i.v. or s.c.).

Excretion: After 4 hours about 20% is seen in the urine, with most of the remainder found in the liver, GI tract and kidney. After 72 hours, 70% of a radioactive FRAGMIN dose has been excreted. Less FRAGMIN is found in the liver than standard heparin; the kidneys are the major site of FRAGMIN excretion (approximately 70% based on animal studies). Dalteparin sodium, in contrast to heparin, is not cleared by a saturable mechanism; low doses are expressed in plasma and increasing the dose does not modify its clearance.

Special Populations and Conditions

Renal Insufficiency: In a study of 8 patients with chronic renal failure undergoing hemodialysis administered FRAGMIN 5000 IU intravenously, a half-life of about 5.7 hours was observed, compared to that of about 2 hours as previously reported in healthy volunteers receiving FRAGMIN intravenously (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Use in Patients with Renal Impairment).

In a multicenter, open-label, prospective cohort study (DIRECT study) of critically ill patients with severe acute or chronic renal insufficiency or dialysis (mean creatinine clearance of 18.9 ml/min), 138 evaluable patients received at least one dose of subcutaneous dalteparin 5,000 IU once daily as thromboprophylaxis. The median duration of dalteparin administration was 7 days. Trough anti-Xa levels were measured twice weekly, 20 hours after the prior dalteparin dose, to assess for dalteparin bioaccumulation (defined as anti-Xa levels > 0.40 IU/mL). No patient (0%; 95% CI: 0, 3.0) had bioaccumulation, during the study. The median (inter-quartile range [IQR]) trough anti-Xa level was <0.10 IU/mL (<0.10, <0.10). Serial anti-Xa levels were measured at approximately 3, 10, and 17 days after the start of dalteparin; Peak levels were between 0.29 IU/mL and 0.34 IU/mL and trough levels were below the lower limit of detection (<0.06 IU/mL) irrespective of the duration of treatment. These peak anti-Xa levels achieved with prophylactic dose dalteparin were consistent with peak prophylactic levels of anticoagulation of 0.20–0.40 IU/ml observed in other hospitalized medical and surgical patients.8, 13

Pregnant Women: In a prospective trial, the EThIG study, 810 pregnant women were assigned to one of three management strategies according to pre-defined risk factors related to history of VTE and thrombophilic profile. Low-risk women (group I), received 50–100 IU dalteparin/ kg body weight/ day for 14 days postpartum, or earlier when additional risk factors occurred. Women at high (group II) or very high risk (group III) received dalteparin from enrolment until six weeks postpartum (50–100 IU and 100–200 IU/ kg/ day, respectively). Risk-stratified heparin prophylaxis was associated with a low incidence of symptomatic VTE and few clinically important adverse events. Symptomatic VTE occurred in five women (0.6 %; 95% CI 0.2, 1.5%). There were no events in group I; three women in group II suffered an event (2 antepartum, 1 postpartum) and two in group III (both postpartum). Bleeding was classified as serious in 24 episodes (3.0% 95% CI: 1.9, 4.4 %) in 22 women (2.7% 95% CI: 1.8, 4.2 %), and no cases of fatal bleeding occurred. Thrombocytopenia occurred in 18 women (2.2%; 95% CI: 1.4, 3.6%), with no cases with clinical or laboratory features of heparin-induced thrombocytopenia (HIT).4

Pediatric population: There is limited safety and efficacy information on the use of dalteparin in pediatric patients. If dalteparin is used in these patients, anti-Xa levels should be monitored. (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

A large prospective study investigated the efficacy, safety and relation of dose to plasma anti-Xa activity of dalteparin in prophylaxis and therapy of arterial and venous thrombosis in 48 paediatric patients (from 31 weeks preterm to 18 years).33 The treatment duration was 3 to 6 months. In 10 patients who received dalteparin (95 ± 52 IU/kg sc qd) for thromboprophylaxis, no thromboembolic events occurred. The dose for antithrombotic therapy was 129 ± 43 IU/kg sc qd. In the 23 patients given dalteparin for primary antithrombotic therapy, 7/23 (30%) had complete recanalization, 7/23 (30%) had partial recanalization, and 9/23 (40%) had no recanalization. In the 8 patients administered dalteparin for secondary antithrombotic therapy following successful thrombolysis, recanalisation was maintained or improved. In the 5 patients receiving dalteparin following failed thrombolysis, no recanalization was seen. Minor bleeding, reported in 2/48 children (4%), resolved after dose reduction. Patient platelet counts ranged from 37,000/μl to 574,000/μl. A reduction in platelet count ≥50% of the initial value was not observed in any patient of this study; dalteparin doses required to achieve target anti Xa activities were inversely related to age; the predictability of the anticoagulant effect with weight adjusted doses appears to be reduced in children.

Overweight population: In a prospective, cohort study, 37 overweight patients were a priori stratified into three weight classes: (A) within 20 % of ideal body weight (IBW) (N=13), (B) 20- 40% of IBW (n=14), and (C) greater than 40% of IBW (n=10). All patients, with serum creatinine levels <150µmol/L, received dalteparin sodium 200 IU/kg based on actual body weight subcutaneously once daily for the treatment of DVT or pulmonary embolism for a minimum of 5 days. All patients had peak anti-Xa levels measured 3-4 h following their Day 3 injection and trough anti-Xa levels measured immediately prior to injections on Day 3 and Day 5. The largest patient weighted 190 kg with a BMI of 58. Patients were stratified per weight in three different groups: A, B, C with mean daily doses of dalteparin respectively of 14,030 IU, 17,646 IU, and 23,565 IU. Mean (SD) trough anti-Xa levels on Day 3 were 0.12 (0.05) anti-Xa IU/ml for group A, 0.11 (0.03) anti-Xa IU/ml for group B and 0.11 (0.03) anti-Xa IU/ml for group C (p>0.2). Similar trough anti-Xa levels were observed on Day 5. Mean (SD) peak anti-Xa levels on Day 3 were 1.01 (0.20), anti-Xa IU/ml, 0.97 (0.21) anti-Xa IU/ml and 1.12 (0.22) anti- Xa IU/ml for groups A, B and C respectively. No thromboembolic or bleeding complications occurred during dalteparin therapy in any patients. 24

Intensive Care Unit (ICU) Patients: In a large international randomized, controlled multicenter study34, the thromboprophylactic effect of dalteparin 5,000 IU once daily was compared to unfractionated heparin (UFH) 5,000 IU twice daily in 3746 critically ill medical and surgical patients who were admitted in the intensive care unit (ICU). The primary outcome was proximal leg deep vein thrombosis (DVT) as determined by periodic compression ultrasound. The median duration of study drug in both groups was 7 days. Proximal leg DVT was reported by 5.1% patients in the dalteparin group and 5.8% patients in the UFH group. The proportion of patients with pulmonary emboli was 1.3% in the dalteparin group and 2.3% in the UFH group. The rates of major bleeding and death in the hospital were 5.5% and 22.1% in the dalteparin group, and 5.6% and 24.5% in the UFH group. Of these parameters, only the rate of pulmonary emboli showed a statistically significant difference between treatment groups.

Storage And Stability

Store at room temperature, (15 - 30ºC).
The 25 000 IU/mL multi-dose vial must be used within 2 weeks after initial penetration.

Special Handling Instructions

No special handling required.

Dosage Forms, Composition And Packaging

Dosage forms

Solution for injection 10 000 IU (anti-Xa)/mL, ampoules 10 x 1 mL.
Solution for injection 25 000 IU (anti-Xa)/mL, 3.8 mL multi-dose vials.
Solution for injection 2 500 IU (anti-Xa)/mL, 4 mL single-dose vials.

Solution for injection 2 500 IU (anti-Xa)/0.2 mL, single dose syringes* 10 x 0.2 mL
Solution for injection 3 500 IU (anti-Xa)/0.28 mL, single dose syringes* 10 x 0.28 mL
Solution for injection 5 000 IU (anti-Xa)/0.2 mL, single dose syringes* 10 x 0.2 mL
Solution for injection 7 500 IU (anti-Xa)/0.3 mL, single dose syringes*, packages of 5
Solution for injection 10 000 IU (anti-Xa)/0.4 mL, single dose syringes*, packages of 5
Solution for injection 12 500 IU (anti-Xa)/0.5 mL, single dose syringes*, packages of 5
Solution for injection 15 000 IU (anti-Xa)/0.6 mL, single dose syringes*, packages of 5
Solution for injection 18 000 IU (anti-Xa)/0.72 mL, single dose syringes*, packages of 5

* Prefilled syringe with safety needle device

FRAGMIN may be administered subcutaneously (s.c.) or intravenously (i.v.)

Composition

Solution for injection: 1 mL solution for injection contains:

Dalteparin sodium

(Low molecular weight heparin sodium)

Ampoule
10 000 IU

(anti-Xa)

Multi-dose vial
25 000 IU

(anti-Xa)

Single-dose Vial
2 500 IU

(antiXa)

Sodium chloride*

q.s.

--

8.22 mg

Benzyl alcohol

--

14 mg

--

Hydrochloric acid

pH adjustment

pH adjustment

pH adjustment

Sodium hydroxide

pH adjustment

pH adjustment

pH adjustment

Water for injection

ad 1 mL

ad 1 mL

ad 1 mL

*
The hypotonicity is adjusted with sodium chloride. The amount is calculated from the result of the osmolality/anti-Xa activity.

Prefilled syringe with safety needle device

Dalteparin sodium

2 500

IU/0.2 mL

3 500

IU/0.28

mL

5 000

IU/0.2 mL

7 500

IU/0.3 mL

10 000

IU/0.4 mL

12 500

IU/0.5 mL

15 000

IU/0.6 mL

18 000

IU/0.72

mL

LMWH*

Anti-Xa

Anti-Xa

Anti-Xa

Anti-Xa

Anti-Xa

Anti- Xa

Anti- Xa

Anti- Xa

Sodium chloride**

q.s.

0-2.7mg

-

-

-

-

-

-

Hydrochloric acid

pH adjustment

pH adjustment

pH adjustment

pH adjustment

pH adjustment

pH adjustment

pH adjustment

pH adjustment

Sodium Hydroxide

pH adjustment

pH adjustment

pH adjustment

pH adjustment

pH adjustment

pH adjustment

pH adjustment

pH adjustment

Water for injection

ad 0.2 mL

ad 0.28 mL

ad 0.2 mL

ad 0.3 mL

ad 0.4 mL

ad 0.5 mL

ad 0.6 mL

ad 0.72 mL

*
Low Molecular Weight Heparin Sodium
**
The hypotonicity is adjusted with sodium chloride. The amount is calculated from the result of the osmolality/anti-Xa activity.

Potency: Potency is described in International anti-Xa units (IU). One unit (anti-Xa) of dalteparin sodium, weight average molecular weight 6000 Daltons, corresponds to the activity of one unit of the 1st International Standard for Low Molecular Weight Heparin with respect to inhibition of coagulation Factor Xa in plasma utilizing the chromogenic peptide substrate S-2765 (N-α-Benzyloxycarbonyl-D-arginyl-glycyl-arginine-pNA•2HCl).

 

Control #: 193875
21 March 2016

What's New

No Current Announcements.

Other Resources

Contact Pfizer Medical Information

Report an Adverse Event
1 866 723-7111