10 000 IU (anti-factor Xa)/1 mL, Ampoule 25 000 IU (anti-factor Xa)/mL 3.8 mL, Multi-Dose Vial

Prefilled syringe with safety needle device

2 500 IU (anti-factor Xa)/0.2 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

Anticoagulant/Antithrombotic Agent

Pfizer Canada Inc 17,300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 (r) Pfizer Health AB Pfizer Canada Inc, Licensee

Submission Control Number: 118805

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 10 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 15 OVERDOSAGE 19 ACTION AND CLINICAL PHARMACOLOGY 20 STORAGE AND STABILITY 21 SPECIAL HANDLING INSTRUCTIONS 21 DOSAGE FORMS, COMPOSITION AND PACKAGING 21

PART II: SCIENTIFIC INFORMATION 24

PHARMACEUTICAL INFORMATION 24 CLINICAL TRIALS 25 DETAILED PHARMACOLOGY 33 TOXICOLOGY 37 REFERENCES 40

PART III: CONSUMER INFORMATION. 43

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

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 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, 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 repeated high doses of FRAGMIN (100- 120 IU/kg given twice daily or 200 IU/kg once daily) 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).

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.

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 population, Pregnant Women).

: 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.

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

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).

: 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/uL). 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.

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).

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.

: 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.

: 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.

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.

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 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. 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.

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.

Pediatrics

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.

: 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).

* 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.

As with all antithrombotic agents, there is a risk of systemic bleeding with FRAGMIN administration. Care should be taken with FRAGMIN use in high dose treatment of 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 and periodic measurements of hemoglobin, and anti-Xa determinations. 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).

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 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

	FRAGMIN 1 N=385 n (%)	Heparin 2 N=265 n (%)	Placebo N=108 n (%)
Major bleeding	11 (2.9)	3 (1.1)	4 (3.7)
Wound or Perioperative	11 (2.9)	3 (1.1)	4 (3.7)
Bleed	10 (2.6)	2 (0.8)	4 (3.7)
Wound hematoma	1 (0.3)	1 (0.4)	0 (0.0)

Treatment for at least 5-7 days

2500 IU s.c. 2 hours before surgery, then 2500 IU daily
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
	General Surgery Associated with Other Risk Factors *		FRAGMIN vs Warfarin sodium * *			FRAGMIN vs Heparin *
	FRAGMIN 1 N=543 n (%)	Heparin 2 N=533 n (%)	FRAGMIN 3 started before surgery N=496 n (%)	FRAGMIN 4 started after surgery N=487 n (%)	Warfarin sodium 5 N=489 n (%)	FRAGMIN 1 N=69 n (%)	Heparin 2 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

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

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
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
2500 IU s.c. at least 4 hours after surgery, then 5000 IU s.c. once daily
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 Events 3,4	15 (1.0%)	7 (1.0%)	4 (0.5%)

Treatment was administered for 5 to 8 days
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
Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently
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

	FRAGMIN 1 N=338 n (%)	Oral Anticoagulant 2 N=335 n (%)	p-value *
Major bleeding	19 (5.6)	12 (3.6)	0.270

FRAGMIN 200 IU/kg s.c. administered once daily for the first month, then approximately 150 IU/kg s.c.for months 2-6

2FRAGMIN 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	8 (0.43)	7 (0.38)
Day 14	8 (0.43)	7 (0.38)
Day 21	43 (2.35)	42 (2.32)
Day 90	107 (6.12)	103 (6.01)
Hemorrhage 1
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)

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.

Skeletal Effects

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

Liver

Transient elevation of liver transaminases (ASAT, ALAT) has been observed for FRAGMIN. This observation has not been correlated to any long-term effect on liver function.

Hypersensitivity

Mild, non-immunological thrombocytopenia is common but usually reversible during treatment. Skin rash, allergic reactions and skin necrosis are rare, and occur with all low molecular weight heparins. Hypersensitivity reactions, including angioedema and anaphylactoid reactions, have been observed rarely with unfractionated heparin and low molecular weight heparins. FRAGMIN therapy should be discontinued in patients showing local or systemic allergic responses.

Heparin-induced Thrombocytopenia

Severe immunologically-mediated thrombocytopenia has been observed rarely with FRAGMIN use, resulting in arterial and/or venous thrombosis or thromboembolism (see WARNINGS AND PRECAUTIONS, Hematologic, Platelets/Thrombocytopenia,).

Other

Pain at injection site has been observed.

Post-Marketing Adverse Reactions

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

Bleeding:

intracranial hemorrhage, gastrointestinal hemorrhage, retroperitoneal hemorrhage have been reported occasionally leading to fatality

Blood and Lymphatic System:

thrombocytopenia, thrombocythemia

Skin and Subcutaneous Tissue Disorders:

skin necrosis, alopecia

Immune System Disorders:

immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications), anaphylactic reactions

Injury, Poisoning and Procedural Complications:

spinal or epidural hematoma

DRUG INTERACTIONS

Drug-Drug Interactions

FRAGMIN should be used with caution in patients receiving oral anticoagulants, platelet inhibitors, non-steroidal anti-inflammatories and thrombolytic agents 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).

Drug-Food Interactions

Drug-Herb Interactions

Drug-Lab tests Interactions

Drug-Lifestyle Interactions

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.

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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).

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.

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.

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.

Isotonic NaCl Infusion

mL 10 000 IU

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.

ACTION AND CLINICAL PHARMACOLOGY

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 an average molecular weight of 5000 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).

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.

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:

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.

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).

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

DOSAGE FORMS, COMPOSITION AND PACKAGING

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)/0.2 mL, single dose syringes * 10 x 0.2 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

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

* * 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, average molecular weight 5000, 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-a- Benzyloxycarbonyl-D-arginyl-glycyl-arginine-pNA *2HCl).

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Dalteparin sodium Chemical name: Sodium salt of depolymerized heparin obtained by nitrous acid degradation of heparin from pork intestinal mucosa. The majority of the components have a 2-O-sulfo-.alpha.-L-idopyranosuronic acid structure at the non-reducing end and a 6-O-sulfo-2,5-anhydro-D-mannitol structure at the reducing end of their chain. The molecular weight of 90% of the components is between 2 000 and 9 000 and the average molecular weight is about 5 000; the sulphur content is about 11%. The degree of sulphation is 2 to 2.5 per disaccharide unit. Molecular formula and molecular mass: FRAGMIN is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa. It is composed of strongly acidic sulphated polysaccharide chains with an average molecular weight of 5000 and about 90% of the material within the range 2000-9000. Structural formula: Physicochemical properties: White or yellowish white powder. Dalteparin sodium is soluble in water. pH (1% w/w solution) 5.0 - 7.5.

CLINICAL TRIALS

Thromboprophylaxis in Conjunction with Surgery: Study 1 Demographics and Trial Design

Study 1 Results:

In the intent-to-treat analysis, the incidence of proximal DVT was significantly lower for patients treated with FRAGMIN (dalteparin sodium injection) compared with patients treated with heparin (6/67 vs 18/69; p=0.012). Further, the incidence of pulmonary embolism detected by lung scan was also significantly lower in the group treated with FRAGMIN (9/67 vs 19/69; p=0.032).

Study 2 Demographics and Trial Design

Study 2 Results:

For patients with interpretable venograms, the frequencies of deep vein thrombosis (DVT) in patients receiving preoperative and postoperative FRAGMIN and warfarin for all DVTs were 36 (10.7%) of 337, 44 (13.1%) of 336, and 81 (24.0%) of 338, respectively (p<0.001 for both preoperative and postoperative FRAGMIN vs. warfarin); for proximal DVT, 3 (0.8%) of 354, 3 (0.8%) of 358, and 11 (3.0%) of 363 (p= 0.04 and p= 0.03 for preoperative and postoperative FRAGMIN vs. warfarin, respectively).

Studies 3 and 4 Demographics and Trial Design

Studies 3 and 4 Results:

FRAGMIN was shown to reduce the risk of DVT in patients at risk for thromboembolic complications. As summarized in the following tables, FRAGMIN 2500 IU was superior to placebo and similar to heparin in reducing the risk of DVT.

Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Treatment of Deep Vein Thrombosis (DVT) Study 1: Study Demographics and Trial Design

Study 1 Results:

Subcutaneous FRAGMIN and heparin in DVT were found to be equally safe and efficacious. The Heparin group required more dose adjustments. Leg pain disappeared more rapidly in patients receiving FRAGMIN.

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

Study Demographics and Trial Design

Study Results:

A total of 27 (8.0%) and 53 (15.7%) patients in the experimental and control arms, respectively, experienced at least one episode of an adjudicated, symptomatic DVT and/or PE during the 6- month study period. In the intent-to-treat population, the primary comparison of the cumulative probability of the first VTE recurrence over the 6-month study period was highly statistically significant (2-sided log-rank test, p=0.0017) in favor of the experimental regimen. The estimated cumulative probability of recurrence at 6 months was reduced from 0.172 in the control arm to 0.087 in the experimental arm, reflecting a 52% reduction in the relative risk of VTE (RR=0.48; 95% CI, 0.30-0.77; likelihood test, p=0.0016).

Unstable Coronary Artery Disease, i.e. Unstable Angina and Non-Q-Wave Myocardial Infarction:

Study 1: Study Demographics and Trial Design

Study 1 Results:

The combined incidence of the double endpoint of death or myocardial infarction was lower for FRAGMIN compared with placebo at 6 days after initiation of therapy. These results were observed in an analysis of all-randomized and all-treated patients. The combined incidence of death, MI, need for intravenous (i.v.) heparin or i.v. nitroglycerin, and revascularization was also lower for FRAGMIN than for placebo (see table below).

Efficacy of FRAGMIN in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

Study 2: Study Demographics and Trial Design

Study 2 Results:

The incidence of the combined triple endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 to 8 days) was 9.3% for FRAGMIN and 7.6% for heparin (p=0.323).

Reduction of Deep Vein Thrombosis in Hospitalized Patients with Severely Restricted Mobility during Acute Illness.

Study Demographics and Trial Design

Study Results: .

The primary efficacy endpoint was defined as at least one of the following within Days 1 to 21 of the study: asymptomatic proximal DVT (diagnosed by compression ultrasound), a confirmed symptomatic DVT, a confirmed pulmonary embolism or sudden death. The primary endpoint was evaluated at Day 21, and the follow-up period was up to Day 90. These patients were >=40 years of age with an acute medical condition requiring a projected hospitalization of >= 4 days and had <=3 days of prior immobilization and were confined to bed during waking hours

The study included patients with congestive heart failure (NYHA Class III or IV), acute respiratory failure not requiring ventilatory support, and the following acute conditions with at least one risk factor occurring in >1% of treated patients: acute infection (excluding septic shock), acute rheumatic disorder, acute lumbar or sciatic pain, vertebral compression, or acute arthritis of the lower extremities. Risk factors include > 75 years of age, cancer, previous DVT/PE, obesity and chronic venous insufficiency. When given at a dose of 5000 IU once a day s.c., FRAGMIN significantly reduced the incidence of thromboembolic events including verified DVT by Day 21 (see table below). The prophylactic effect was sustained through Day 90. Decrease mortality due to thromboembolic events and complications has not been demonstrated.

Efficacy of FRAGMIN in the reduction of Deep Vein Thrombosis in Hospitalized Patients with Severely Restricted Mobility During Acute Illness

RR indicates relative risk. Only 1 event per patient (most severe) was recorded.

95% CIs were not produced if <5 patients in either treatment group experienced an event.

DETAILED PHARMACOLOGY

FRAGMIN is a low molecular weight heparin produced on a large scale by a highly reproducible method based on partial nitrous acid depolymerization of heparin. FRAGMIN has an average molecular weight of 5000 with about 90% of the material between 2000-9000. FRAGMIN contains molecules with high and with low affinity for antithrombin. The figure below shows the molecular weight distribution of FRAGMIN and standard heparin.

The organ distribution of tritium-labelled dalteparin sodium was determined in rats and compared to heparin. Regardless of the dose injected or the route of administration (i.v. or s.c.) the highest deposit of radioactivity was found in the liver (up to 19%), followed by the kidney and intestine. On the basis of specific activity (dpm/g tissue), the kidney had the highest concentration of radioactive material. No significant difference between the tissue distribution of heparin and dalteparin sodium were seen after 72 hours. At 72 hours, the total amount of radioactivity remaining in the body (dose 600 IU/kg) was 12.3% for dalteparin sodium and 13.5% for heparin, and showed a similar pattern to that seen at 4 hours.

It has been demonstrated that heparin is eliminated from plasma via a saturable cellular clearance mechanism (i.e. binding and/or uptake into endothelial or reticuloendothelial cells) and also via a non-saturable renal clearance mechanism. In a study designed to compare the elimination kinetics of heparin and dalteparin sodium in the rabbit, it was demonstrated that cellular clearance of dalteparin sodium is considerably less important than for heparin. Saturation of the reticuloendothelial system prior to dalteparin sodium administration had no effect on its plasma elimination rate. In contrast, under similar conditions, the plasma half-life of heparin was prolonged by 3-4 times. In the dog, more than 70% of the administered radioactivity was excreted in the urine in 24 hours, independent of application route.

Specific activity of FRAGMIN is consistent with that of unfractionated heparin regarding anti-Xa activity, but differs in its effects on APTT, see table below.

(units/mg)

* According to the 1st International Standard of LMW heparin. APTT 60 IU/mg, anti-Xa 165 IU/mg.

Following the continuous i.v. infusion in 8 healthy volunteers of FRAGMIN or heparin in the dose 20 lU/kg/hr, important differences were noted. After 10 hours, anti-Xa levels (mean 1.80) were significantly higher in the FRAGMIN group, than in the heparin group (mean 0.86). APTT was only moderately elevated (increase 88%) in the FRAGMIN group, as compared to the heparin group (increase 263%, see figure below)

Heparin administration releases lipoprotein lipase from tissue sites into the circulation, resulting in a profound derangement of lipoprotein metabolism. Lipoprotein lipase catalyses the hydrolysis of plasma triglycerides at the capillary endothelium, and the products of lipolysis are taken up directly by the tissues. When heparin has displaced the lipases from their tissue sites, hydrolysis proceeds in the circulating blood with the production of free fatty acids which are subsequently removed with a different tissue distribution. An extensive intravascular lipolysis rather than a controlled hydrolysis and removal of triglycerides

in the capillary vessels may have an impact on the distribution of lipid energy between different organs. FRAGMIN and heparin were administered intravenously to 6 healthy volunteers who simultaneously received a continuous infusion of the fat emulsion, Intralipid *. The mean Intralipid concentration decreased by 83% after heparin and by 38% after FRAGMIN (p<0.001). FRAGMIN was associated with a smaller increase of free fatty acids (p<0.05) and plasma LPL activities (p<0.01) than was heparin. In a study of 70 patients with chronic end-stage renal failure followed over a period of 12 months, a significant (p<0.05) increase in the number of hypertriglyceridemic patients was observed in the heparin-treated group compared to patients treated with FRAGMIN. In a number of studies, it has been noted that low molecular weight heparins do not affect platelet function to the same extent as does heparin. In a randomized single-blind, cross-over study, heparin resulted in a striking decrease in platelet adhesion to collagen in all patients, while FRAGMIN had no such effect. The heparin mobilizable-pool of platelet factor 4 (PF-4) is of interest because its mobilization by heparin may be relevant to the antithrombotic effect of heparin. Five healthy volunteers were recruited for an i.v. study and 8 for an s.c. study. The double-blind, cross-over studies assessed how heparin and FRAGMIN affected the pool. After various experimental treatments with heparin and FRAGMIN, the level of PF-4 still mobilizable by a challenging dose of 60 U/kg heparin was analyzed. Heparin liberated PF-4 to a significantly higher extent than FRAGMIN. Plasma F-4 level was significantly higher following i.v. administration of heparin and FRAGMIN (214 vs. 154 ng/mL respectively, at 5 min. post-administration; p<0.02). After the heparin challenge, significantly more plasma PF-4 was found for the FRAGMIN groups for both i.v. and s.c. administration. This suggests that the heparin mobilizable pool of PF-4 is more severely depleted by heparin treatment, than by FRAGMIN treatment. Other studies have confirmed that FRAGMIN has less effect on hemostasis. Other parameters which, when tested, have shown a difference from heparin in some studies are ATIII, Factor VIII, thrombin time, whole blood activated clotting time (WBACT), and fibrin monomers in hemodialysis studies. FRAGMIN administration appears to gives rise to transient elevation of liver transaminases to the same extent as heparin. There is a single report of the levels not returning to normal after withdrawal of treatment. Levels nonetheless returned to normal after 2 weeks.

In 8 healthy volunteers, a single i.v. injection of FRAGMIN in the doses 40 and 60 lU/kg showed that the half-life was independent of the dose and was approximately 2 hours, i.e twice as long as for heparin. Both doses of FRAGMIN were eliminated according to first order kinetics. There was a direct proportionality between the dose and the AUC obtained. APTT was moderately prolonged in a dose-dependent way, but had returned to normal after 4 hours, when still measurable anti-Xa levels existed.

While it is known that heparin exhibits striking dose-dependent kinetics, there have been differing conclusions as to whether FRAGMIN exhibits dose-dependent or independent kinetics. Whatever the case, it is apparent that the kinetics of FRAGMIN differ remarkably from those of heparin. The following data indicates a mild dose-dependent response for 2 doses of FRAGMIN, both of which have a half-life (t2) in excess of twice the heparin value. The volumes of distribution between different doses of FRAGMIN and heparin do not differ significantly.

Pharmacokinetic parameters after single intravenous injections of Heparin (mean + SD n = 8).

* * *p=.0001 of difference between heparin 40 IU/kg and Heparin fragment Kabi 2165 40 IU/kg or 60 IU/kg.

A further study, extending the dose range, confirmed the slight dose-dependent kinetics of FRAGMIN. At doses of 30 and 120 IU/kg, t2 were found to be 88 +- 77 min., and 154 +- 16 min, respectively. These results, indicating that kinetics may be slightly dose-dependent, do not alter the recommended dosing regimens.

The plasma concentration of dalteparin sodium following s.c. administration is easily predicted since there is a direct relationship between the administered dose and the anti-Xa activity in plasma (measured as area under the activity curve). It has been demonstrated that following i.v. administration, FRAGMIN has a plasma half-life which is twice that of heparin. The pharmacokinetic profile of FRAGMIN administered s.c. is less dose- dependent than that of heparin.

In a study of 6 volunteers, the half-life after s.c. injection of FRAGMIN in the doses 2500, 5000 and 10 000 IU anti-Xa, was 3.4, 3.3 and 3.9 hours respectively. Areas under the curve (AUC) for the 3 dosages were 1.70, 3.77 and 9.33, respectively.

A study of 8 healthy volunteers in which FRAGMIN 5000 IU was administered s.c. twice daily for several days revealed no cumulative effect on APTT, thrombin time or residual Factor Xa activity in plasma.

In the animal studies, the kidney was implicated as the major organ for removal of the drug. FRAGMIN clearance from kidneys has been confirmed from studies in the administration of FRAGMIN to patients with impaired renal function. The t2 for anti-Xa activity in these patients was 6.3 - 7 hours, much longer than for healthy volunteers.

The bioavailability of FRAGMIN administered i.v. cannot be measured directly. Rather it is the anticoagulant activity which is determined. By definition, IU of FRAGMIN are assessed as anti-Xa activity after injection of the drug. Therefore the bioavailability of i.v. administered FRAGMIN is expected to be near 100%, as nearly all of the injected drug is free to bind with ATIII. Strong association of FRAGMIN with other plasma proteins has not been reported. The bioavailability of FRAGMIN administered by other routes can be assessed as a comparison to the different anti-Xa levels achieved.

I.v. and s.c. administration of FRAGMIN lead to similar pharmacokinetic values. Compared with heparin, FRAGMIN is absorbed from the subcutaneous depot to a much greater extent; 80-90% compared with 10-20% for heparin. A cross-over study in 6 healthy volunteers, who received s.c. and i.v. injections of FRAGMIN in the dose 120 anti-Xa lU/kg gave the following results: the half-life after i.v. injection was 199 +- 17 min (mean +- SD). The volume of distribution was 3.4 +- 0.5 L and the total clearance 20.5 +- 2.5 mL/min. The elimination of the anti-Xa activity was monoexponential and a first order process. As previously determined, the half-life after s.c. injection was longer than heparin (228 +- 40 min). The absorption rate was the rate limiting step. Peak levels were consistent with other studies and reached after 4 hours, when anti-Xa levels of 0.6 IU +- 0.1 were obtained. The bioavailability of FRAGMIN administered s.c. was 87 +- 6%, from a comparison of s.c. and i.v. administration AUCs.

TOXICOLOGY

No LD50 has been determined in studies of single lethal acute doses given to mice. Given both and s.c., doses of 100 000 IU/kg were tolerated. Any deaths recorded were the result of hemorrhagic complications at the s.c. injection site. Short-term Toxicity Rats treated with large doses administered s.c. once daily for 9 consecutive days registered increases in platelets and bleeding time, and injection site hematomas in some animals at doses of 500 - 1000 IU/kg/day. At higher doses, 5000 - 20 000 IU/kg/day, bleeding from injection site hematoma could prove fatal, and decreases in Hb, PCV and RBC were recorded.

Beagle dogs treated with 250 - 1000 IU/kg/day administered s.c. for 26 weeks yielded no serious toxicological changes. Some dogs were reported to have enlarged livers at the higher dose levels, and for heparin at 250 IU/kg/day, although no significant histopathological liver changes were observed. Microradiographic examination and determination of gravity and specific ash of the skeletons of the dogs showed significant differences between treated and control groups. Therefore, dalteparin sodium has a weak osteopenic effect. Heparin has a comparable effect. Dalteparin sodium was administered s.c. once daily to Sprague Dawley rats at the dose levels of 250, 500 or 1000 IU/kg/day for 26 weeks. Twenty rats/sex/group were killed at the end of the treatment period and the remaining 10 animals/sex/group were killed after a 6-week recovery period. There was no evidence of any systemic toxicity and the only significant finding was the presence of dose-related and reversible small hemorrhages at the injection sites. A dose-related and proportional increase in plasma anti-Xa activity was seen during the study, with peak levels attained at about 1 hour post dose. In a 52-week intravenous toxicity study, beagle dogs (5 males and 5 females/group) received dalteparin sodium i.v. at the dose levels of 300, 1000 or 3000 IU/kg/day for 52 weeks. At the end of the treatment period, 4 dogs/sex/group were killed and the remaining dogs (1 animal/sex/group) were kept untreated for 5 weeks prior to sacrifice. Dalteparin sodium was well tolerated in dogs after repeated i.v. administration of doses up to 1000 IU/kg/day. Subcutaneous hemorrhages at the injection sites occurred in all drug-treated groups, with dose- dependency. At the highest dose level (3000 IU/kg/day), slightly increased liver weights were observed in males and a decrease in the ratio of cortical bone versus bone width was found in females. In the mid and high-dose groups, both sexes showed a decrease in serum glutamate-oxaloacetate transaminase (SGOT) activity and an increase in globulin fraction. Male animals in the active treatment groups showed increased levels of serum potassium, cholesterol and phospholipids, decrease in gamma globulin fraction ratio, and an increase in plasma glucose. Females of high dose group showed a decrease in total protein and an increase in chlorine. No organ toxicity was revealed in any of the toxicity studies. No significant adverse changes were found in the reproductive toxicity studies and no mutagenic effect was detected.

Toxicologically, FRAGMIN (dalteparin sodium) exhibits a dose-related effect on bleeding. In human studies, this effect manifests itself in bleeding side effects ranging from mild events such as injection site hematoma, wound hematoma, epistaxis, haematuria, bruising, petechiae, oral mucosal bleeding, vaginal bleeding, anal bleeding, through to more serious events. While injection site hematomas occur at 5%, major bleedings are rare.

Both FRAGMIN and heparin give rise to similar transient elevation of the liver 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. There is a single report of the levels not returning to normal after withdrawal of treatment. Levels nonetheless returned to normal after 2 weeks. This may be indicative of clinically important effect on the liver, the significance of which is not entirely clear, as FRAGMIN is known to be distributed less in the liver than heparin. Heparin-treated patients are known to be at risk for the development of osteoporosis after long- term, high-dose therapy. A similar risk is not known for FRAGMIN, however patients on long-term therapy may also be at risk.

REFERENCES

Haemostasis 1993; 23 (suppl. 1): 99-102. Holmer E, Kurachi K, Soderstrom G. The molecular weight dependence of the rate enhancing effect of heparin on the inhibition of thrombin, FXa, FIXa, FXIa, FXIIa and kallikrein by antithrombin. Biochem J, 1981; 193: 395-400. Holmer E, Mattsson C, Nilsson S. Anticoagulant and antithrombotic effects of heparin and low molecular weight heparin fragments in rabbits. Thromb Res 1982a; 25:475-485. Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Sodeberg K, Holmqvist A, Mant M, Dear R, Baylis B, Mah A, Brant R for the North American Fragmin Trial Investigators. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients. A double-blind, randomized comparison. Arch Intern Med 2000; 160: 2199-2207. Jorgensen PS, Knudsen JB, Broeng L, Josephsen L. Bjerregaard P, Hagen K, et al. The thromboprophylactic effect of a low-molecular weight heparin (Fragmin) in hip fracture surgery. A placebo-controlled study. Clin Orthop 1992; 278:95-100. Koller M, Schoch U, Buchmann P, Largiader F, von Felten A, Frick PG. Low molecular weight heparin (Kabi 2165) as thromboprophylaxis in elective visceral surgery. A randomized, double-blind study versus unfractionated heparin. Thromb Haemost 1986; 56(3):243-246. Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar A, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M. Lowmolecular weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349:146-153. Leizorovicz A, Cohen AT, Turpie AG et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110(7):874-879. Ljungberg B, Blomback M, Johnsson H, Lins LE. A single dose of a low molecular weight heparin fragment for anticoagulation during hemodialysis. Clin Nephrol 1987; 33(11):1188-1191. Ockelford PA, Patterson J, Johns AS. A double-blind randomized placebo-controlled trial of thromboprophylaxis in major elective general surgery using once daily injections of a low molecular weight heparin fragment (Fragmin). Thromb Haemostas 1989; 62(4):1046-1049. Padilla A et al. Inhibition of thrombin generation by heparin and low molecular weight (LMW) heparins in the absence and presence of platelet factor 4 (PF4). British Journal of Haematology, 1992; 82: 406-413. Schrader J, Knadt M, Zurcher C, Kostering H, Scheler F. Comparison of unfractionated heparin and low molecular weight heparin during long-term use in chronic haemodialysis and haemofiltration patients. Haemostasis 1986; 16(suppl 2):48-58. Torholm C, Broeng L, Jorgensen PS, Bjerregaard P, Josephsen L, Jorgensen PK, et al. Thromboprophylaxis by low-molecular-weight heparin in elective hip fracture surgery. A placebo-controlled study. J Bone Joint Surg Br 1991; 73-B:434-438 IMPORTANT: PLEASE READ

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Parenteral	Solution Ampoule: 10 000 IU (anti-factor Xa)/1 mL; Multi-Dose Vial: 25 000 IU (anti-factor Xa)/mL 3.8 mL Prefilled syringe with safety needle device 2 500 IU (anti-factor Xa)/0.2 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 vial only. For a complete listing, see Dosage Forms, Composition and Packaging section

Dosage	Anti-Xa levels (IU/mL) at peak 3 - 4 hours post s.c. injections * Mean +- SD
2500 IU	0.20 +- 0.08
5000 IU	0.49 +- 0.13
100 IU/kg	0.61 +- 0.17
120 IU/kg	0.91 +- 0.32
200 IU/kg	1.2 +- 0.43

Weight (kg)	Dosage (IU)
46-56	10 000
57-68	12 500
69-82	15 000
83 and above	18 000

Weight (kg)	Dosage (IU)
< 56	7 500
57-68	10 000
69-82	12 500
83-98	15 000
> 99	18 000

Dalteparin sodium (Low molecular weight heparin sodium)	Ampoule 10 000 IU (anti-Xa)	Multi-dose vial 25 000 IU (anti-Xa)
Sodium chloride *	q.s.	--
Benzyl alcohol	--	14 mg
Hydrochloric acid	pH adjustment	pH adjustment
Sodium hydroxide	pH adjustment	pH adjustment
Water for injection	ad 1 mL	ad 1 mL

Weight (kg)	Scheduled Dose (IU)	Reduced Dose (IU)	Mean Dose Reduction (%)
< 56	7 500	5 000	33
57-68	10 000	7 500	25
69-82	12 500	10 000	20
83-98	15 000	12 500	17
> 99	18 000	15 000	17

Dalteparin sodium	2 500 IU/0.2 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-X a	Anti-X a	Anti-X a	Anti-X a	Anti- X a	Anti- X a	Anti- X a
Sodium chloride * *	q.s.	-	-	-	-	-	-
Hydrochloric acid	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
Water for injection	ad 0.2 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

Trial design	Diagnosis	Dosage, route of administration and duration	Study subjects (n=number)	Mean age (Range)	Gender
Single-center, double-blind study comparing FRAGMIN to heparin	Patients undergoing hip replacement surgery	FRAGMIN 5000 IU qd s.c. starting the evening before surgery, or Heparin 5000 IU tid s.c., starting the morning of surgery. Treatment in both groups was continued for up to 9 days postoperatively.	140 enrolled, 139 treated. 136 underwent surgery: 67 FRAGMIN and 69 heparin.	69 yrs (range 42-87 yrs)	58.8% female

Indication	Dosing Regimen
Indication	FRAGMIN 2500 IU qd s.c.	Placebo qd s.c.
All Treated Abdominal Surgery Patients	102	102
Treatment Failures in Evaluable Patients Total Thromboembolic Events Proximal DVT Distal DVT PE	4/91 (4.4%) 1	16/91 (17.6%)
	0	5/91 (5.5%)
	4/91 (4.4%)	11/91 (12.1%)
	0	2/91 (2.2%) 2

	Dalteparin, n/N (%)	Placebo, n/N (%)	RR (95% CI)
Primary end point (day 21)	42/1518 (2.77)	73/1473 (4.96)	0.55 (0.38-0.80)
Venous thromboembolism and	42/1518 (2.77)	73/1473 (4.96)	0.55 (0.38-0.80)
sudden death
Sudden death	5/1829 (0.27)	3/1807 (0.17)	1.65 (...)
Pulmonary embolism, fatal	0/1829 (0.00)	2/1807 (0.11)	0.00 (...)
Pulmonary embolism, symptomatic	5/1759 (0.28)	4/1740 (0.23)	1.22 (...)
Deep vein thrombosis: distal,	3/1759 (0.17)	4/1739 (0.23)	0.74 (...)
symptomatic
Deep vein thrombosis: proximal,	2/1759 (0.11)	7/1739 (0.40)	0.28 (...)
symptomatic
Deep vein thrombosis: proximal,	27/1507 (1.79)	53/1453 (3.65)	0.48 (0.31-0.77)
asymptomatic
Secondary end point at day 14
All-cause mortality	8/1846 (0.43)	7/1831 (0.38)	1.13 (0.41-3.12)
Secondary end point at day 21
Deep vein thrombosis: proximal	32/1508 (2.12)	64/1464 (4.37)	0.49 (0.32-0.74)
and symptomatic distal
All-cause mortality	43/1829 (2.35)	42/1807 (2.32)	1.01 (0.66-1.54)
Secondary endpoint at day 90
Symptomatic venous	15/1615 (0.93)	21/1583 (1.33)	0.70 (0.36-1.35)
thromboembolism
(all deep vein thrombosis and
pulmonary embolism)
All symptomatic pulmonary	5/1615 (0.31)	6/1583 (0.38)	0.82 (0.25-2.67)
embolism
All symptomatic deep vein	10/1614 (0.62)	15/1579 (0.95)	0.65 (0.29-1.45)
thrombosis
All-cause mortality	107/1747 (6.12)	103/1715 (6.01)	1.02 (0.78-1.33)

	APTT	Anti-Xa	Ratio anti-Xa APTT
FRAGMIN *	60	165	2.6
Heparin	170	170	1

Dose (IU/kg)	t 2 (min)	AUC (IU/ML x min)	Clearance (IU/ML/min)	Vd (1)
Heparin KabiVitrum (40)	57 +- 12	71 +- 18	39 +- 14	3.13 +- 0.88
Fragmin (40)	* * * 126 +- 21	191 +- 61	15 +- 5	2.57 +- 0.65
Fragmin (60)	ns 139 +- 28	274 +- 64	15 +- 3	2.92 +- 0.78