FRAGMIN 8 Adverse Reactions

dalteparin sodium

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8.1 Adverse Reaction Overview

Clinically significant adverse reactions observed with use of Fragmin and other LMWHs include bleeding events and local reactions, with a low incidence of thrombocytopenia and allergic reactions.

The safety of long term dalteparin administration has not been established.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

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 2.0 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.

Table 8 – 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	11 (2.9)	3 (1.1)	4 (3.7)
Perioperative 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 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.

Table 9 – 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*
	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.

Table 10 – 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%)
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.

Table 11 – Bleeding Events for Extended Treatment of Symptomatic VTE to Prevent Recurrence of VTE in Patients with Cancer (CLOT trial)
	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.

Table 12 – 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.

Table 13 – Other Adverse Drug Reactions
MedDRA System Organ Class	Adverse Drug Reactions	Frequency
Blood and lymphatic system disorders	Mild, reversible non-immunological thrombocytopenia	Common
Blood and lymphatic system disorders	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	Spinal or epidural haematoma	Unknown
* 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.

Anticoagulation for Hemodialysis and Hemofiltration

Chronic renal failure, patients with no other known bleeding risk:
In a study investigating a modified Fragmin dosing regimen that permitted dose adjustment, involving 152 patients undergoing 3 or 4 hemodialysis (HD) sessions per week, with each session planned for 4 hours or less, for maximum study duration of 20 HD sessions, no patients experienced major bleeding and no deaths were reported. All patients started with a 5000 IU bolus but dose adjustments of 500 IU or 1000 IU were permitted, session-to-session, as indicated, based upon the occurrence of clotting or bleeding events. For 1 (0.7%) patient, a clinically relevant non-major bleed was reported, and for 38 (25%) patients, minor bleeds were reported.

A total of 218 all-cause AEs were reported in the study, with 95 (62.5%) of 152 patients reporting at least 1 AE. The most often reported treatment-related AE was arteriovenous fistula site haemorrhage, reported in 15 (9.9%) patients. Post procedural haemorrhage was reported in 6 (3.9%) patients. Contusion was reported in 5 (3.3%) patients. These AEs were considered by the Investigator to be related to study drug.

Skeletal Effects
Use of LMWHs over extended periods has been reported to be associated with development of osteopenia.

8.2.1 Clinical Trial Adverse Reactions - Pediatrics

In a 3-month pediatric study (FRAG-A001-201) in 38 patients (with or without cancer) treated for symptomatic VTE, 19 (50.0%) patients experienced 53 treatment-related AEs. The most common (greater than 10%) adverse reactions were injection site bruising (30%), contusion (12%), and epistaxis (10%). Major bleeding (intestinal hematoma) occurred in one patient (2%). Discontinuation due to adverse reactions occurred in 12% of patients, most often due to thrombocytopenia (4%).

The long-term effects of treatment with Fragmin in pediatric patients, including effects on growth and bone metabolism, are unknown.

8.3 Less Common Clinical Trial Adverse Reactions

The less common clinical trial adverse reaction data are not available.

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

The less common clinical trial adverse reaction data - pediatrics are not available.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

The abnormal laboratory findings are not available.

8.5 Post-Market Adverse Reactions

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

Table 14 – Post-Marketing Experience Adverse Drug Reactions
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 Platelets/Thrombocytopenia	Rare
	Thrombocytopenia	Unknown
	Thrombocythemia	Unknown
Immune system disorders	Hypersensitivity reactions	Uncommon
	Anaphylactic reactions	Rare
	Urticaria	Uncommon
Skin and subcutaneous tissue disorders	Skin necrosis	Very rare
	Alopecia	Common
	Rash	Unknown
	Pruritus	Uncommon
	Erythema	Uncommon
General disorders and administration site conditions	Retroperitoneal hemorrhage*	Very rare
	Gastrointestinal hemorrhage*	Unknown
	Intracranial hemorrhage*	Unknown
	Hemorrhage (bleeding at any site)	Common
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

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8 Adverse Reactions

8.1 Adverse Reaction Overview

Clinically significant adverse reactions observed with use of Fragmin and other LMWHs include bleeding events and local reactions, with a low incidence of thrombocytopenia and allergic reactions.

The safety of long term dalteparin administration has not been established.

8.2 Clinical Trial Adverse Reactions

Bleeding

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.

Table 8 – 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	11 (2.9)	3 (1.1)	4 (3.7)
Perioperative 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 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

Table 9 – 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*
	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

Treatment of Acute Deep Vein Thrombosis

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.

Table 10 – 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%)
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.

Table 11 – Bleeding Events for Extended Treatment of Symptomatic VTE to Prevent Recurrence of VTE in Patients with Cancer (CLOT trial)
	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.

Table 12 – 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.

Table 13 – Other Adverse Drug Reactions
MedDRA System Organ Class	Adverse Drug Reactions	Frequency
Blood and lymphatic system disorders	Mild, reversible non-immunological thrombocytopenia	Common
Blood and lymphatic system disorders	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	Spinal or epidural haematoma	Unknown
* 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.

Anticoagulation for Hemodialysis and Hemofiltration

Skeletal Effects
Use of LMWHs over extended periods has been reported to be associated with development of osteopenia.

8.2.1 Clinical Trial Adverse Reactions - Pediatrics

The long-term effects of treatment with Fragmin in pediatric patients, including effects on growth and bone metabolism, are unknown.

8.3 Less Common Clinical Trial Adverse Reactions

The less common clinical trial adverse reaction data are not available.

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

The less common clinical trial adverse reaction data - pediatrics are not available.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

The abnormal laboratory findings are not available.

8.5 Post-Market Adverse Reactions

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

Table 14 – Post-Marketing Experience Adverse Drug Reactions
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 Platelets/Thrombocytopenia	Rare
	Thrombocytopenia	Unknown
	Thrombocythemia	Unknown
Immune system disorders	Hypersensitivity reactions	Uncommon
	Anaphylactic reactions	Rare
	Urticaria	Uncommon
Skin and subcutaneous tissue disorders	Skin necrosis	Very rare
	Alopecia	Common
	Rash	Unknown
	Pruritus	Uncommon
	Erythema	Uncommon
General disorders and administration site conditions	Retroperitoneal hemorrhage*	Very rare
	Gastrointestinal hemorrhage*	Unknown
	Intracranial hemorrhage*	Unknown
	Hemorrhage (bleeding at any site)	Common
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

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