Adverse Drug 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.
Clinical Trial Adverse Drug Reactions
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.
|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.
Associated with Other Risk Factors*
Elective Hip Surgery
FRAGMIN vs Warfarin sodium**
FRAGMIN vs Heparin*
started before surgery
started after surgery
Warfarin sodium5 N=489
- 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.
120 IU/kg/12 hr. s.c.1
i.v. and s.c.2
q 12 hr. s.c.
N=760 n (%)
Major Bleeding Events3,4
- 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.
- FRAGMIN 200 IU/kg s.c. administered once daily for the first month, then approximately 150 IU/kg s.c.for months 2-6
- 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.
Fatal, day 21
Major, day 14
Major, day 21
Minor, day 14
Minor, day 21
- 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
Blood and lymphatic system
Mild, reversible non-immunological
Transient elevation of liver
transaminases (ASAT, ALAT)*
Immune system disorders
Skin and subcutaneous tissue
Skin rash, Allergic reactions and Skin necrosis
General disorders and
administration site conditions
Pain at injection site
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.
Use of LMWHs over extended periods has been reported to be associated with development of osteopenia.
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.
Post-Marketing Adverse Reactions
In post-marketing experience, the following undesirable effects have been reported:
MedDRA System Organ
Adverse Drug Reactions
Blood and lymphatic system
Severe immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications), see WARNINGS AND PRECAUTIONS, Hematologic, Platelets/Thrombocytopenia,
Immune system disorders
Skin and subcutaneous
General disorders and administration site
Hemorrhage (bleeding at any site)
Injury, poisoning and
Spinal or epidural hematoma
* 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.