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 3500 IU (anti-factor Xa)/0.28 mL 5 000 IU (anti-factor Xa)/0.2 mL 7 500 IU (anti-factor Xa)/0.3 mL 10 000 IU (anti-factor Xa)/0.4 mL 12 500 IU (anti-factor Xa)/0.5 mL 15 000 IU (anti-factor Xa)/0.6 mL 16 500 IU (anti-factor Xa)/0.66 mL 18 000 IU (anti-factor Xa)/0.72 mL
Solution for injection 10 000 IU (anti-factor Xa)/mL, ampoules 10 x 1 mL
Solution for injection 25 000 IU (anti-factor Xa)/mL, 3.8 mL multi-dose vials
Solution for injection 2 500 IU (anti-factor Xa)/0.2 mL, single dose syringes* 10 x 0.2 m
Solution for injection 3 500 IU (anti-factor Xa)/0.28 mL, single dose syringes* 10 x 0.28 m
Solution for injection 5 000 IU (anti-factor Xa)/0.2 mL, single dose syringes* 10 x 0.2 m
Solution for injection 7 500 IU (anti-factor Xa)/0.3 mL, single dose syringes*, packages of
Solution for injection 10 000 IU (anti-factor Xa)/0.4 mL, single dose syringes*, packages of
Solution for injection 12 500 IU (anti-factor Xa)/0.5 mL, single dose syringes*, packages of
Solution for injection 15 000 IU (anti-factor Xa)/0.6 mL, single dose syringes*, packages of
Solution for injection 16 500 IU (anti-factor Xa)/0.66 mL, single dose syringes*, packages of
Solution for injection 18 000 IU (anti-factor Xa)/0.72 mL, single dose syringes*, packages of 5
* Prefilled syringe with safety needle device: clear glass barrel with stainless steel needle (27 G 1/2") and preassembled with safety needle guard device.
Fragmin may be administered subcutaneously (s.c.) or intravenously (i.v.)
Water for injection
ad 1 mL
Potency: Potency is described in International anti-Xa units (IU). One unit (anti-Xa) of dalteparin sodium, weight average molecular weight 6000 Daltons, corresponds to the activity of one unit of the 1st International Standard for LMWH with respect to inhibition of coagulation Factor Xa in plasma utilizing the chromogenic peptide substrate S-2765 (N-α-Benzyloxycarbonyl-D-arginyl-glycyl-arginine-pNA •2HCl).
Fragmin (Dalteparin Sodium Injection) is indicated for:
Pediatrics (2 weeks – 18 years): Health Canada has not authorized an indication for pediatric use. There is limited safety and efficacy information on the use of dalteparin in pediatric patients (see Monitoring and Laboratory Tests, 7.1.3 Pediatrics, and Use in Pediatrics (2 weeks – 18 years)).
Geriatrics: Elderly patients may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised (see Monitoring and Laboratory Tests and 7.1.4 Geriatrics).
Fragmin (dalteparin sodium injection) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, any non-medicinal ingredient (including benzyl alcohol when using the 25,000 IU multi-dose vial (see 7 WARNINGS AND PRECAUTIONS, 7.1.1 Pregnant Women) to other low molecular weight heparins (LMWHs) and/or heparin or pork products, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
Fragmin (dalteparin sodium injection) is also contraindicated in patients who have the following:
Serious Warnings and Precautions
Fragmin may be given by subcutaneous (s.c.) injection or by intermittent or continuous intravenous (i.v.) infusion, depending upon the circumstances. Clinical trials conducted in support of clinical uses outlined below generally used subcutaneous dosing.
Fragmin must NOT be administered intramuscularly (see 7 WARNINGS AND PRECAUTIONS).
The multi-dose vial of Fragmin (25,000 IU/mL) which contains benzyl alcohol must not be used in premature or newborn babies, pediatric patients and pregnant women.
Use in Patients with Renal Impairment
Renal impaired patients, particularly those with severe renal impairment (CrCl <30 mL/min), treated with Fragmin should be monitored carefully.
Administration of LMWHs 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 10 CLINICAL PHARMACOLOGY). Literature data suggest that in critically ill patients with severe renal insufficiency, thromboprophylaxis with Fragmin at 5,000 IU once daily, does not appear to be associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding (see Renal Insufficiency).
Use in Pediatrics (2 weeks – 18 years)
Dosage requirements in pediatrics with VTE are based on age and body weight in order to achieve therapeutic anti-Xa levels between 0.5 and 1.0 IU/mL at 4 hours post-administration (see Pediatrics).
Starting doses by s.c. administration twice daily (q12h) per age groups are 150 IU/kg (for 2 weeks to < 2 years); 125 IU/kg (for 2 years to < 8 years); and 100 IU/kg (for 8 years to ≤ 18 years). Adjust dose in increments or decrements of 25 IU/kg to achieve therapeutic anti-Xa levels.
Thromboprophylaxis in Conjunction with Surgery
The dose of Fragmin required for adequate prophylaxis without substantially increasing bleeding risk varies depending on patient risk factors.
General surgery with associated risk of thromboembolic complications: 2500 IU s.c. administered 1-2 hours before the operation, and thereafter 2500 IU s.c. each morning until the patient is mobilized, in general 5-7 days or longer.
General surgery associated with other risk factors (see Selection of General Surgery Patients): 5000 IU s.c. is given the evening before the operation and then 5000 IU s.c. the following evenings. Treatment is continued until the patient is mobilized, in general for 5-7 days or longer.
As an alternative, 2500 IU s.c. is given 1-2 hours before the operation, with 2500 IU s.c. given again no sooner than 4 hours after surgery, but at least 8 hours after the previous dose, provided primary hemostasis is obtained. Starting on the day after surgery, 5000 IU s.c. is given each morning, in general for 5-7 days or longer.
Elective hip surgery:5000 IU s.c. is given the evening before the operation and then 5000 IU s.c. the following evenings. Treatment is continued until the patient is mobilized, in general for 5-7 days or longer.
As an alternative 2500 IU s.c. is given 1-2 hours before the operation and 2500 IU s.c. 4-8 hours after surgery, provided primary hemostasis is obtained. Starting on the day after surgery, 5000 IU s.c. is given each morning, in general for 5-7 days or longer.
The pre-operative dose may be omitted and an initial dose of 2500 IU s.c. administered 4-8 hours after the operation, provided primary hemostasis is obtained. Starting on the day after surgery, 5000 IU s.c. is given each morning, in general for 5-7 days or longer. Omission of the pre-operative dose may reduce risk of peri-operative bleeding, however increased risk of venous thromboembolic events is possible. This option is based on the results of the North American Fragmin Trial (NAFT), which excluded patients at high risk of bleeding, i.e., documented cerebral or gastrointestinal bleeding within 3 months prior to surgery, defective hemostasis, e.g., thrombocytopenia (<100 x 109/L), ongoing anticoagulant treatment.
Treatment of Acute Deep Vein Thrombosis The following dosage is recommended: 200 IU/kg body weight given s.c. once daily. The expected plasma anti-Xa levels during subcutaneous treatment would be <0.3 IU anti-Xa/mL before injection and <1.7 IU anti-Xa/mL 3 - 4 hours after injection. In order to individualize the dose, a functional anti-Xa assay should be performed 3 - 4 hours post-injection. The single daily dose should not exceed 18 000 IU. The following weight ranges 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.
*For patient weighing 83 kg and above, data from one single publication suggest that in the thrombosis treatment setting, a weight-adjusted dose beyond the recommended maximum dose of 18000 International Units/day (the largest patient weighed 190 kg and received a daily dose of 38000 IU) results in mean peak anti-Xa levels that are within the therapeutically acceptable range (see Obesity).
Extended Treatment of Symptomatic Venous Thromboembolism (VTE) to Prevent Recurrence of VTE in Patients with Cancer
Month 1: 200 IU/kg body weight given s.c. once daily for the first 30 days of treatment, which can either be administered based on actual body weight, or approximated based on weight ranges as shown in the table below:
83 and above*
The total daily dose should not exceed 18,000 IU daily.
* For patient weighing 83 kg and above, data from one single publication suggests that in the thrombosis treatment setting, a weight-adjusted dose beyond the recommended maximum dose of 18,000 International Units/day (the largest patient weighed 190 kg and received a daily dose of 38,000 IU) results in mean peak anti-Xa levels that are within the therapeutically acceptable range (see Obesity).
Months 2-6: Approximately 150 IU/kg given s.c. once daily using the table shown below.
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 last 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.
Deep Vein Thrombosis in Hospitalized Patients with Severely Restricted Mobility
In hospitalized patients with severely restricted mobility during acute illness, the recommended dose of Fragmin is 5000 IU administered by s.c. injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.
Anticoagulation for Hemodialysis and Hemofiltration
Chronic renal failure, patients with no other known bleeding risk:
Optimisation of Fragmin dose may be required for each individual patient as different types of dialysis circuits and membranes and inter-patient variability lead to different clotting stimuli.
Hemodialysis and hemofiltration for a maximum of 4 hours: a single bolus injection of 5000 IU can be administered, either intravenously or into the arterial side of the dialyser, at the start of the procedure. Alternatively, the dose can be given as an intravenous bolus injection of 30 - 40 IU/kg body weight followed by intravenous infusion of 10 - 15 IU/kg body weight per hour. Either regimen normally produces plasma levels lying within the range of 0.5-1.0 IU anti-Xa/mL.
The 5000 IU starting dose for the single bolus dosing regimen can be adjusted, session-to-session, based on the outcome of the previous dialysis; the dose may be increased or decreased in steps of 500 or 1000 anti-Xa IU until a satisfactory outcome is obtained.
The following available prefilled syringes may be used for appropriate dosing and administration:
2 500 IU (anti-factor Xa)/0.2 mL 3 500 IU (anti-factor Xa)/0.28 mL 5 000 IU (anti-factor Xa)/0.2 mL 7 500 IU (anti-factor Xa)/0.3 mL 10 000 IU (anti-factor Xa)/0.4 mL 12 500 IU (anti-factor Xa)/0.5 mL
Hemodialysis and hemofiltration for more than 4 hours: intravenous bolus injection of 30 - 40 IU/kg body weight followed by intravenous infusion of 10 - 15 IU/kg body weight per hour. This dose normally produces plasma levels lying within the range of 0.5 - 1.0 IU anti-Xa/mL.
Acute renal failure, patients with high bleeding risk:
Intravenous bolus injection of 5 - 10 IU/kg body weight, followed by intravenous 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.
Reconstitution is not required for Fragmin. See Dilution below for further instructions.
Fragmin solution for injection (10 000 IU (anti-factor Xa)/1 mL)may be mixed with isotonic sodium chloride (9 mg/mL) or isotonic glucose infusion (50 mg/mL) solutions in 500 mL glass infusion bottles and plastic containers. This will provide a post‑dilution concentration of 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.
The infusion rate is 10 mL/hour. The solution should be used within 24 hours.
Patients who miss their scheduled dose should be advised to contact their healthcare professional and not take two doses at the next dosage time.
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.
Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.
Fragmin should NOT be administered intra‑muscularly.
Fragmin CANNOT BE USED INTERCHANGEABLY (UNIT FOR UNIT) WITH UNFRACTIONATED HEPARIN (UFH) OR OTHER 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.
The needle shield of the prefilled syringes may contain latex (natural rubber) which may potentially cause allergic reactions in individuals with hypersensitivity to latex.
Use in Patients with Prosthetic Heart Valves: Cases of prosthetic valve thrombosis have been reported in these patients who have received LMWHs 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 7.1.1 Pregnant Women).
Use in Unstable Coronary Artery Disease: When thrombolytic treatment is considered appropriate in patients with unstable angina and non-Q-wave myocardial infarction, concomitant use of an anticoagulant such as Fragmin may increase the risk of bleeding.
Fragmin should be used with caution in patients with a history of gastrointestinal ulceration.
Hemorrhage: Bleeding may occur in conjunction with unfractionated heparin or LMWH 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 Bleeding, 8.5 Post-Marketing Adverse Reactions).
Platelets/Thrombocytopenia: Platelet counts should be determined prior to the start of treatment with Fragmin and, subsequently, twice weekly for the duration of treatment. Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of Fragmin. Its incidence is unknown at present.
Caution is recommended when administering Fragmin to patients with congenital or drug induced thrombocytopenia or platelet defects.
During Fragmin administration, special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100 000/μL). A positive or unknown result obtained from in vitro tests for antiplatelet antibody in the presence of Fragmin or other LMWHs 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 8.2 Clinical Trial Adverse Reactions).
Heparin and LMWH can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium or taking potassium sparing drugs. Plasma potassium should be measured in patients at risk.
Monitoring Fragmin Activity: Determination of anti‑factor Xa levels in plasma is the only method available for monitoring Fragmin activity. Routine clotting assays are unsuitable for monitoring its anticoagulant activity. Only at very high plasma Fragmin levels is activated partial thromboplastin time (APTT) prolongation observed. Prolongation of APTT during hemodialysis and treatment of acute deep venous thrombosis should only be used as a criterion of overdose. Dose increases aimed at prolonging APTT could cause overdosing and bleeding.
Measurement of peak anti-Xa levels at about 4 hours post-dose should be considered for certain special patient populations 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.
Due to pharmacokinetic differences in neonates and young infants (≤ 2 years), a larger starting dose (e.g. 150 IU/kg) is required with upward dose adjustments expected (see 4.2 Recommended Dose and Dosage Adjustment, Use in Pediatrics (2 weeks – 18 years). Close monitoring of anti-Xa levels in pediatrics is warranted.
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 (see 10.3 Pharmacokinetics). Fragmin should be administered as directed (see 4 DOSAGE AND ADMINISTRATION).
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 8.2 Clinical Trial Adverse Drug Reactions).
As with all antithrombotic agents, there is a risk of systemic bleeding with dalteparin sodium administration. Care should be taken with dalteparin sodium use in newly operated patients. After treatment is initiated, patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain, periodic measurements of hemoglobin, and anti-Xa determinations.
Long term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with dalteparin the risk of osteoporosis cannot be excluded.
Safety and efficacy of LMWHs in high weight (e.g., >120 kg) and low weight (e.g., <46 kg) patients have not been fully determined. Individualized clinical and laboratory monitoring are recommended in these patients.
However, data from one single publication suggests that in the thrombosis treatment setting, a weight-adjusted dose beyond the recommended maximum dose of 18000 International Units/day (the largest patient weighed 190 kg and received a daily dose of 38000 IU) results in mean peak anti-Xa levels that are within the therapeutically acceptable range (see Obesity).
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with LMWHs 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 2 CONTRAINDICATIONS and 8 ADVERSE REACTIONS).
When a higher dose (5000 IU s.c.) of Fragmin is administered for thromboprophylaxis in conjunction with surgery, no spinal/epidural invasion should be performed for at least 12 hours following the last dose of Fragmin and the next dose should be held until at least 12 hours after the anaesthetic procedure. Alternatively, when a lower dose (2500 IU s.c.) of Fragmin is administered, the dose can be initiated 1 - 2 hours prior to surgery. Fragmin injection should be given after spinal/epidural anaesthesia and only if the anaesthesiologist considers the spinal/epidural puncture as uncomplicated. Indwelling catheters should not be removed or manipulated for at least 10 - 12 hours following the last dose of Fragmin.
In patients receiving higher therapeutic dalteparin doses (such as 100IU/kg -120 IU/kg every 12 hours or 200 IU/kg once daily), the interval for the insertion or removal of the epidural or spinal catheter should be a minimum of 24 hours. Extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction.
Use in Knee Surgery: The risk of bleeding in knee surgery patients receiving LMWHs 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 LMWH in this patient population.
Selection of General Surgery Patients: Risk factors associated with postoperative venous thromboembolism following general surgery include history of venous thromboembolism, varicose veins, obesity, heart failure, malignancy, previous long bone fracture of a lower limb, bed rest for more than 5 days prior to surgery, predicted duration of surgery of more than 30 minutes, and age 60 years or above.
Fragmin should be used with caution in patients with renal insufficiency, particularly in patients with severe renal insufficiency (CrCl < 30 mL/min). These patients should be carefully monitored because the half-life for anti-Xa activity after administration of Fragmin may be prolonged in this patient population (see 10 CLINICAL PHARMACOLOGY and Use in Patients with Renal Impairment). Although anti-Xa monitoring is the most appropriate measure of the pharmacodynamics effects of Fragmin, it remains a poor predictor of haemorrhage risk, nonetheless monitoring of anti-factor Xa activity may be considered in patients with severe renal impairment (CrCl < 30 mL/min). Dose reduction should be considered in patients with severe renal impairment.
Meanwhile, data from publications based on one study suggests that in critically ill patients with severe renal insufficiency, thromboprophylaxis with Fragmin at 5,000 IU once daily, does not appear to be associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding (see Renal Insufficiency).
A post-hoc subgroup analysis of a randomized open-label controlled study (CLOT study) was performed on patients with cancer and renal impairment who received Fragmin for up to 6 months at a dose level of 200 IU/kg daily for Month 1 and 150 IU/kg daily for Month 2-6. The bleeding rates increased as renal function decreased. The bleeding rates were 11.8% (any bleeding) and 4.1% (major bleeding) for patients with normal renal function and were 15.4% (any bleeding) and 7.7% (major bleeding) for patients with moderate renal impairment (CrCl ≥30 and <60 ml/min). For patients with severe renal impairment (CrCl <30 ml/min), the bleeding rates were 55.6% (any bleeding) and 22.2% (major bleeding).
The multi-dose vial of Fragmin (25,000 IU/mL) contains benzyl alcohol (14 mg/mL) as a preservative. Benzyl alcohol has been associated with serious adverse events, including a potentially fatal “Gasping Syndrome” in neonates. Cases of Gasping Syndrome have been reported in neonates when benzyl alcohol has been administered in amounts of 99-404 mg/kg/day. Manifestations of the disease include: metabolic acidosis, respiratory distress, gasping respirations, central nervous system dysfunction, convulsions, intracranial hemorrhages, hypoactivity, hypotonia, cardiovascular collapse and death. Benzyl alcohol containing formulations must not be used in premature or newborn babies. Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys’ capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old. Other formulations without benzyl alcohol are available. Because benzyl alcohol may cross the placenta, Fragmin preserved with benzyl alcohol should not be used in pregnant women.
There are also postmarketing reports of prosthetic valve thrombosis in pregnant women with prosthetic heart valves while receiving LMWHs 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 LMWHs or unfractionated heparin. Any attempt to anticoagulate such patients should normally only be undertaken by medical practitioners with documented expertise and experience in this clinical area.
Data from one single publication suggests that ante partum thromboprophylaxis is warranted in pregnant women with idiopathic thrombosis or symptomatic thrombophilia (see Pregnancy and Breast-feeding).
Caution is recommended when treating patients with an increased risk of haemorrhage, such as perinatal women (see Hematologic).
Teratogenic Effects: Available data from published literature have not reported a clear association with dalteparin and adverse developmental outcomes.
A prospective study “Efficacy of Thromboprophylaxis as an Intervention during Gravidity” (EThIG) involved 810 pregnant women and investigated a pregnancy-specific scheme for risk stratification (low, high, very high risk of VTE) with daily doses of Fragmin between 50 and 150 IU/kg body weight (in single cases up to max. 200 IU/kg body weight). Out of 810 pregnant women, 26 had no pregnancy outcome data. Out of 784 pregnancies with known outcomes: the incidence of miscarriage was 4.9%, premature births 15.9%, physical malformations 2.5%, and small for gestational age 11.2%.
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.
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 (2 weeks – 18 years): There is limited safety and efficacy data on the use of Fragmin in pediatric patients (see 8.2.1 Clinical Trial Adverse Reactions - (Pediatrics) and Pediatric population). If Fragmin is used in pediatric patients, anti-Xa levels should be monitored (see Monitoring and Laboratory Tests and 4 DOSAGE AND ADMINISTRATION).
Elderly patients receiving LMWHs 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.
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 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.
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.
The following table summarizes major bleeding events that occurred in pivotal trials of Fragmin for thromboprophylaxis in general surgery associated with thromboembolic complications.
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.
General Surgery Associated with Other Risk Factors*
Elective Hip Surgery
Fragmin vs Warfarin sodium**
Fragmin vs Heparin*
started before surgery
started after surgery
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.
Major Bleeding Events3,4
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.
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
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 disorders
Mild, reversible non-immunological thrombocytopenia
Transient elevation of liver transaminases (ASAT, ALAT)*
Immune system disorders
Skin and subcutaneous tissue disorders
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
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.
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.
The less common clinical trial adverse reaction data are not available.
The less common clinical trial adverse reaction data - pediatrics are not available.
The abnormal laboratory findings are not available.
In post-marketing experience, the following undesirable effects have been reported:
Severe immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications), see Platelets/Thrombocytopenia
Spinal or epidural hematoma
Pediatric population: The most common adverse events reported in patients who were <18 years of age were thrombocytopenia, haemorrhage, error in drug administration, thrombosis, and alopecia.
The drug interactions overview is not available.
Interactions with individual behaviours have not been established.
Fragmin should be used with caution in patients receiving oral anticoagulants, platelet inhibitors, non-steroidal anti-inflammatories, thrombolytic agents and dextran because of increased risk of bleeding. Acetylsalicylic acid (ASA), unless contraindicated, is recommended in patients treated for unstable angina or non-Q-wave myocardial infarctions (see 4 DOSAGE AND ADMINISTRATION, 8 ADVERSE REACTIONS).
Because NSAIDs and ASA analgesic/anti-inflammatory doses reduce production of vasodilatory prostaglandins, and thereby renal blood flow and renal excretion, particular care should be taken when administering dalteparin concomitantly with NSAIDs or high dose ASA in patients with renal failure.
Interactions with food have not been established.
Interactions with herbs have not been established.
Interactions with lab tests have not been established
Fragmin is a LMWH with antithrombotic properties. It acts by potentiating the activity of antithrombin III, inhibiting formation of both Factor Xa and thrombin by antithrombin. However, it preferentially potentiates inhibition of Factor Xa, resulting in only slight increases of clotting time, i.e., activated partial thromboplastin time (APTT). 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).
Doses of Fragmin Injection of up to 10,000 anti-Xa IU administered subcutaneously as a single dose or two 5,000 IU doses 12 hours apart to healthy subjects did not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT. Subcutaneous administration of doses of 5,000 IU twice daily of Fragmin for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.
Specific activity of Fragmin is consistent with that of unfractionated heparin regarding anti-Xa activity but has less effects on APTT. For Fragmin, 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. Fragmin is also associated with smaller increases in free fatty acids and plasma lipoprotein lipase activities than heparin.
Fragmin administration appears to give 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.
120 IU/kg i.v.
2.2 ± 0.3 IU/mL
119 ± 17 min
392 ± 68.6 IU*min/mL
20.5 ± 2.5 mL/min
3.4 ± 0.5 L
120 IU/kg s.c.
0.6 ± 0.1 IU/mL
228 ± 40 min
339 ± 49.5
The absolute bioavailability of Fragmin measured as the anti-Factor Xa activity after subcutaneous injection is 87 ± 6%. Compared with heparin, Fragmin is well absorbed following subcutaneous injection. The plasma concentration of dalteparin sodium following subcutaneous administration is easily predicted since there is a direct relationship between the administered dose and the anti-Factor Xa activity in plasma. Increasing the dose from 2500 IU to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was proportionally greater by about one-third. 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).
The volume of distribution was found to be approximately 3 litres (40 to 60 mL/kg).
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.).
After administration of IV doses of 40, 60 and 120 IU/kg, mean plasma half-lives were 2.1 ± 0.3 , 2.3 ± 0.4 hours, and 2.0 ± 0.3 respectively that was twice as long as for heparin. The half life after subcutaneous injection of Fragmin in the doses 2500, 5000 and 10 000 IU anti Xa, was 3.4, 3.3 and 3.9 hours respectively. Longer plasma half-lives were observed following subcutaneous injections possibly due to delayed absorption.
Dalteparin is primarily excreted by the kidneys; however, the biological activity of the renally eliminated fragments is not well characterized. In 72 hours, approximately 70 % of radioactive Fragmin dose has been excreted in urine, however less than 5% of anti-Xa activity is detectable in the urine. The mean plasma clearances of dalteparin anti-Factor Xa activity in normal volunteers following single IV bolus doses of 120 IU/kg was 20.5 ± 2.45 mL/min. Dalteparin sodium, in contrast to heparin, is not cleared by a saturable mechanism, thus elimination half-life is dose independent.
Pediatrics: A prospective study by Nohe et al. investigated the efficacy, safety and inverse age relation in the dose of dalteparin to achieve therapeutic plasma anti-Xa activity in 48 paediatric patients (from 31 weeks preterm to 18 years) with arterial and venous thrombosis.Anti-Xa levels were adjusted 4 hours post-dose to 0.2 to 0.4 IU/mL for prophylaxis and to 0.4 to 1.0 IU/mL for therapy. The treatment duration was 3 to 6 months. In 10 patients who received dalteparin (95 ± 52 IU/kg s.c. once daily) for thromboprophylaxis, no thromboembolic events occurred. The dose for antithrombotic therapy was 129 ± 43 IU/kg sc once daily. In the 23 patients given dalteparin for primary antithrombotic therapy, 7/23 (30%) had complete recanalization, 7/23 (30%) had partial recanalization, and 9/23 (40%) had no recanalization. In the 8 patients administered dalteparin for secondary antithrombotic therapy following successful thrombolysis, recanalisation was maintained or improved. In the 5 patients receiving dalteparin following failed thrombolysis, no recanalization was seen. Minor bleeding, reported in 2/48 children (4%), resolved after dose reduction.
Study FRAG-A001-201 was an open-label, multi-center, Phase 2 clinical trial to determine twice-daily dosing recommendations for dalteparin (s.c. injection 12 hours apart), as a function of age, in order to achieve therapeutic anti-Xa levels (0.5 to 1.0 IU/mL) at 4 hours (±1 h) post-dose. A total of 38 pediatric patients with (N = 26) or without (N = 12) cancer received dalteparin for up to 3 months for the treatment and secondary prophylaxis of VTE, with starting doses defined for 5 age groups (Table 16). All patients had dose adjustments in increments or decrements of 25 IU/kg in order to achieve 0.5 to 1.0 IU/mL during the 7-day dose adjustment period. A total of 26 patients completed the study and 12 prematurely discontinued (4 due to adverse events, 3 patients withdrew consent and 5 for other reasons). At study completion, 21 (61.8%) patients had achieved resolution of the qualifying VTE; 7 (20.6%) patients showed regression, 2 (5.9%) patients showed no change, no patients showed progression and 4 (11.8%) patients did not contribute data for this analysis. In addition, 1 (2.9%) patient experienced a new VTE during the study. None of the patients received concomitant treatment with vitamin K antagonists.
Supplementary data on the dose of dalteparin required to achieve therapeutic anti-Xa levels were obtained from the Kids-DOTT and Mayo Clinic Studies with similar dosage recommendations. The median doses of dalteparin (IU/kg) to achieve required therapeutic anti- Xa levels per age group are presented in Table 16. Time to achieve therapeutic anti-Xa levels during the dose adjustment was approximately 4 days for patients aged < 8 years, and 2 days for patients aged ≥ 8 years in Study FRAG-A001-201.
Store at room temperature, (15 - 30ºC).
The 25 000 IU/mL multi-dose vial must be used within 2 weeks after initial penetration.
Follow standard guidelines for disposal of prefilled syringe with safety needle device.
Do not remove any small air bubbles from the prefilled syringe before injection.
Control #: 266850 DEC 29, 2022
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