FRAGMIN (dalteparin sodium) Dosage And Administration

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Dosing Considerations

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 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.

Dosage

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 ACTION AND 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 bleeding8, 13 (see ACTION AND CLINICAL PHARMACOLOGY – Special Populations and Conditions, 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 ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatric population).

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

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

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

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

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

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

Table 8: Recommended Dosage for Treatment of Acute Deep Vein Thrombosis
Weight (kg)Dosage (IU)
46-5610 000
57-6812 500
 
69-8215 000
83 and above*18 000

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

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

*For patient weighing 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 range31 (see ACTION AND CLINICAL PHARMACOLOGY – Special Populations and Conditions, Overweight population)

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

Month 1: 200 IU/kg body weight given s.c. once daily for the first 30 days of treatment, which can either be administered based on actual body weight, or approximated based on weight ranges as shown in the table below:

Table 9:
Month 1 - Recommended Dosage for Extended Treatment and Preventative Recurrence of Symptomatic VTE in Cancer Patients

Weight (kg)

Dosage (IU)

46-5610 000

57-68

12 500

69-82

15 000

83 and above*

18 000

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 range31 (see ACTION AND CLINICAL PHARMACOLOGY – Special Populations and Conditions, Overweight population).

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

Table 10:
Months 2 to 6 - Recommended Dosage for Extended Treatment and Preventative Recurrence of Symptomatic VTE in Cancer Patients
Weight (kg)Dosage (IU)
≤567 500
57-6810 000
69-8212 500
83-9815 000
≥9918 000

Dose reductions for chemotherapy-induced thrombocytopenia

In the case of chemotherapy- induced thrombocytopenia with platelet counts <50,000/mm3, FRAGMIN should be interrupted until the platelet count recovers above 50,000/mm3. For platelet counts between 50,000 and 100,000/mm3, FRAGMIN should be reduced by 17% to 33% of the 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.

Table 11:
Weight Based Dose Adjustment for Treatment of Chemotherapy-induced Thrombocytopenia
Month 1:
Weight (kg)Scheduled Dose (IU)Reduced Dose (IU)Mean Dose Reduction (%)
46-5610 000 7 50025
57-6812 50010 00020
69-8215 00012 50017
83 and above18 00015 00017
Month 2 – 6:
Weight (kg)Scheduled Dose (IU)Reduced Dose (IU)Mean Dose Reduction (%)
≤567 500 5 00033
57-6810 0007 50025
69-8212 50010 00020
83-9815 00012 50017
≥9918 00015 00017

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

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

Deep Vein Thrombosis in Hospitalized Patients with Severely Restricted Mobility

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

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.

Dilution

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

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

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

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