Posology : מינונים

2 DOSAGE AND ADMINISTRATION

General
DO NOT ADMINISTER DALTEPARIN BY THE INTRAMUSCULAR ROUTE.
2.1 Recommended Dosage
Treatment of Acute Deep Venous Thrombosis and Pulmonary Embolism

FRAGMIN can be administered subcutaneously either as a single daily injection or as two daily injections.

Once daily administration:
200 IU/kg body weight is administered SC once daily. Monitoring of the anticoagulant effect is not necessary. The single daily dose should not exceed 18000 IU.
Twice daily administration:
Alternatively, a dose of 100 IU/kg total body weight administered SC twice daily may be given.
Monitoring of the anticoagulant effect is generally not necessary but should be considered for specific patient populations [see Warnings and Precautions (5.1)].

Maximum plasma levels are obtained 3-4 hours after SC injection when samples should be taken.
Recommended plasma levels are between 0.5-1.0 IU anti-Xa/ml.

Simultaneous anticoagulation with oral vitamin K antagonists can be started immediately.
Treatment with FRAGMIN is continued until the prothrombin complex levels (factor II, VII, IX and X) have decreased to a therapeutic level. At least five days of combined treatment is normally required.
Outpatient treatment is feasible using the same doses recommended for treatment in a medical institution.

Prevention of Clotting During Haemodialysis and Haemofiltration

Administer dalteparin intravenously (IV), selecting the appropriate regimen from those described below.
•   Patients with Chronic renal insufficiency or patients with no known risk of bleeding: These patients normally require few dose adjustments, and therefore frequent monitoring of anti-Xa levels is not necessary for most patients. Recommended doses usually produce plasma levels between 0.5 to 1.0 IU anti-Xa/mL during dialysis.

•   Hemodialysis and hemofiltration up to a maximum of 4 hours:
Either 30 to 40 IU/kg total body weight IV bolus injection followed by 10 to 15 IU/kg/hour IV infusion, or a single IV bolus injection of 5000 IU.

•   Hemodialysis and hemofiltration longer than 4 hours:
Administer 30 to 40 IU/kg total body weight IV bolus injection, followed by 10 to 15 IU/kg/hour IV infusion.

•     Patients with Acute renal failure or patients with high risk of bleeding: Administer 5 to 10 IU/kg total body weight as IV bolus injection, followed by 4 to 5 IU/kg/hour IV infusion.
Patients undergoing acute hemodialysis have a narrower therapeutic range than patients on chronic hemodialysis, and should undergo comprehensive monitoring of anti-Xa levels. Recommended plasma levels are between 0.2 to 0.4 IU anti-Xa/mL.

Thromboprophylaxis in Conjunction with Surgery

Administer dalteparin subcutaneously (SC). Monitoring of the anticoagulant effect is generally not necessary. If done, samples should be taken during maximum plasma levels (3 to 4 hours after an SC injection). Recommended doses usually produce peak plasma levels between 0.1 and 0.4 IU anti-Xa/mL.

• General surgery:
Select the appropriate regimen from those listed below.

• Patients at risk for thromboembolic complications:
2500 IU SC within 2 hours before surgery and 2500 IU SC each postoperative morning until the patient is mobilized (generally 5 to 7 days or longer).
• Patients with additional risk factors for thromboembolism (e.g., malignancy): Administer dalteparin until the patient is mobilized (generally 5 to 7 days or longer).
- Start on day before surgery - 5000 IU SC on the evening before surgery.
Following surgery, 5000 IU SC each evening.
- Start on day of surgery - 2500 IU SC within 2 hours before surgery and 2500 IU SC 8 to 12 hours later, but no sooner than 4 hours after the end of surgery. Starting on the day after surgery, 5000 IU SC each morning.

•     Orthopedic surgery (such as hip replacement surgery):
Administer dalteparin for up to 5 weeks after surgery, selecting one of the regimens listed below.
- Preoperative start: Evening before surgery - 5000 IU SC on the evening before surgery. Following surgery, 5000 IU SC each evening.
- Preoperative start: Day of surgery - 2500 IU SC within 2 hours before surgery and 2500 IU SC 8 to 12 hours later, but no sooner than 4 hours after the end of surgery. Starting on the day after surgery, 5000 IU SC each morning.
- Postoperative start - 2500 IU SC 4 to 8 hours after surgery, but no sooner than 4 hours after the end of surgery. Starting on the day after surgery, 5000 IU SC each day.

Thromboprophylaxis in Patients with Restricted Mobility

Administer 5000 IU of dalteparin subcutaneously (SC) once daily, generally for 12 to 14 days or longer in patients with continued restricted mobility. Monitoring of the anticoagulant effect is generally not necessary.

Unstable Coronary Artery Disease, ( Unstable Angina and Non-ST-elevation Myocardial Infarction) 
Administer dalteparin 120 IU/kg total body weight subcutaneously (SC) every 12 hours up to a maximum dose of 10,000 IU/12 hours. Unless specifically contraindicated, patients should also receive concomitant therapy with acetylsalicylic acid (75 to 325 mg/day). Continue treatment until the patient is clinically stable (generally at least 6 days), or longer if considered of benefit by the physician.

Thereafter, extended treatment with a fixed dose of dalteparin is recommended until a revascularization procedure is performed (such as percutaneous interventions [PCI] or coronary artery bypass graft [CABG]). The total treatment period should not exceed 45 days.

The dose of dalteparin is selected according to the patient’s gender and weight: - For women weighing less than 80 kg and men weighing less than 70 kg, administer 5000 IU SC every 12 hours.
- For women weighing at least 80 kg and men weighing at least 70 kg, administer 7500 IU SC every 12 hours.

Monitoring of the anticoagulant effect is generally not necessary but should be considered for specific patient populations [See Warnings and Precautions (5.1)].
Samples should be taken during maximum plasma levels (3 to 4 hours after a SC injection). Recommended peak plasma levels are between 0.5 and 1.0 IU anti-Xa/mL.

Extended treatment of symptomatic VTE to reduce recurrence of VTE in patients with cancer 
• Month 1
Administer dalteparin 200 IU/kg total body weight subcutaneously (SC) once daily for the first 30 days of treatment. The total daily dose should not exceed 18,000 IU daily.
• Months 2-6
Dalteparin should be administered at a dose of approximately 150 IU/kg subcutaneously, once daily using fixed dose syringes and Table 1 shown below.

Table 1: Dosage determination for months 2-6

Body Weight (kg)          Dalteparin Dose (IU)
≤56                         7500

57 to 68                      10,000

69 to 82                      12,500
83 to 98                      15,000

≥99                         18,000

2.2 Dose reductions for chemotherapy-induced thrombocytopenia
Thrombocytopenia
In the case of chemotherapy-induced thrombocytopenia with platelet counts <50,000/mm3, dalteparin should be interrupted until the platelet count recovers above 50,000/mm3.

For platelet counts between 50,000 and 100,000/mm3, dalteparin should be reduced by 17% to 33% of the initial dose depending on the patient’s weight (Table 2). Once the platelet count recovered to ≥100,000/mm3, dalteparin should be re-instituted at full dose.

Table 2: Dose Reduction of Dalteparin for Thrombocytopenia 50,000-100,000/mm3 
Body Weight (kg)                    Scheduled                     Reduced                Mean Dose Dalteparin Dose (IU)            Dalteparin Dose           Reduction
(IU)                  (%)
≤56                              7500                         5000                   33 57 to 68                          10,000                        7500                   25 69 to 82                          12,500                       10,000                  20 83 to 98                          15,000                       12,500                  17 ≥99                             18,000                       15,000                  17 Body Weight (kg)                      Scheduled                     Reduced                  Mean Dose Dalteparin Dose (IU)            Dalteparin Dose             Reduction (IU)                    (%)

2.3 Renal failure
In the case of significant renal failure, defined as a creatinine level >3 x ULN, the dose of dalteparin should be adjusted to maintain an anti-Xa therapeutic level of 1 IU/mL (range 0.5-1.5 IU/mL) measured 4-6 hours after the dalteparin injection. If the anti-Xa level is below or above the therapeutic range, the dose of dalteparin should be increased or reduced, respectively, by one syringe formulation and the anti-Xa measurement should be repeated after 3-4 new doses. This dose adjustment is to be repeated until the anti-Xa therapeutic level is achieved.
2.4 Compatibility
FRAGMIN is compatible with isotonic sodium chloride (9 mg/ml) or isotonic glucose (50 mg/ml) infusion solution in glass bottles and plastic containers. The solution should be used within 12 hours.
Compatibility between FRAGMIN and other products has not been investigated.

2.5 Administration
Latex Allergy: Persons with latex allergies should not handle the FRAGMIN prefilled syringe because the needle shield may contain natural rubber latex which may cause allergic reactions.
Subcutaneous injection technique: Patients should be sitting or lying down and FRAGMIN administered by deep subcutaneous injection. FRAGMIN may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area around the navel or the thigh is used, using the thumb and forefinger, you must lift up a fold of skin while giving the injection.
The entire length of the needle should be inserted at a 45 to 90-degree angle.
Inspect FRAGMIN prefilled syringes and vials visually for particulate matter and discoloration prior to administration 
2.6 Pediatric Patients

FRAGMIN is not indicated for Pediatric Patients.