1 INDICATIONS AND USAGE

1.1 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

FRAGMIN® Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy [see Clinical Studies (14.1)].

1.2 Prophylaxis of Deep Vein Thrombosis

FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

• In patients undergoing hip replacement surgery [see Clinical Studies (14.2)];
• In patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.3)];
• In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness [see Clinical Studies (14.4)].

1.3 Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

FRAGMIN is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months [see Clinical Studies (14.5)].

Limitations of Use
Fragmin is not indicated for the acute treatment of VTE.

2 DOSAGE AND ADMINISTRATION

FRAGMIN is administered by subcutaneous injection. It must not be administered by intramuscular injection.

FRAGMIN Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.

Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of FRAGMIN activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN. [See Warnings and Precautions (5)].

2.1 Adult Dosage

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of FRAGMIN Injection is 120IU/kg of body weight, but not more than 10,000IU, subcutaneously every 12hours with concurrent oral aspirin (75 to 165mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8days. Concurrent aspirin therapy is recommended except when contraindicated.

Table1 lists the volume of FRAGMIN, based on the 9.5mL multiple-dose vial (10,000IU/mL), to be administered for a range of patient weights.

Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery: Table2 presents the dosing options for patients undergoing hip replacement surgery. The usual duration of administration is 5 to 10days after surgery; up to 14days of treatment with FRAGMIN have been well tolerated in clinical trials.

Abdominal Surgery: In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of FRAGMIN is 2500IU administered by subcutaneous injection once daily, starting 1 to 2hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 to 10days.

In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of FRAGMIN is 5000IU subcutaneously the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10days. Alternatively, in patients with malignancy, 2500IU of FRAGMIN can be administered subcutaneously 1 to 2hours before surgery followed by 2500IU subcutaneously 12hours later, and then 5000IU once daily postoperatively. The usual duration of administration is 5 to 10days.

Medical Patients During Acute Illness: In medical patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN is 5000IU administered by subcutaneous injection once daily. In clinical trials, the usual duration of administration was 12 to 14days.

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer: In patients with cancer and symptomatic venous thromboembolism, the recommended dosing of FRAGMIN is as follows: for the first 30days of treatment administer FRAGMIN 200IU/kg total body weight subcutaneously once daily. The total daily dose should not exceed 18,000IU. Table3 lists the dose of FRAGMIN to be administered once daily during the first month for a range of patient weights.

Month 1

Months 2 to 6

Administer FRAGMIN at a dose of approximately 150IU/kg, subcutaneously once daily during Months2 through 6. The total daily dose should not exceed 18,000IU. Table4 lists the dose of FRAGMIN to be administered once daily for a range of patient weights during months2-6.

Safety and efficacy beyond six months have not been eva luated in patients with cancer and acute symptomatic VTE [see Warnings and Precaution (5) and Adverse Reactions (6.1)].

2.2 Dose reductions for thrombocytopenia in patients with cancer and acute symptomatic VTE

In patients receiving FRAGMIN who experience platelet counts between 50,000 and 100,000/mm3, reduce the daily dose of FRAGMIN by 2,500IU until the platelet count recovers to ≥100,000/mm3. In patients receiving FRAGMIN who experience platelet counts <50,000/mm3, discontinue FRAGMIN until the platelet count recovers above 50,000/mm3.

2.3 Dose reductions for renal insufficiency in extended treatment of acute symptomatic venous thromboembolism in patients with cancer

In patients with severely impaired renal function (CrCl <30mL/min), monitor anti-Xa levels to determine the appropriate FRAGMIN dose. Target anti-Xa range is 0.5-1.5IU/mL. When monitoring anti-Xa in these patients, perform sampling 4-6hrs after FRAGMIN dosing and only after the patient has received 3-4doses.

2.4 Administration

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 90degree angle.

Inspect FRAGMIN prefilled syringes and vials visually for particulate matter and discoloration prior to administration

After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2weeks. Discard any unused solution after 2weeks.

Instructions for using the prefilled single-dose syringes preassembled with needle guard devices

Fixed dose syringes: To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

Graduated syringes: Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

3 DOSAGE FORMS AND STRENGTHS

2,500IU/ 0.2mL single-dose prefilled syringe
5,000IU/ 0.2mL single-dose prefilled syringe
7,500IU/ 0.3mL single-dose prefilled syringe
10,000IU/ 0.4mL single-dose prefilled syringe
10,000IU/ 1mL single-dose graduated syringe
12,500IU/ 0.5mL single-dose prefilled syringe
15,000IU/ 0.6mL single-dose prefilled syringe
18,000IU/ 0.72mL single-dose prefilled syringe
95,000IU/ 3.8mL multiple-dose vial
95,000IU/ 9.5mL multiple-dose vial

4 CONTRAINDICATIONS

• Active major bleeding
• History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis.
• Hypersensitivity to dalteparin sodium (e.g.,pruritis, rash, anaphylactic reactions) [see Adverse Reactions (6.2)]
• In patients undergoing Epidural/Neuraxial anesthesia, do not administer FRAGMIN [See Boxed Warning];
  • As a treatment for unstable angina and non_q wave MI
  • For prolonged VTE prophylaxis.
• Hypersensitivity to heparin or pork products

5 WARNINGS AND PRECAUTIONS

5.1 Increased Risk of Hemorrhage

Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity , [see Boxed Warning and Adverse Reactions (6.2) and Drug Interactions (7)].

Use FRAGMIN with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery. Fragmin may enhance the risk of bleeding in patients with thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding. Bleeding can occur at any site during therapy with FRAGMIN.

5.2 Thrombocytopenia

Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present. In clinical practice, cases of thrombocytopenia with thrombosis, amputation and death have been observed.[See Contraindications (4)] Closely monitor thrombocytopenia of any degree.

In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of <50,000/mm3 occurred in <1% of patients.

In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6months in the FRAGMIN treatment arm, platelet counts of <100,000/mm3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the FRAGMIN arm and 8.1% of patients in the OAC arm. FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm3.

5.3 Benzyl Alcohol

Each multiple-dose vial of FRAGMIN contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Because benzyl alcohol may cross the placenta, use caution when administering FRAGMIN preserved with benzyl alcohol to pregnant women. If anticoagulation with FRAGMIN is needed during pregnancy, use preservative-free formulations, where possible. [See Use in Specific Populations (8.1)].

5.4 Laboratory Tests

Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with FRAGMIN. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of FRAGMIN activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN. Anti-Factor Xa may be used to monitor the anticoagulant effect of FRAGMIN, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding occurs during FRAGMIN therapy.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not accurately reflect the rates observed in practice.

Hemorrhage

The incidence of hemorrhagic complications during treatment with FRAGMIN Injection has been low. The most commonly reported side effect is hematoma at the injection site. The risk for bleeding varies with the indication and may increase with higher doses.

Unstable Angina and Non-Q-Wave Myocardial Infarction

Table5 summarizes major bleeding reactions that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

Hip Replacement Surgery

Table6 summarizes: 1)all major bleeding reactions and, 2)other bleeding reactions possibly or probably related to treatment with FRAGMIN (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.

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