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NAFT

NAFT Trial Proves FRAGMIN^® More Effective Than Warfarin in Early Postoperative* Dosing

Multicenter, randomized, double-blind clinical trial comparing 3 prophylactic regimens in 1472 patients undergoing hip replacement surgery during the acute hospital stay (days 0-6±2)

Patients were randomized to one of three treatment groups:


1.	PRE-OPERATIVE FRAGMIN GROUP: FRAGMIN 2500 IU s.c. within 2 hours before surgery, followed by another dose of FRAGMIN 2500 IU s.c. at least 4 hours (6.6 ± 2.3 hr) after surgery. FRAGMIN 5000 IU once daily s.c. began on postoperative day 1.

2.	POST-OPERATIVE FRAGMIN GROUP: FRAGMIN 2500 IU s.c. at least 4 hours (6.6 ± 2.4 hr) after surgery. FRAGMIN 5000 IU once daily s.c. began on postoperative day 1.

3.	WARFARIN GROUP: Warfarin sodium the evening of the day of surgery, then continued daily at a dose adjusted for INR 2 to 3 (initial dose 10mg^†).

The primary end point was DVT confirmed by bilateral ascending radiocontrast venography performed after surgery in each group (mean, 5.7 days)

* Early postop dosing is considered 4-8 hours after surgery

† 5mg in patients ≥ 70 years or < 57kg



	‡	Based on a post hoc analysis

		In preop dosing, FRAGMIN^® was associated with an incidence of proximal DVT of 0.8% (3/354) vs. 3.0% (11/363) with warfarin (P=0.04)^§34

		§ Another study evaluated the efficacy and safety of FRAGMIN^® vs warfarin in patients undergoing hip-replacement surgery. In preop dosing, FRAGMIN^® was associated with an incidence of proximal DVT of 5.2% vs 8.4% (P=0.185) and an incidence of overall DVT of 14.6% vs 25.8% (P=0.006) with warfarin.

		In preop dosing, FRAGMIN^® was associated with a total DVT incidence of 10.7% (36/337) vs. 24.0% (81/338) with warfarin (P<0.001)³⁴



	\|\|	Major bleeding: clinically overt bleeding associated with a fall in hemoglobin level of 20 g/L or more; if it required a transfusion of 2 units of blood or more; if it was intracranial, intraocular, intraspinal, or retroperitoneal; or if it occurred into a prosthetic joint.

The incidence of major bleeding reported by investigators was similar among groups

Conclusions

		FRAGMIN^® initiated preoperatively or postoperatively in close proximity to surgery resulted in substantive risk reduction for all and proximal DVT compared with warfarin

		FRAGMIN^® initiated postoperatively in close proximity to surgery is more effective than warfarin with similar incidence in major bleeding




		In clinical trials of FRAGMIN® preop dosing was associated with fewer incidences of total DVT compared to warfarin³⁴



		FRAGMIN® is the only LMWH indicated for once-daily, early postop dosing³⁰

		NAFT Trial Proves FRAGMIN® Is More Effective Than Warfarin in Early Postop Dosing³⁴

Important Safety Information

SPINAL/EPIDURAL HEMATOMAS
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins 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 (also see WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions).

FRAGMIN^® is contraindicated in patients with active major bleeding or with known hypersensitivity to the drug, heparin, or pork products, or with thrombocytopenia associated with a positive antiplatelet antibody test

Patients undergoing regional anesthesia should not receive FRAGMIN^® for unstable angina or non–Q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive FRAGMIN^® for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of FRAGMIN^® recommended for these indications

FRAGMIN^® Injection is not intended for intramuscular administration

FRAGMIN^® cannot be used interchangeably (unit for unit) with unfractionated heparin or other low–molecular-weight heparins

FRAGMIN^®, like other anticoagulants, should be used with extreme caution in patients who have an increased risk of hemorrhage; bleeding can occur at any site during therapy. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site

FRAGMIN^® should be used with extreme caution in patients with history of heparin-induced thrombocytopenia

In FRAGMIN^® clinical trials supporting non-cancer indications, platelet counts of <100,000/mm³ and <50,000/mm³ occurred in <1% and <1%, respectively

In a clinical trial of patients with cancer and acute symptomatic VTE treated for up to 6 months 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 oral anticoagulant arm. FRAGMIN^® dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm³

Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with administration of FRAGMIN^®. The incidence of this complication is unknown at present. In clinical practice, rare cases of thrombocytopenia with thrombosis have also been observed

FRAGMIN^® should be used with caution in patients with bleeding diathesis, thrombocytopenia, or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding

Each multiple-dose vial of FRAGMIN^® contains benzyl alcohol as a preservative [which] has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Because benzyl alcohol may cross the placenta, FRAGMIN^® preserved with benzyl alcohol should be used with caution in pregnant women and only if clearly needed. If anticoagulation with FRAGMIN^® is needed during pregnancy, preservative-free formulations should be used, where possible

FRAGMIN^® should be used with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding (see PRECAUTIONS, Laboratory Tests). Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non–Q-wave myocardial infarction (see DOSAGE AND ADMINISTRATION)

Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bulleous eruption) have occurred rarely. A few cases of anaphylactoid reactions have been reported

The most commonly reported side effect is hematoma at the injection site

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