CLOT The Randomized Comparison of Low-Molecular-Weight Heparin [LMWH] versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer30 Entry criteria and solid tumor sites at baseline Data reflect number of patients with specified tumor site. 90% of patients had solid tumors and 67% had metastatic disease at randomization30 Approximately 10% of patients had hematologic cancer30 CLOT study design30 Dose of warfarin was adjusted to achieve a target INR of 2.5 (therapeutic range: 2.0 to 3.0). †IU=international units. ‡SC=subcutaneously. §OAC was initiated at randomization. Total daily dose of FRAGMIN® was 18,000 IU30, 1 Dose reductions for thrombocytopenia in patients with cancer and acute symptomatic VTE:1 In patients receiving FRAGMIN® who experience platelet counts between 50,000 and 100,000/mm3, reduce the daily dose of FRAGMIN® by 2,500 IU until the platelet count recovers to >100,000/mm3. In patients receiving FRAGMIN® who experience platelet counts <50,000/mm3, FRAGMIN® should be discontinued until the platelet count recovers above 50,000/mm3. Dose reductions for renal insufficiency in extended treatment of acute symptomatic VTE in patients with cancer:1 In patients with severely impaired renal function (creatinine clearance <30 mL/min), monitoring for anti-Xa levels is recommended to determine the appropriate FRAGMIN® dose. The target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, sampling should be performed 4 to 6 hours after FRAGMIN® dosing and only after the patient has received 3 to 4 doses The FRAGMIN® CLOT Study Randomized, prospective, multicenter, open-label, 6-month trial 676 patients with active cancer* and newly diagnosed, symptomatic proximal DVT, PE, or both30 * Active cancer was defined as a diagnosis of cancer, other than basal cell or squamous cell carcinoma of the skin, within 6 months before enrollment, any treatment for cancer within the previous 6 months, or recurrent or metastatic cancer.30 Outcome measures (6 months)30 Primary—the first episode of symptomatic recurrent proximal DVT, PE, or both Secondary—clinically overt bleeding (both major bleeding and any bleeding) and death FRAGMIN® - The Only LMWH Approved for Extended Treatment of VTE in Patients With Cancer Over 90% of patients in the FRAGMIN® group remained VTE-free during 6 months of treatment * Intent-to-treat population. Most of the difference occurred early (during month 1) when patients in the FRAGMIN® group continued to receive FRAGMIN® 200 IU/kg SC. The benefit was maintained over 6 months.1 Two patients in each group did not experience a qualifying thrombotic event and were, therefore, excluded from the efficacy analysis — One patient had a thrombosis in an arm vein, 1 had an asymptomatic thrombosis in the leg, and the other 2 did not have a confirmed PE † Two patients were excluded from efficacy analysis because they did not have a qualifying thrombotic event. FRAGMIN® Achieves a Statistically Significant Reduction in Probability of Recurrent VTE Kaplan-Meier probability graph Hazard radio=0.48; 95% confidence interval, 0.30 to 0.77. ‡ An event was defined as an objectively verified, symptomatic episode of recurrent DVT, PE, or both during the 6-month study period. § Intent-to-treat population. Proven Protection With Comparable Bleeding Over 6 Months in Patients With Cancer * Three patients assigned to OAC therapy did not receive the study drug and were not included in the safety analysis.30 † Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that occurred at different time intervals were counted once in each interval in which the event occurred.1 During weeks 2 to 4 of treatment, major bleeding was experienced by more patients in the FRAGMIN® group (2.7%) than by patients in the warfarin group (0.3%)1 Major bleeding was defined as any bleeding that was accompanied by a decrease in hemoglobin ≥2 g/dL in connection with clinical symptoms; occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); required transfusion of ≥2 units of blood products; or led to death30 FRAGMIN® Exhibits a Comparable Incidence of Any Bleeding vs Warfarin Over 6 Months Any bleeding also included major bleeding.30 One bleeding event (hemoptysis in a patient in the FRAGMIN® arm at day 71) was fatal30 Conclusion In patients with cancer and acute VTE, FRAGMIN® is more effective than warfarin in reducing the risk of VTE recurrence without increasing the risk of bleeding30		Cancer and its therapies increase the risk of thrombosis10,22-27 Thrombosis is one of the most common complications in patients with cancer9
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 Legal Notices | Privacy Policy | Prescribing Information This Web site contains information relating to various medical conditions and their treatment. Such information is provided for educational purposes only and is not meant to substitute the advice of a physician or other health care professional. The laws, regulatory requirements and medical practices for pharmaceutical products vary from country to country. The information provided in this Web site is intended for residents/physicians of the United States only. The products discussed herein may have different product labeling in different countries. FRAGMIN® is a registered trademark of Pfizer Health AB and is licensed to Eisai Inc. Brought to you by Eisai. © 2008 Eisai Inc. All rights reserved. Frweb001a