FDA label 24cb30e3-93c1-4f87-a6eb-2b59bccb9b1a

WARNING: SPINAL/EPIDURAL HEMATOMAS Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants. A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of FRAGMIN and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 ) ]. WARNING: SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants. A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of FRAGMIN and neuraxial procedures is not known. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 ) ].

5 WARNINGS AND PRECAUTIONS Use caution in conditions with increased risk of hemorrhage ( 5.1 ) Monitor thrombocytopenia of any degree closely ( 5.2 ) Multiple-dose formulations contain benzyl alcohol ( 5.3 ) Periodic blood counts recommended ( 5.4 ) 5.1 Risk of Hemorrhage including Spinal / Epidural Hematoma Spinal or epidural hemorrhage and subsequent 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 ) ]. To reduce the potential risk of bleeding associated with the concurrent use of dalteparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dalteparin [see Clinical Pharmacology ( 12.3 ) ] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dalteparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. No additional hemostasis-altering medications should be administered due to the additive effects. Patients on preoperative FRAGMIN thromboprophylaxis can be assumed to have altered coagulation. The first postoperative FRAGMIN thrombophylaxis dose (2500 IU) should be administered 6 to 8 hrs postoperatively. The second postoperative dose (2500 or 5000 IU) should occur no sooner than 24 hrs after the first dose. Placement or removal of a catheter should be delayed for at least 12 hours after administration of 2500 IU once daily of FRAGMIN, at least 15 hours after the administration of 5000 IU once daily of FRAGMIN, and at least 24 hours after the administration of higher doses (200 IU/kg once daily, 120 IU/kg twice daily) of FRAGMIN. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided. Although a specific recommendation for timing of a subsequent FRAGMIN dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30mL/minute, additional considerations are necessary because elimination of FRAGMIN may be more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of FRAGMIN (2500 IU or 5000 IU once daily) and at least 48 hours for the higher dose (200 IU/kg once daily, 120 IU/kg twice daily) [see Clinical Pharmacology ( 12.3 ) ] . Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae. 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/mm 3 occurred in < 1% of patients. In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the FRAGMIN treatment arm, platelet counts of < 100,000/mm 3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm 3 . 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/mm 3 . 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 The following serious adverse reactions are described in more detail in other sections of the prescribing information. Risk of Hemorrhage including Spinal/Epidural Hematoma [see Warnings and Precautions ( 5.1 ) ] Thrombocytopenia [see Warnings and Precautions ( 5.2 ) ] Benzyl Alcohol preservative Risk to Premature Infants [see Warnings and Precautions ( 5.3 ) ] Most common adverse reaction is hematoma at the injection site. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Eisai at (1-888-274-2378) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 Table 5 summarizes major bleeding reactions that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction. Table 5 Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction Indication Dosing Regimen Unstable Angina and Non-Q-Wave MI FRAGMIN 120 IU/kg/12 hr subcutaneous 1 n (%) Heparin 2 intravenous and subcutaneous 2 n (%) Placebo every 12 hr subcutaneous n (%) Major Bleeding Reactions 3,4 15/1497 (1.0) 7/731 (1.0) 4/760 (0.5) 1 Treatment was administered for 5 to 8 days. 2 Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 U subcutaneously every 12 hours for 5 to 8 days. 3 Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently 4 Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) a transfusion was required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding. Hip Replacement Surgery Table 6 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. Table 6 Bleeding Reactions Following Hip Replacement Surgery Indication FRAGMIN vs Warfarin Sodium FRAGMIN vs Heparin Dosing Regimen Dosing Regimen Hip Replacement Surgery FRAGMIN 2 5000 IU once daily subcutaneous n (%) Warfarin Sodium 1 oral n (%) FRAGMIN 4 5000 IU once daily subcutaneous n (%) Heparin 5000 U three times a day subcutaneous n (%) Major Bleeding Reactions 3 7/274 (2.6) 1/279 (0.4) 0 3/69 (4.3) Other Bleeding Reactions 5 Hematuria 8/274 (2.9) 5/279 (1.8) 0 0 Wound Hematoma 6/274 (2.2) 0 0 0 Injection Site Hematoma 3/274 (1.1) NA 2/69 (2.9) 7/69 (10.1) 1 Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5. 2 Includes three treated patients who did not undergo a surgical procedure. 3 A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of ≥2 g/dL or transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage. 4 Includes two treated patients who did not undergo a surgical procedure. 5 Occurred at a rate of at least 2% in the group treated with FRAGMIN 5000 IU once daily. Six of the patients treated with FRAGMIN experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial hemorrhage or died of bleeding complications. In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who started FRAGMIN before surgery; 2.5% (12/487) for patients who started FRAGMIN after surgery; and 3.1% (15/489) for patients treated with warfarin sodium. Abdominal Surgery Table 7 summarizes bleeding reactions that occurred in clinical trials which studied FRAGMIN 2500 and 5000 IU administered once daily to abdominal surgery patients. Table 7 Bleeding Reactions Following Abdominal Surgery Indication FRAGMIN vs Placebo FRAGMIN vs FRAGMIN Dosing Regimen Dosing Regimen Abdominal Surgery FRAGMIN 2500 IU once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) FRAGMIN 2500 IU once daily subcutaneous n (%) FRAGMIN 5000 IU once daily subcutaneous n (%) Postoperative Transfusions 14/182 (7.7) 13/182 (7.1) 89/1025 (8.7) 125/1033 (12.1) Wound Hematoma 2/79 (2.5) 2/77 (2.6) 1/1030 (0.1) 4/1039 (0.4) Reoperation Due to Bleeding 1/79 (1.3) 1/78 (1.3) 2/1030 (0.2) 13/1038 (1.3) Injection Site Hematoma 8/172 (4.7) 2/174 (1.1) 36/1026 (3.5) 57/1035 (5.5) Indication FRAGMIN vs Heparin Dosing Regimen Abdominal Surgery FRAGMIN 2500 IU once daily subcutaneous n (%) Heparin 5000 U twice daily subcutaneous n (%) FRAGMIN 5000 IU once daily subcutaneous n (%) Heparin 5000 U twice daily subcutaneous n (%) Postoperative Transfusions 26/459 (5.7) 36/454 (7.9) 81/508 (15.9) 63/498 (12.7) Wound Hematoma 16/467 (3.4) 18/467 (3.9) 12/508 (2.4) 6/498 (1.2) Reoperation Due to Bleeding 2/392 (0.5) 3/392 (0.8) 4/508 (0.8) 2/498 (0.4) Injection Site Hematoma 1/466 (0.2) 5/464 (1.1) 36/506 (7.1) 47/493 (9.5) In a trial comparing FRAGMIN 5000 IU once daily to FRAGMIN 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding reactions was 4.6% and 3.6%, respectively (n.s.). In a trial comparing FRAGMIN 5000 IU once daily to heparin 5000 U twice daily, in the malignancy subgroup the incidence of bleeding reactions was 3.2% and 2.7%, respectively for FRAGMIN and Heparin (n.s.). Medical Patients with Severely Restricted Mobility During Acute Illness Table 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness. Table 8 Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness Indication Dosing Regimen Medical Patients with Severely Restricted Mobility FRAGMIN 5000 IU once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) Major Bleeding Reactions 1 at Day 14 8/1848 (0.4) 0/1833 (0) Major Bleeding Reactions 1 at Day 21 9/1848 (0.5) 3/1833 (0.2) 1 A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) intraocular, spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of ≥ 2 units of blood products; 4) required significant medical or surgical intervention; or 5) led to death. Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with FRAGMIN and one in the group receiving placebo). Patients with Cancer and Acute Symptomatic Venous Thromboembolism Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding. At the end of the six-month study, a total of 46 (13.6%) patients in the FRAGMIN arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the FRAGMIN arm at Day 71) was fatal. Table 9 Bleeding Reactions (Major and Any) (As treated population) 1 Study period FRAGMIN 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5 months OAC FRAGMIN 200 IU/kg (max 18,000 IU) subcutaneous once daily x 5-7 days and OAC for 6 months (target INR 2-3) Number at risk Patients with Major Bleeding n (%) Patients with Any Bleeding n (%) Number at risk Patients with Major Bleeding n (%) Patients with Any Bleeding n (%) Total during study 338 19 (5.6) 46 (13.6) 335 12 (3.6) 62 (18.5) Week 1 338 4 (1.2) 15 (4.4) 335 4 (1.2) 12 (3.6) Weeks 2-4 332 9 (2.7) 17 (5.1) 321 1 (0.3) 12 (3.7) Weeks 5-28 297 9 (3.0) 26 (8.8) 267 8 (3.0) 40 (15.0) 1 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. Thrombocytopenia [see Warnings and Precautions ( 5.2 ) ] Elevations of Serum Transaminases In FRAGMIN clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with FRAGMIN. In the FRAGMIN clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with FRAGMIN for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively. Other Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been reported. Local Reactions: Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with FRAGMIN and reported at a rate of at least 2% in the group treated with FRAGMIN, was reported in 4.5% of patients treated with FRAGMIN 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with FRAGMIN 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day. 6.2 Post-Marketing Experience The following adverse reactions have been identified during postapproval use of FRAGMIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete) [see Boxed Warning ]. Skin necrosis has occurred. There have been cases of alopecia reported that improved on drug discontinuation.

<table> <col width="28%"/> <col width="24%"/> <col width="24%"/> <col width="24%"/> <tbody> <tr> <td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule "> Table 5 </td> </tr> <tr> <td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule "> Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction </td> </tr> <tr> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> Indication </td> <td align="center" colspan="3" styleCode=" Botrule Toprule Lrule Rrule "> Dosing Regimen </td> </tr> <tr> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> Unstable Angina and Non-Q-Wave MI </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="underline">FRAGMIN</content> 120 IU/kg/12 hr subcutaneous¹ n (%) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="underline">Heparin</content> ² intravenous and subcutaneous² n (%) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="underline">Placebo</content> every 12 hr subcutaneous n (%) </td> </tr> <tr> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> Major Bleeding Reactions^3,4 </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 15/1497 (1.0) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 7/731 (1.0) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4/760 (0.5) </td> </tr> </tbody> </table>

<table> <col width="24%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <tbody> <tr> <td align="center" colspan="5" styleCode=" Botrule Toprule Lrule Rrule "> Table 6 </td> </tr> <tr> <td align="center" colspan="5" styleCode=" Botrule Toprule Lrule Rrule "> Bleeding Reactions Following Hip Replacement Surgery </td> </tr> <tr> <td align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule "> Indication </td> <td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN vs Warfarin Sodium </td> <td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN vs Heparin </td> </tr> <tr> <td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> Dosing Regimen </td> <td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> Dosing Regimen </td> </tr> <tr> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> Hip Replacement Surgery </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="underline">FRAGMIN</content> ² 5000 IU once daily subcutaneous n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="underline">Warfarin</content> Sodium¹ oral n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="underline">FRAGMIN</content> ⁴ 5000 IU once daily subcutaneous n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <content styleCode="underline">Heparin</content> 5000 U three times a day subcutaneous n (%) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Major Bleeding Reactions³ </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 7/274 (2.6) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 1/279 (0.4) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 0 </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3/69 (4.3) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Other Bleeding Reactions⁵ Hematuria </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 8/274 (2.9) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 5/279 (1.8) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 0 </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 0 </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Wound Hematoma </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 6/274 (2.2) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 0 </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 0 </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 0 </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Injection Site Hematoma </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3/274 (1.1) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> NA </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2/69 (2.9) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 7/69 (10.1) </td> </tr> </tbody> </table>

<table> <col width="24%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <tbody> <tr> <td align="center" colspan="5" styleCode=" Botrule Toprule Lrule Rrule "> Table 7 </td> </tr> <tr> <td align="center" colspan="5" styleCode=" Botrule Toprule Lrule Rrule "> Bleeding Reactions Following Abdominal Surgery </td> </tr> <tr> <td align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule "> Indication </td> <td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN vs Placebo </td> <td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN vs FRAGMIN </td> </tr> <tr> <td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> Dosing Regimen </td> <td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> Dosing Regimen </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Abdominal Surgery </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN 2500 IU once daily subcutaneous n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Placebo once daily subcutaneous n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN 2500 IU once daily subcutaneous n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN 5000 IU once daily subcutaneous n (%) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Postoperative Transfusions </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 14/182 (7.7) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 13/182 (7.1) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 89/1025 (8.7) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 125/1033 (12.1) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Wound Hematoma </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2/79 (2.5) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2/77 (2.6) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 1/1030 (0.1) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4/1039 (0.4) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Reoperation Due to Bleeding </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 1/79 (1.3) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 1/78 (1.3) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2/1030 (0.2) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 13/1038 (1.3) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Injection Site Hematoma </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 8/172 (4.7) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2/174 (1.1) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 36/1026 (3.5) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 57/1035 (5.5) </td> </tr> <tr> <td align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule "> Indication </td> <td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN vs Heparin </td> </tr> <tr> <td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule "> Dosing Regimen </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Abdominal Surgery </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN 2500 IU once daily subcutaneous n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Heparin 5000 U twice daily subcutaneous n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> FRAGMIN 5000 IU once daily subcutaneous n (%) </td> <td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Heparin 5000 U twice daily subcutaneous n (%) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Postoperative Transfusions </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 26/459 (5.7) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 36/454 (7.9) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 81/508 (15.9) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 63/498 (12.7) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Wound Hematoma </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 16/467 (3.4) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 18/467 (3.9) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 12/508 (2.4) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 6/498 (1.2) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Reoperation Due to Bleeding </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2/392 (0.5) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 3/392 (0.8) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 4/508 (0.8) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 2/498 (0.4) </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Injection Site Hematoma </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 1/466 (0.2) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 5/464 (1.1) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 36/506 (7.1) </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> 47/493 (9.5) </td> </tr> </tbody> </table>