Fragmin

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 HEMATOMAS 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 ( 5.1 , 7 ).

5 WARNINGS AND PRECAUTIONS • Hemorrhage: Use caution in conditions with increased risk of hemorrhage ( 5.1 ) • Thrombocytopenia: Monitor thrombocytopenia of any degree closely ( 5.2 ) • Benzyl Alcohol Preservative: Do not use multiple-dose formulations in neonates and infants as they contain benzyl alcohol ( 5.3 ) • Laboratory Tests: Periodic blood counts recommended ( 5.4 ) 5.1 Risk of Hemorrhage including Spinal/Epidural Hematomas 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 , Adverse Reactions (6.2) , and Drug Interactions (7) ] . To reduce the potential risk of bleeding associated with the concurrent use of FRAGMIN and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of FRAGMIN [see Clinical Pharmacology (12.3) ]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of FRAGMIN 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 thromboprophylaxis dose (2,500 units) should be administered 6 hours to 8 hours postoperatively. The second postoperative dose (2,500 units or 5,000 units) should occur no sooner than 24 hours after the first dose. Placement or removal of a catheter should be delayed for at least 12 hours after administration of 2,500 units once daily of FRAGMIN, at least 15 hours after the administration of 5,000 units once daily of FRAGMIN, and at least 24 hours after the administration of higher doses (200 units/kg once daily, 120 units/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 4 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 <30 mL/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 (2,500 units or 5,000 units once daily) and at least 48 hours for the higher dose (200 units/kg once daily, 120 units/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 adult patients with cancer and acute symptomatic VTE 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 Oral Anti-Coagulant (OAC) arm. FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm 3 . In the clinical trial of pediatric patients with or without cancer with acute symptomatic VTE treated for up to 3 months with FRAGMIN, platelet counts of <100,000/mm 3 occurred in 37% of patients, including 21% who also had platelet counts less than 50,000/mm 3 . In the same clinical trial, thrombocytopenia was reported as an adverse reaction in 21% of patients. FRAGMIN dose was interrupted in patients whose platelet counts fell below 50,000/mm 3 . 5.3 Risk of Serious Adverse Reactions in Neonates and Infants due to Benzyl Alcohol Preservative Use preservative-free FRAGMIN in neonates and infants. Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and low-birth weight infants treated with medications that contain the preservative benzyl alcohol. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing FRAGMIN in infants, consider the combined daily metabolic load of benzyl alcohol from all sources including FRAGMIN multiple-dose vial (contains 14 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4) ]. 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. Monitor anti-Xa level periodically in pediatric patients. Anti-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 clinically significant adverse reactions are described in more detail in other sections of the prescribing information . • Risk of Hemorrhage including Spinal/Epidural Hematomas [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 reactions (>1%) are: bleeding (including hemorrhage), thrombocytopenia (Type I), hematoma at the injection site, pain at the injection site, transient elevation of transaminases ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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 most commonly reported adverse reactions are hematoma at the injection site and hemorrhagic complications. The risk for bleeding varies with the indication and may increase with higher doses. Unstable Angina and Non-Q-Wave Myocardial Infarction Table 7 summarizes major bleeding reactions that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction. Table 7 Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction Indication Dosing Regimen Unstable Angina and Non-Q-Wave MI FRAGMIN 120 units/kg/12 hours subcutaneous Treatment was administered for 5 days to 8 days. n (%) Heparin Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 units subcutaneously every 12 hours for 5 days to 8 days. intravenous and subcutaneous n (%) Placebo every 12 hours subcutaneous n (%) Major Bleeding Reactions Aspirin (75 mg to 165 mg per day) and beta blocker therapies were administered concurrently. , 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. 15/1497 (1.0) 7/731 (1.0) 4/760 (0.5) Hip Replacement Surgery Table 8 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 8 Bleeding Reactions Following Hip Replacement Surgery Indication FRAGMIN vs Warfarin Sodium FRAGMIN vs Heparin Dosing Regimen Dosing Regimen Hip Replacement Surgery FRAGMIN Includes three treated patients who did not undergo a surgical procedure. 5,000 units once daily subcutaneous Warfarin Sodium 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. oral FRAGMIN Includes two treated patients who did not undergo a surgical procedure. 5,000 units once daily subcutaneous Heparin 5,000 units three times a day subcutaneous n (%) n (%) n (%) n (%) Major Bleeding Reactions 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. 7/274 (2.6) 1/279 (0.4) 0 3/69 (4.3) Other Bleeding Reactions Occurred at a rate of at least 2% in the group treated with FRAGMIN 5,000 units once daily. 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) 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. 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 9 summarizes bleeding reactions that occurred in clinical trials which studied FRAGMIN 2,500 units and 5,000 units administered once daily to abdominal surgery patients. Table 9 Bleeding Reactions Following Abdominal Surgery Indication FRAGMIN vs Placebo FRAGMIN vs FRAGMIN Dosing Regimen Dosing Regimen Abdominal Surgery FRAGMIN 2,500 units once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) FRAGMIN 2,500 units once daily subcutaneous n (%) FRAGMIN 5,000 units once daily subcutaneous n (%) Postoperative Transfusions 14/182 (7.7) 13/182 (7.1) 89/1,025 (8.7) 125/1,033 (12.1) Wound Hematoma 2/79 (2.5) 2/77 (2.6) 1/1,030 (0.1) 4/1,039 (0.4) Reoperation Due to Bleeding 1/79 (1.3) 1/78 (1.3) 2/1,030 (0.2) 13/1,038 (1.3) Injection Site Hematoma 8/172 (4.7) 2/174 (1.1) 36/1,026 (3.5) 57/1,035 (5.5) Table 9 Cont. Bleeding Reactions Following Abdominal Surgery Indication FRAGMIN vs Heparin Dosing Regimen Abdominal Surgery FRAGMIN 2,500 units once daily subcutaneous n (%) Heparin 5,000 units twice daily subcutaneous n (%) FRAGMIN 5,000 units once daily subcutaneous n (%) Heparin 5,000 units 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 5,000 units once daily to FRAGMIN 2,500 units 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 5,000 units once daily to heparin 5,000 units 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 10 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness. Table 10 Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness Indication Dosing Regimen Medical Patients with Severely Restricted Mobility FRAGMIN 5,000 units once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) Major Bleeding Reactions 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. at Day 14 8/1,848 (0.4) 0/1,833 (0) Major Bleeding Reactions at Day 21 9/1,848 (0.5) 3/1,833 (0.2) 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). Adult Patients with Cancer and Acute Symptomatic VTE Table 11 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of adult patients with cancer and acute symptomatic VTE. 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 11 Bleeding Reactions (Major and Any) (As treated population) 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. Study period FRAGMIN 200 units/kg (max. 18,000 units) subcutaneous once daily x 1 month, then 150 units/kg (max. 18,000 units) subcutaneous once daily x 5 months OAC FRAGMIN 200 units/kg (max 18,000 units) subcutaneous once daily x 5 to 7 days and OAC for 6 months (target INR 2 to 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 to 4 332 9 (2.7) 17 (5.1) 321 1 (0.3) 12 (3.7) Weeks 5 to 28 297 9 (3.0) 26 (8.8) 267 8 (3) 40 (15) 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 was reported in 4.5% of patients treated with FRAGMIN 5,000 units once daily vs 11.8% of patients treated with heparin 5,000 units 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 5,000 units once daily vs 13% of patients treated with heparin 5,000 units three times a day. Pediatric Patients with Symptomatic VTE The data below reflect exposure to FRAGMIN from two studies in pediatric patients from newborn to less than 18 years of age with or without cancer and symptomatic VTE (n = 50). Patients were started on FRAGMIN using age and weight-based dosing via subcutaneous injection twice daily. Anti-Xa levels were measured prior to the 4 th dose and then periodically to determine whether dose adjustments were required, using 25 units/kg increments, to achieve a target anti-Xa level of 0.5 units/mL to 1.0 units/mL. The median time on treatment with FRAGMIN was 86 days (range 2 days to 170 days). In pediatric patients with symptomatic VTE, the most common (greater than 10%) adverse reactions were injection site bruising (30%), contusion (12%), and epistaxis (10%). Major bleeding was defined as any fatal bleeding, clinically overt bleeding with a decrease in hemoglobin of ≥2g/dL in 24 hours, overt bleeding deemed by the attending physician to be unrelated to the subject's underlying condition and accompanied by blood product administration, overt bleeding that was retroperitoneal, intracranial, intraspinal, intraocular, or intraarticular, or overt bleeding deemed by the attending physician to necessitate permanent discontinuation of trial medication. Major bleeding (intestinal hematoma) occurred in one patient (2%). Discontinuation due to adverse reactions occurred in 12% of patients, most often due to thrombocytopenia (4%). Neonatal Patients No controlled clinical trials have been conducted with FRAGMIN in neonatal patients with VTE; however, data are available from a non‑interventional retrospective medical chart review study of 16 neonates with VTE in the UK who were admitted to hospital between January 2010 and December 2021 and were treated with FRAGMIN. The mean (±SD) duration of dalteparin treatment was 62±30 days. For these 16 neonatal patients, the mean (±SD) daily dose of dalteparin at initiation was 365±196 units/kg (median:309 units/kg). The mean (±SD) daily dose of dalteparin including dose at initiation and dose changes was 575±320 units/kg (median: 450 units/kg). After the initial dose, all patients required one or more dose changes; 15 of 16 patients required dose increases due to anti-Xa level being initially below the target range of 0.5 units/mL to 1 units/mL. The safety profile in neonates was similar to other pediatric patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval 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 FRAGMIN 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 ] . Musculoskeletal system: Osteoporosis Skin or subcutaneous tissues disorders: Skin necrosis, cases of alopecia reported that improved on drug discontinuation Metabolism and nutrition disorders: Hyperkalemia

<table width="90%"><col width="30%"/><col width="30%"/><col width="20%"/><col width="20%"/><thead><tr><th align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Table 7</content></th></tr><tr><th align="center" colspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><content styleCode="bold">Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction</content></th></tr></thead><tbody><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Indication</paragraph></td><td align="center" colspan="3" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Dosing Regimen</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Unstable Angina and Non-Q-Wave MI</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph><content styleCode="underline">FRAGMIN</content> 120 units/kg/12 hours subcutaneous<footnote ID="_Reft5f1">Treatment was administered for 5 days to 8 days.</footnote> n (%)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph><content styleCode="underline">Heparin</content><footnote ID="_Reft5f2">Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 units subcutaneously every 12 hours for 5 days to 8 days.</footnote> intravenous and subcutaneous<footnoteRef IDREF="_Reft5f2"/> n (%)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph><content styleCode="underline">Placebo</content> every 12 hours subcutaneous n (%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Major Bleeding Reactions<footnote ID="_Reft5f3">Aspirin (75 mg to 165 mg per day) and beta blocker therapies were administered concurrently.</footnote>^,<footnote ID="_Reft5f4">Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of &#x2265;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.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph>15/1497 (1.0)</paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph>7/731 (1.0)</paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph>4/760 (0.5)</paragraph></td></tr></tbody></table>

<table width="90%"><col width="21%"/><col width="21%"/><col width="21%"/><col width="20%"/><col width="19%"/><thead><tr><th align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Table 8</content></th></tr><tr><th align="center" colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><content styleCode="bold">Bleeding Reactions Following Hip Replacement Surgery</content></th></tr></thead><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Indication</paragraph></td><td align="center" colspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>FRAGMIN vs Warfarin Sodium</paragraph></td><td align="center" colspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>FRAGMIN vs Heparin</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Dosing Regimen</paragraph></td><td align="center" colspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Dosing Regimen</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Hip Replacement Surgery</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="middle"><paragraph><content styleCode="underline">FRAGMIN</content><footnote ID="_Reft6f2">Includes three treated patients who did not undergo a surgical procedure.</footnote> 5,000 units once daily subcutaneous</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="middle"><paragraph><content styleCode="underline">Warfarin</content> Sodium<footnote ID="_Reft6f1">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.</footnote> oral</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="middle"><paragraph><content styleCode="underline">FRAGMIN</content><footnote ID="_Reft6f4">Includes two treated patients who did not undergo a surgical procedure.</footnote> 5,000 units once daily subcutaneous</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="middle"><paragraph><content styleCode="underline">Heparin</content> 5,000 units three times a day subcutaneous</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n (%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n (%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n (%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n (%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Major Bleeding Reactions<footnote ID="_Reft6f3">A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of &#x2265;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.</footnote></paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>7/274 (2.6)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>1/279 (0.4)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>3/69 (4.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Other Bleeding Reactions<footnote ID="_Reft6f5">Occurred at a rate of at least 2% in the group treated with FRAGMIN 5,000 units once daily.</footnote> Hematuria</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>8/274 (2.9)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5/279 (1.8)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Wound Hematoma</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6/274 (2.2)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Injection Site Hematoma</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3/274 (1.1)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>NA</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2/69 (2.9)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7/69 (10.1)</paragraph></td></tr></tbody></table>

<table width="90%"><col width="21%"/><col width="19%"/><col width="15%"/><col width="19%"/><col width="26%"/><thead><tr><th align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Table 9</content></th></tr><tr><th align="center" colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><content styleCode="bold">Bleeding Reactions Following Abdominal Surgery</content></th></tr></thead><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Indication</paragraph></td><td align="center" colspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>FRAGMIN vs Placebo</paragraph></td><td align="center" colspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>FRAGMIN vs FRAGMIN</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Dosing Regimen</paragraph></td><td align="center" colspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Dosing Regimen</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Abdominal Surgery</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>FRAGMIN 2,500 units once daily subcutaneous n (%)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Placebo once daily subcutaneous n (%)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>FRAGMIN 2,500 units once daily subcutaneous n (%)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>FRAGMIN 5,000 units once daily subcutaneous n (%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Postoperative Transfusions</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>14/182 (7.7)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>13/182 (7.1)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>89/1,025 (8.7)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>125/1,033 (12.1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Wound Hematoma</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2/79 (2.5)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2/77 (2.6)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1/1,030 (0.1)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4/1,039 (0.4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Reoperation Due to Bleeding</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1/79 (1.3)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1/78 (1.3)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2/1,030 (0.2)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13/1,038 (1.3)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Injection Site Hematoma</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>8/172 (4.7)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2/174 (1.1)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>36/1,026 (3.5)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>57/1,035 (5.5)</paragraph></td></tr></tbody></table>