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

In a double-blind, randomized, placebo-controlled clinical trial, patients who recently experienced unstable angina with EKG changes or non-Q-wave myocardial infarction (MI) were randomized to FRAGMIN Injection 120 units/kg or placebo every 12 hours subcutaneously. In this trial, unstable angina was defined to include only angina with EKG changes. All patients, except when contraindicated, were treated concurrently with aspirin (75 mg once daily) and beta blockers. Treatment was initiated within 72 hours of the event (the majority of patients received treatment within 24 hours) and continued for 5 days to 8 days. A total of 1,506 patients were enrolled and treated; 746 received FRAGMIN and 760 received placebo. The mean age of the study population was 68 years (range 40 years to 90 years) and the majority of patients were white (99.7%) and male (63.9%). The combined incidence of the endpoint of death or myocardial infarction was lower for FRAGMIN compared with placebo at 6 days after initiation of therapy. These results were observed in an analysis of all-randomized and all-treated patients. The combined incidence of death, MI, need for intravenous heparin or intravenous. nitroglycerin, and revascularization was also lower for FRAGMIN than for placebo (see Table 13).

In a second randomized, controlled trial designed to evaluate long-term treatment with FRAGMIN (6 days to 45 days), data were also collected comparing 1 week (5 days to 8 days) treatment of FRAGMIN 120 units/kg every 12 hours subcutaneously with heparin at an APTT-adjusted dosage. All patients, except when contraindicated, were treated concurrently with aspirin (100 mg per day to 165 mg per day). Of the 1,499 patients enrolled, 1,482 patients were treated; 751 received FRAGMIN and 731 received heparin. The mean age of the study population was 64 years (range 25 years to 92 years) and the majority of patients were white (96.0%) and male (64.2%). The incidence of the combined endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 days to 8 days) was 9.3% for FRAGMIN and 7.6% for heparin (p = 0.323).

14.2 Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery

In an open-label randomized study, FRAGMIN 5,000 units administered once daily subcutaneously was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with FRAGMIN was initiated with a 2,500 units dose subcutaneously within 2 hours before surgery, followed by a 2,500 units dose subcutaneously the evening of the day of surgery. Then, a dosing regimen of FRAGMIN 5,000 units subcutaneously once daily was initiated on the first postoperative day. The first dose of warfarin sodium was given the evening before surgery, then continued daily at a dose adjusted for INR 2 to 3. Treatment in both groups was then continued for 5 days to 9 days postoperatively. Of the 580 patients enrolled, 553 were treated and 550 underwent surgery. Of those who underwent surgery, 271 received FRAGMIN and 279 received warfarin sodium. The mean age of the study population was 63 years (range 20 years to 92 years) and the majority of patients were white (91.1%) and female (52.9%). The incidence of deep vein thrombosis (DVT), as determined by evaluable venography, was significantly lower for the group treated with FRAGMIN compared with patients treated with warfarin sodium (see Table 14).

In a second single-center, double-blind study of patients undergoing hip replacement surgery, FRAGMIN 5,000 units once daily subcutaneously starting the evening before surgery, was compared with heparin 5,000 units subcutaneously three times a day, starting the morning of surgery. Treatment in both groups was continued for up to 9 days postoperatively. Of the 140 patients enrolled, 139 were treated and 136 underwent surgery. Of those who underwent surgery, 67 received FRAGMIN and 69 received heparin. The mean age of the study population was 69 years (range 42 years to 87 years) and the majority of patients were female (58.8%). In the intent-to-treat analysis, the incidence of proximal DVT was significantly lower for patients treated with FRAGMIN compared with patients treated with heparin (6/67 vs 18/69; p = 0.012). The incidence of pulmonary embolism detected by lung scan was also significantly lower in the group treated with FRAGMIN (9/67 vs 19/69; p = 0.032).

A third multi-center, double-blind, randomized study evaluated a postoperative dosing regimen of FRAGMIN for thromboprophylaxis following total hip replacement surgery. Patients received either FRAGMIN or warfarin sodium, randomized into one of three treatment groups. One group of patients received the first dose of FRAGMIN 2,500 units subcutaneous within 2 hours before surgery, followed by another dose of FRAGMIN 2,500 units subcutaneous at least 4 hours (6.6 ± 2.3 hours) after surgery. Another group received the first dose of FRAGMIN 2,500 units subcutaneous at least 4 hours (6.6 ± 2.4 hours) after surgery. Then, both of these groups began a dosing regimen of FRAGMIN 5,000 units once daily subcutaneous on postoperative day 1. The third group of patients received warfarin sodium the evening of the day of surgery, then continued daily at a dose adjusted to maintain INR 2 to 3. Treatment for all groups was continued for 4 days to 8 days postoperatively, after which time all patients underwent bilateral venography.

In the total enrolled study population of 1,501 patients, 1,472 patients were treated; 496 received FRAGMIN (first dose before surgery), 487 received FRAGMIN (first dose after surgery) and 489 received warfarin sodium. The mean age of the study population was 63 years (range 18 years to 91 years) and the majority of patients were white (94.4%) and female (51.8%).

Administration of the first dose of FRAGMIN after surgery was as effective in reducing the incidence of thromboembolic reactions as administration of the first dose of FRAGMIN before surgery (44/336 vs 37/338; p =0.448). Both dosing regimens of FRAGMIN were more effective than warfarin sodium in reducing the incidence of thromboembolic reactions following hip replacement surgery.

14.3 Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications

Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes, or who have additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary embolism.

FRAGMIN administered once daily subcutaneously beginning prior to surgery and continued for 5 days to 10 days after surgery, reduced the risk of DVT in patients at risk for thromboembolic complications in two double-blind, randomized, controlled clinical trials performed in patients undergoing major abdominal surgery. In the first study, a total of 204 patients were enrolled and treated; 102 received FRAGMIN and 102 received placebo. The mean age of the study population was 64 years (range 40 years to 98 years) and the majority of patients were female (54.9%). In the second study, a total of 391 patients were enrolled and treated; 195 received FRAGMIN and 196 received heparin. The mean age of the study population was 59 years (range 30 years to 88 years) and the majority of patients were female (51.9%). FRAGMIN 2,500 units were superior to placebo and similar to heparin in reducing the risk of DVT (see Tables 15 and 16).

In a third double-blind, randomized study performed in patients undergoing major abdominal surgery with malignancy, FRAGMIN 5,000 units subcutaneous once daily was compared with FRAGMIN 2,500 units subcutaneous once daily. Treatment was continued for 6 days to 8 days. A total of 1,375 patients were enrolled and treated; 679 received FRAGMIN 5,000 units and 696 received 2,500 units. The mean age of the combined groups was 71 years (range 40 years to 95 years). The majority of patients were female (51.0%). FRAGMIN 5,000 units once daily was more effective than FRAGMIN 2,500 units once daily in reducing the risk of DVT in patients undergoing abdominal surgery with malignancy (see Table 17).

14.4 Prophylaxis of Deep Vein Thrombosis in Medical Patients at Risk for Thromboembolic Complications Due to Severely Restricted Mobility During Acute Illness

In a double-blind, multi-center, randomized, placebo-controlled clinical trial, general medical patients with severely restricted mobility who were at risk of VTE were randomized to receive either FRAGMIN 5,000 units or placebo subcutaneously once daily during Days 1 to 14 of the study. These patients had an acute medical condition requiring a projected hospital stay of at least 4 days, and were confined to bed during waking hours. The study included patients with congestive heart failure (NYHA Class III or IV), acute respiratory failure not requiring ventilatory support, and the following acute conditions with at least one risk factor occurring in >1% of treated patients: acute infection (excluding septic shock), acute rheumatic disorder, acute lumbar or sciatic pain, vertebral compression, or acute arthritis of the lower extremities. Risk factors include >75 years of age, cancer, previous DVT/PE, obesity, and chronic venous insufficiency. A total of 3,681 patients were enrolled and treated: 1,848 received FRAGMIN and 1,833 received placebo. The mean age of the study population was 69 years (range 26 years to 99 years), 92.1% were white and 51.9% were female. The primary efficacy endpoint was evaluated at Day 21 and was defined as at least one of the following within Days 1 to 21 of the study: asymptomatic DVT (diagnosed by compression ultrasound), a confirmed symptomatic DVT, a confirmed pulmonary embolism or sudden death. The follow-up extended through Day 90.

When given at a dose of 5,000 units once a day subcutaneously, FRAGMIN significantly reduced the incidence of thromboembolic reactions including verified DVT by Day 21 (see Table 18). The prophylactic effect was sustained through Day 90.

14.5 Patients with Cancer and Acute Symptomatic VTE

Adult Patients

In a prospective, multi-center, open-label, clinical trial, 676 patients with cancer and newly diagnosed, objectively confirmed acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were studied. Patients were randomized to either FRAGMIN 200 units/kg subcutaneous (max 18,000 units subcutaneous daily for one month) then 150 units/kg subcutaneous (max 18,000 units) subcutaneous daily for five months (FRAGMIN arm) or FRAGMIN 200 units/kg subcutaneous (max 18,000 units) subcutaneous daily for 5 days to 7 days and oral anticoagulant for six months (OAC arm). In the OAC arm, oral anticoagulation was adjusted to maintain an INR of 2 to 3. Patients were evaluated for recurrence of symptomatic VTE every two weeks for six months.

The median age of patients was 64 years (range: 22 years to 89 years); 51.5% of patients were females; 95.3% of patients were Caucasians. Types of tumors were: gastrointestinal tract (23.7%), genito-urinary (21.5%), breast (16%), lung (13.3%), hematological tumors (10.4%), and other tumors (15.1%).

A total of 27 (8.0%) and 53 (15.7%) patients in the FRAGMIN and OAC arms, respectively, experienced at least one episode of an objectively confirmed, symptomatic DVT and/or PE during the 6-month study period. Most of the difference occurred during the first month of treatment (see Table 19). The benefit was maintained over the 6-month study period.

In the intent-to-treat population that included all randomized patients, the primary comparison of the cumulative probability of the first VTE recurrence over the 6 months study period was statistically significant (p <0.01) in favor of the FRAGMIN arm, with most of the treatment difference evident in the first month.

Pediatric Patients

The efficacy of FRAGMIN is based on a single-arm, open-label, multi-center clinical trial in 38 pediatric patients with or without cancer and symptomatic deep vein thrombosis and/or pulmonary embolism. This study included 26 patients with an active malignancy and 12 patients without cancer. Of the 38 total patients, 3 patients were less than 2 years, 8 patients were 2 years to less than 8 years, 7 patients were 8 years to less than 12 years, and 17 patients were 12 years to less than or equal to 18 years. Patients were treated with FRAGMIN for up to 3 months, with starting doses by age and weight.

The efficacy of FRAGMIN was established by the achievement of therapeutic anti-Xa levels by Day 7 of therapy during the dose adjustment period and supported by the number of patients with lack of VTE progression or new VTE.

The efficacy population included pediatric patients who achieved a therapeutic anti-Xa level (0.5 mg per day to 1 units/mL) in the 7-day dose adjustment period (N = 34). The median doses of FRAGMIN (units/kg) required to achieve a therapeutic anti-Xa level during the dose adjustment period are presented in Table 20. Therapeutic anti-Xa levels were achieved within a mean of 2.6 days (range: 1 days to 7 days).

At study completion, 21 patients (62%) achieved resolution of the qualifying VTE, 7 patients (21%) showed regression, 2 patients (6%) showed no change, and no patients showed progression of the qualifying VTE. One patient (3%) experienced a new VTE during the study while on treatment.

14.6 Neonatal Patients

The efficacy of FRAGMIN in neonatal patients is based on a retrospective, non-interventional, multi-center study in 16 neonatal patients with deep vein thrombosis. Of the 16 total patients, the median gestational age was 39.1 weeks and median age at first FRAGMIN dose was 13.5 days. Patients were treated with FRAGMIN for up to 3.5 months, with starting doses determined by weight.

The efficacy of FRAGMIN was established by the achievement of VTE resolution and/or completion of FRAGMIN treatment and was supported by the number of patients with lack of VTE progression or new VTE.

The efficacy population included neonatal patients who completed a treatment course of FRAGMIN and/or achieved VTE resolution. The median starting dose of FRAGMIN and the median dose (units/kg) required to achieve a therapeutic anti-Xa level during the dose adjustment period are presented in Table 21. Therapeutic anti-Xa levels were documented for 8 of the 16 patients.

At the end of follow-up, resolution of the baseline VTE was documented for 4 patients (25%). No patients were reported to have either partial regression of the VTE or a new VTE. Of the remaining 12 patients, 1 patient (6%) switched to another anticoagulant after 3 days for an unknown reason (no adverse events related to FRAGMIN were documented) and 11 patients (69%) were reported to have completed their course of therapy.