RHONE-POULENC RORER RHONE-POULENC RORER PHARMACEUTICALS INC. 500 ARCOLA ROAD P 0 BOX 1200 COLLEGEVILLE. PA 19426-0107 TEL 610-454-8000 January 15, 1998 Bruce A. MacLeod, MD The Mercy Hospital of Pittsburgh 1400 Locust St. Pittsburgh, PA 15219-5516 Dear Dr. MacLeod: Your Professional Representative, Ms. Nikki Rebich, has forwarded to me your request for the following information on our product Lovenox (enoxaparin sodium) injection. Lovenox is a low molecular weight heparin indicated for the prevention of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), following hip or knee replacement surgery and in patients undergoing abdominal surgery who are at risk for thromboembolic complications. The recommended dosing is as follows: Hip and knee replacement surgery, 30 mg twice daily administered by subcutaneous (sc) injection with the initial dose given 12-24 hours post-operatively provided hemostasis has been established. Treatment should be continued throughout the period of post-operative care until the risk of deep vein thrombosis has diminished. Up to 14 days administration has been well tolerated in controlled clinical trials. The average duration of administration was 7 to 10 days. Abdominal surgery, 40 mg once daily administered by sc injection with the initial dose given 2 hours prior to surgery. The subsequent dose, provided hemostasis has been established, is administered 24 hours after the initial pre-operative dose and continued once daily for 7-10 days. Treatment should be continued throughout the period of post-operative care until the risk of deep vein thrombosis has diminished. Up to 12 days administration has been well tolerated in clinical trials. Enoxaparin has been available in France since 1987 and is also marketed in other European countries as Lovenox/Clexane. The following discussion is for your information only and is not a recommendation for the use of Lovenox in a manner which may be inconsistent with approved product labeling. Use in Unstable Angina Lovenox is not indicated for use in patients with unstable coronary artery disease. However, there have been published studies regarding its use in the treatment of patients with unstable angina or non-Q-wave myocardial infarction. Two pivotal trials published thus far are presented below and additional references are listed in the attached bibliography. TIMI IIA Trial ============== In this multicenter, open label dose-ranging trial, the safety and efficacy of two weight-adjusted doses of Lovenox regimens were evaluated in 630 patients with non Q-wave myocardial infarction or unstable angina (Antman, 1997). Primary efficacy assessment was the combined triple endpoints of death, myocardial infarction, or recurrent angina requiring revascularization. The total treatment period was 14 days, consisting of an acute hospitalization phase and a post-discharge phase. During the acute phase, patients were initially given a 30 mg bolus of Lovenox. Subsequently, Lovenox was administered subcutaneously at one of following weight-adjusted doses: * 1.25mg/kg ql2h Dose Tier 1 (n=321) * 1.0 mg/kg ql2h Dose Tier 2 (n=309) Patients received this weight-adjusted dosing for a minimum of 48 hours and a maximum of 8 days. However, the median duration of therapy for dose tier 1 and dose tier 2 were 39 hours and 27 hours, respectively. Blood levels were drawn during this treatment phase to determine the anti-Xa activities of the drug at peak and trough. In patients treated at dose tier 1, the mean peak and trough anti-Xa levles (IU/mL) at steady-state were significantly higher than those treated at dose tier 2, (1.5 and 0.6 vs. 1.0 and 0.5; p < 0.01). At post-discharge, all patients received prolonged fixed subcutaneous dosing of either Lovenox 60 mg (patients > 65 kg) or Lovenox 40 mg (patients < 65 kg) every 12 hours. Concomitant medications consist of aspirin (325 mg at enrollment and 100-325 mg thereafter for study duration). In addition, other antianginal therapy (e.g. beta-adrenergic blockers, nitrates and calcium channel blockers) may be administered at the discretion of the treating physician. The incidence of the combined triple endpoints, which was assessed at 14 days, was similar in both dose tiers, as shown below: Triple Endpoints Dose Tier 1 Dose Tier 2 (n=321) (n=309) Death 7 (2.2%) 2 (0.6%) OMI 7 (2.2%) 9 (2.9%) Recurrent angina necessitating revascularization 4 (1.2%) 5 (1.6%) Combined Triple Endpoints 18 (5.6%) 16 (5.2%) However, the incidence of major hemorrhage, which occurred primarily at instrumented sites, was higher in patients who were treated at dose tier 1 than those treated at dose tier 2, (6.5% vs. 1.5%). There were several consistent observations across both tiers with regards to this adverse event: the patients were older, lighter in weight and were more likely to have received intravenous nitrates, unfractionated heparin (for catheterizations) and other concomitant antiplatelet agents in addition to aspirin. Furthermore, there was a tendency for the peak-anti-Xa levels to be higher in these patients than those who did not experience a major hemorrhage. Thrombocytopenia, defined as a platelet count < 100,000/MM3, was only observed in 2 patients treated at dose tier 2 (0.7%). From these results, a weight-adjusted Lovenox dose of 1.0 mg/kg every 12 hours (as an acute phase regimen) was determined to be well tolerated without forgoing efficacy considerations. The authors indicated that a Phase III trial (TIMI IIB) is currently ongoing to determine the safety and efficacy of Lovenox use for long-term management of unstable angina or non-Q-wave Mi. However, no data from that study is yet available. ESSENCE Trial ============= Cohen et al. (1997) presented the results from a randomized, double-blind, multinational study in which the use of Lovenox was more effective than unfractionated heparin (UFH) in patients with unstable angina (UA) or non-Q-wave myocardial infarction (MI). Also known as the ESSENCE trial, this study had an enrollment of 3,171 patients. Patients assigned to Lovenox (n=1607) received 1.0 mg/kg subcutaneously every 12 hours; while those randomized to unfractionated heparin (n=1564) were initially given an intravenous bolus followed by a dose-adjusted infusion (based upon activated partial-thromboplastin time, aPTT). In addition, all patients received aspirin 100-325 mg daily. In 96% of treated patients (n=3,107), therapy was initiated within 24 hours of the qualifying anginal episode, with the majority of these patients being treated within 12-18 hours, (data-on-file). The median duration of therapy was 2.6 days (range: 2-8 days). The primary efficacy assessment was the combined triple endpoints of death, MI or recurrent angina at follow-up on day 14. These endpoints were also evaluated at 48 hours and at 30 days as part of the secondary efficacy assessments. The risk of death, MI or recurrent angina (combined triple endpoints) was significantly lower in patients who were treated with Lovenox than those treated with UFH at 14 days, and was sustained through 30 days. Time of Assessment Lovenox UFH Relative Risk P Value Reduction 48 hours 99(6.2%) 115(7.4%) 16.2% 0.18 14 days 266(16.6%) 309(19.8%) 16.2% 0.02 30 days 318(19.8%) 364 (23.3%) 15.0% 0.02 Additionally, the need for coronary revascularization and angiography procedures during the 30 day study period was lower in the Lovenox arm. Lovenox UFH P Value Coronary Revascularization 434 (27.0%) 504(32.2%) 0.001 CABG 198 (12.3%) 214 (13.7%) 0.25 PTCA 236 (14.7%) 293 (18.7%) 0.002 Coronary Angiography (data-on-file) 770 (47.9%) 812 (51.9%) 0.024 Adverse events (see table below) were assessed at Day 30 in patients who received treatment. With regards to major hemorrhage, there were no significant difference between the two treatment groups. However, the incidence of minor hemorrhage was higher in the Lovenox group (11.9% vs. 7.2%), due to injection site echymosis or hematoma, and contributed to the increase in overall hemorrhage for patients treated with Lovenox (18.4% vs. 14.2%). During treatment, the incidence of overall hemorrhage was also higher in the Lovenox group (9.4% vs. 4.4%). Adverse Events Lovenox UFH P Value n=1578 n=1529 (at Day 30) Overall Hemorrhage 297 (18.4%) 217 (14.2%) 0.001 Major 102 (6.5%) 107 (7.0%) 0.75 Minor 188 (11.9%) 110 (7.2%) < 0.001 Hemorrhagic Stroke 0 (0%) 1 (0.1%) Transient Ischernic Attack (TIA) 1 (0.1%) 8 (0.5%) n/a Based on these results from this trial, the authors conclude that the combination of subcutaneous Lovenox (1 mg/kg q12h) plus aspirin is significantly more effective than the combination of unfractionated heparin plus aspirin in the early treatment of unstable angina and non-Q-wave myocardial infarction. Please refer to the enclosed product labeling for full disclosure of prescribing information. If you require further assistance, please contact the Drug Information Center at (610) 454-8110 between the hours of 8:00am to 7:00pm EST, Monday through Friday. Thank you for your interest in Rh6ne-Poulenc Rorer products and for the courtesy extended to Ms. Rebich. Sincerely Sherry LeBroc us, RN Drug Information Specialist seb: 176419 cc: 1506 Ms. Nikki Rebich Enclosures: Lovenox labeling Antman (1997) Cohen(1997) BIBLIOGRAPHY Use in Unstable Angina TIMI 1 1A Trial Antman E, et al. Dose-Ranging trial of enoxaparin for unstable angina: results of TIM11 1A. J Am Coll Cardiol. 1997;29:1474-82. Antman E, Mccabe C, Marble S, et al. Dose ranging trial of enoxaparin for unstable angina: results of TIMI 11A. Circulation, 1996;94(8)(Suppl 1):1554. Smith R, Townsend G, Berry B, et al. Enoxaparin for unstable angina and ancrod for cardiac surgery following heparin allergy. Ann Pharmacotherap)L 1996;30:476-480. Spencer F, Liu L, Zhang Q, et al. Enoxaparin suppresses platelet-dependent thrombin generation in vivo among patients with unstable angina and non-q-wave myocardial infarction. JACC. 1997;29(2)(SuppIA): 304A(abstract). ESSENCE Trial Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Enql J Med. 1997:337(7):447-452. Data-on-file at RPR Inc. Collegeville, PA.