Managed Care - September 2008 - (Page C10)

5.8 Benzyl Alcohol Lovenox multiple-dose vials contain benzyl alcohol as a preservative. The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “Gasping Syndrome”. Because benzyl alcohol may cross the placenta, Lovenox multiple-dose vials, preserved with benzyl alcohol, should be used with caution in pregnant women and only if clearly needed [see Use in Specific Populations (8.1)]. 5.9 Laboratory Tests Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with Lovenox. 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 Lovenox activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of Lovenox in patients with significant renal impairment. If during Lovenox therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of Lovenox [see Clinical Pharmacology (12.3)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Hemorrhage The incidence of major hemorrhagic complications during Lovenox treatment has been low. The following rates of major bleeding events have been reported during clinical trials with Lovenox Injection [see Tables 2 to 7]. Table 2 Major Bleeding Episodes Following Abdominal and Colorectal Surgery 1 Dosing Regimen Lovenox Heparin Indications 40 mg q.d. SC 5000 U q8h SC Abdominal Surgery n = 555 n = 560 23 (4%) 16 (3%) Colorectal Surgery n = 673 n = 674 28 (4%) 21 (3%) 1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major. Table 3 Major Bleeding Episodes Following Hip or Knee Replacement Surgery1 Dosing Regimen Lovenox Lovenox Heparin Indications 40 mg q.d. SC 30 mg q12h SC 15,000 U/24h SC Hip Replacement Surgery n = 786 n = 541 Without Extended Prophylaxis2 31 (4%) 32 (6%) Hip Replacement Surgery With Extended Prophylaxis Peri-operative Period3 n = 288 4 (2%) Extended Prophylaxis Period4 n = 221 0 (0%) Knee Replacement Surgery n = 294 n = 225 2 Without Extended Prophylaxis 3 (1%) 3 (1%) 1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always considered major. In the knee replacement surgery trials, intraocular hemorrhages were also considered major hemorrhages. 2 Lovenox 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery. 3 Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery. 4 Lovenox 40 mg SC once a day for up to 21 days after discharge. NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours post-operative hip replacement surgery prophylactic regimens compared in clinical trials. Injection site hematomas during the extended prophylaxis period after hip replacement surgery occurred in 9% of the Lovenox patients versus 1.8% of the placebo patients. Table 4 Major Bleeding Episodes in Medical Patients With Severely Restricted Mobility During Acute Illness 1 Dosing Regimen Lovenox2 Lovenox2 Placebo 2 Indications 20 mg q.d. SC 40 mg q.d. SC Medical Patients During n = 351 n = 360 n = 362 Acute Illness 1 (<1%) 3 (<1%) 2 (<1%) 1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, (2) if the hemorrhage caused a decrease in hemoglobin of ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always considered major although none were reported during the trial. 2 The rates represent major bleeding on study medication up to 24 hours after last dose. Table 5 Major Bleeding Episodes in Deep Vein Thrombosis With or Without Pulmonary Embolism Treatment 1 Dosing Regimen 2 Lovenox Lovenox Heparin 1.5 mg/kg q.d. SC 1 mg/kg q12h SC aPTT Adjusted Indication IV Therapy Treatment of DVT and PE n = 298 n = 559 n = 554 5 (2%) 9 (2%) 9 (2%) 1 Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major. 2 All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of 2.0 to 3.0) commencing within 72 hours of Lovenox or standard heparin therapy and continuing for up to 90 days. Table 6 Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial Infarction Dosing Regimen Heparin1 Lovenox1 1 mg/kg q12h SC aPTT Adjusted Indication IV Therapy Unstable Angina and n = 1578 n = 1529 Non-Q-Wave MI2,3 17 (1%) 18 (1%) 1 2 3 The rates represent major bleeding on study medication up to 12 hours after dose. Aspirin therapy was administered concurrently (100 to 325 mg per day). Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease by ≥ 3 g/dL or transfusion of 2 or more units of blood products. Intraocular, retroperitoneal, and intracranial hemorrhages were always considered major. Table 7 Major Bleeding Episodes in acute ST-segment Elevation Myocardial Infarction Dosing Regimen Lovenox1 Heparin1 Indication Initial 30-mg IV bolus aPTT Adjusted followed by IV Therapy 1 mg/kg q12h SC acute ST-segment Elevation n = 10176 n = 10151 Myocardial Infarction n (%) n (%) - Major bleeding (including ICH)2 211 (2.1) 138 (1.4) - Intracranial hemorrhages (ICH) 84 (0.8) 66 (0.7) 1 The rates represent major bleeding (including ICH) up to 30 days. 2 Bleedings were considered major if the hemorrhage caused a significant clinical event associated with a hemoglobin decrease by ≥ 5 g/dL. ICH were always considered major. Thrombocytopenia: [See Warnings and Precautions (5.5)] Elevations of Serum Aminotransferases Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than three times the upper limit of normal of the laboratory reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during treatment with Lovenox. Similar significant increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are fully reversible and are rarely associated with increases in bilirubin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like Lovenox should be interpreted with caution. Local Reactions Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of Lovenox. Other Other adverse effects that were thought to be possibly or probably related to treatment with Lovenox, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at least 2% in the Lovenox group, are provided below [see Tables 8 to 11]. Table 8 Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing Abdominal or Colorectal Surgery Dosing Regimen Lovenox Heparin 40 mg q.d. SC 5000 U q8h SC n = 1228 n = 1234 % % Adverse Event Severe Total Severe Total Hemorrhage <1 7 <1 6 Anemia <1 3 <1 3 Ecchymosis 0 3 0 3 1 Excluding unrelated adverse events.

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Managed Care - September 2008

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