Enoxaparinside effects

The following serious adverse reactions are also discussed in other sections of the labeling:

Spinal/epidural hematomas

Increased Risk of Hemorrhage

Thrombocytopenia Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, nausea, ecchymosis, fever, edema, peripheral edema, dyspnea, confusion, and injection site pain To report SUSPECTED ADVERSE REACTIONS, contact NorthStar at 1-800-206-7821 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 reflect the rates observed in clinical practice. During clinical development for the approved indications, 15,918 patients were exposed to enoxaparin sodium. These included 1,228 for prophylaxis of deep vein thrombosis following abdominal surgery in patients at risk for thromboembolic complications, 1,368 for prophylaxis of deep vein thrombosis following hip or knee replacement surgery, 711 for prophylaxis of deep vein thrombosis in medical patients with severely restricted mobility during acute illness, 1,578 for prophylaxis of ischemic complications in unstable angina and non – Q-wave myocardial infarction, 10,176 for treatment of acute ST-elevation myocardial infarction, and 857 for treatment of deep vein thrombosis with or without pulmonary embolism. Enoxaparin sodium doses in the clinical trials for prophylaxis of deep vein thrombosis following abdominal or hip or knee replacement surgery or in medical patients with severely restricted mobility during acute illness ranged from 40 mg subcutaneously once daily to 30 mg subcutaneously twice daily. In the clinical studies for prophylaxis of ischemic complications of unstable angina and non – Q-wave myocardial infarction doses were 1 mg/kg every 12 hours and in the clinical studies for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium doses were a 30 mg intravenous bolus followed by 1 mg/kg every 12 hours subcutaneously. Hemorrhage The following rates of major bleeding events have been reported during clinical trials with enoxaparin sodium (see Tables 2 to 7).

Table 2: Major Bleeding Episodes following Abdominal and Colorectal Surgery* Indications Dosing Regimen Enoxaparin Sodium 40 mg -daily subcutaneously Heparin 5000 U q8h subcutaneously Abdominal Surgery n=555 23 (4%) n=560 16 (3%) Colorectal Surgery n=673 28 (4%) n=674 21 (3%) *Bleeding complications were considered major: if the hemorrhage caused a significant clinical event, or 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 Surgery* Indications Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously Enoxaparin Sodium 30 mg q12h subcutaneously Heparin 15,000 U/24h subcutaneously Hip Replacement Surgery without Extended Prophylaxis † – n=786 31 (4%) n=541 32 (6%) Hip Replacement Surgery with Extended Prophylaxis Peri-operative Period ‡ Extended Prophylaxis Period § – – – n=288 4 (2%) – – n=221 0 (0%) – – Knee Replacement Surgery without Extended Prophylaxis † – n=294 3 (1%) n=225 3 (1%) * Bleeding complications were considered major: if the hemorrhage caused a significant clinical event, or 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. † Enoxaparin sodium 30 mg every 12 hours subcutaneously initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery ‡ Enoxaparin sodium 40 mg subcutaneously once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery § Enoxaparin sodium 40 mg subcutaneously 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 postoperative 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 enoxaparin sodium patients versus 1.8% of the placebo patients.

Table 4: Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility during Acute Illness* Indication Dosing Regimen Enoxaparin Sodium † 20 mg daily subcutaneously Enoxaparin Sodium † 40 mg daily subcutaneously Placebo † Medical Patients during Acute Illness n=351 1 (<1%) n=360 3 (<1%) n=362 2 (<1%) * Bleeding complications were considered major: if the hemorrhage caused a significant clinical event, 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. † 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* Indication Dosing Regimen † Enoxaparin Sodium 1.5 mg/kg daily subcutaneously Enoxaparin Sodium 1 mg/kg q12h subcutaneously Heparin aPTT Adjusted Intravenous Therapy Treatment of DVT and PE n=298 5 (2%) n=559 9 (2%) n=554 9 (2%) *Bleeding complications were considered major: if the hemorrhage caused a significant clinical event, or 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. † 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 enoxaparin sodium 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 Indication Dosing Regimen Enoxaparin Sodium * 1 mg/kg q12h subcutaneously Heparin * aPTT Adjusted Intravenous Therapy Unstable Angina and Non−Q-Wave MI †,‡ n=1578 17 (1%) n=1529 18 (1%) * 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: if the hemorrhage caused a significant clinical event, or 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 Indication Dosing Regimen Enoxaparin Sodium * Initial 30 mg intravenous bolus followed by 1 mg/kg q12h subcutaneously Heparin * aPTT Adjusted Intravenous Therapy Acute ST-Segment Elevation Myocardial Infarction Major bleeding (including ICH) † Intracranial hemorrhages (ICH) n=10176 n (%) 211 84 n=10151 n (%) 138 66 * The rates represent major bleeding (including ICH) up to 30 days † 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. 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 enoxaparin sodium. 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 enoxaparin sodium should be interpreted with caution. Local Reactions Local irritation, pain, hematoma, ecchymosis, and erythema may follow subcutaneous injection of enoxaparin sodium. Adverse Reactions in Patients Receiving Enoxaparin Sodium for Prophylaxis or Treatment of DVT, PE Other adverse reactions that were thought to be possibly or probably related to treatment with enoxaparin sodium, 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 enoxaparin sodium group, are provided below (see Tables 8 to 11).

Table 8: Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium-Treated Patients Undergoing Abdominal or Colorectal Surgery Adverse Reaction Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n=1228 % Heparin 5000 U q8h subcutaneously n=1234 % Severe Total Severe Total Hemorrhage <1 7 <1 6 Anemia <1 3 <1 3 Ecchymosis 0 3 0 3 Table 9: Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium-Treated Patients Undergoing Hip or Knee Replacement Surgery Adverse Reaction Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously Enoxaparin Sodium 30 mg q12h subcutaneously Heparin 15,000 U/24h subcutaneously Placebo q12h subcutaneously Peri-operative Period n=288* % Extended Prophylaxis Period n=131 † % n=1080 % n=766 % n=115 % Severe Total Severe Total Severe Total Severe Total Severe Total Fever 0 8 0 0 <1 5 <1 4 0 3 Hemorrhage <1 13 0 5 <1 4 1 4 0 3 Nausea – – – – <1 3 <1 2 0 2 Anemia 0 16 0 <2 <1 2 2 5 <1 7 Edema – – – – <1 2 <1 2 0 2 Peripheral edema 0 6 0 0 <1 3 <1 4 0 3 *Data represent enoxaparin sodium 40 mg subcutaneously once a day initiated up to 12 hours prior to surgery in 288 hip replacement surgery patients who received enoxaparin sodium peri-operatively in an unblinded fashion in one clinical trial. † Data represent enoxaparin sodium 40 mg subcutaneously once a day given in a blinded fashion as extended prophylaxis at the end of the peri-operative period in 131 of the original 288 hip replacement surgery patients for up to 21 days in one clinical trial.

Table 10: Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium-Treated Medical Patients with Severely Restricted Mobility During Acute Illness Adverse Reaction Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n=360 % Placebo daily subcutaneously n=362 % Dyspnea 3.3 5.2 Thrombocytopenia 2.8 2.8 Confusion 2.2 1.1 Diarrhea 2.2 1.7 Nausea 2.5

1.7 Table 11:

Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium- Treated Patients Undergoing Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism Adverse Reaction Dosing Regimen Enoxaparin Sodium 1.5 mg/kg daily subcutaneously n=298 % Enoxaparin Sodium 1 mg/kg q12h subcutaneously n=559 % Heparin aPTT Adjusted Intravenous Therapy n=544 % Severe Total Severe Total Severe Total Injection Site Hemorrhage 0 5 0 3 <1 <1 Injection Site Pain 0 2 0 2 0 0 Hematuria 0 2 0 <1 <1 2 Adverse Events in Enoxaparin Sodium-Treated Patients with Unstable Angina or Non − Q-Wave Myocardial Infarction Non-hemorrhagic clinical events reported to be related to enoxaparin sodium therapy occurred at an incidence of ≤1%. Non-major hemorrhagic events, primarily injection site ecchymoses and hematomas, were more frequently reported in patients treated with subcutaneous enoxaparin sodium than in patients treated with intravenous heparin. Serious adverse events with enoxaparin sodium or heparin in a clinical trial in patients with unstable angina or non − Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the enoxaparin sodium group are provided below (see Table 12).

Table 12: Serious Adverse Events Occurring at ≥0.5% Incidence in Enoxaparin Sodium-Treated Patients with Unstable Angina or Non−Q-Wave Myocardial Infarction Adverse Event Dosing Regimen Enoxaparin Sodium 1 mg/kg q12h subcutaneously n=1578 n (%) Heparin aPTT Adjusted Intravenous Therapy n=1529 n (%) Atrial fibrillation 11 3 Heart failure 15 11 Lung edema 11 11 Pneumonia 13 9 Adverse Reactions in Enoxaparin Sodium-Treated Patients with Acute ST-Segment Elevation Myocardial Infarction In a clinical trial in patients with acute ST-segment elevation myocardial infarction, thrombocytopenia occurred at a rate of 1.5%.

6.2 Postmarketing

Experience The following adverse reactions have been identified during postapproval use of enoxaparin sodium. 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. There have been reports of epidural or spinal hematoma formation with concurrent use of enoxaparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had a postoperative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis. Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic reactions (e.g. pruritus, urticaria, anaphylactic/anaphylactoid reactions including shock), vesiculobullous rash, cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with thrombosis have been reported. Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues). Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined. Cases of headache, hemorrhagic anemia, eosinophilia, alopecia, hepatocellular and cholestatic liver injury have been reported Osteoporosis has also been reported following long-term therapy.