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Indications
Enoxaparin sodium is a low molecular weight heparin (LMWH) indicated for: Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness ( 1.1 ) Inpatient treatment of acute DVT with or without pulmonary embolism ( 1.2 ) Outpatient treatment of acute DVT without pulmonary embolism ( 1.2 ) Prophylaxis of ischemic complications of unstable angina and non–Q-wave myocardial infarction (MI) ( 1.3 ) Treatment of acute ST-segment elevation myocardial infarction (STEMI) managed medically or with subsequent percutaneous coronary intervention (PCI) ( 1.4 )
1.1Prophylaxis of Deep Vein Thrombosis
Enoxaparin sodium is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): in patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.1) ] in patients undergoing hip replacement surgery, during and following hospitalization in patients undergoing knee replacement surgery in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness
1.2Treatment of Acute Deep Vein Thrombosis
Enoxaparin sodium is indicated for: the inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism , when administered in conjunction with warfarin sodium the outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium
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1.3Prophylaxis of Ischemic Complications of Unstable Angina and Non–Q-Wave Myocardial Infarction
Enoxaparin sodium is indicated for the prophylaxis of ischemic complications of unstable angina and non–Q-wave myocardial infarction, when concurrently administered with aspirin.
1.4Treatment of Acute ST-Segment Elevation Myocardial Infarction
Enoxaparin sodium, when administered concurrently with aspirin, has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically or with percutaneous coronary intervention (PCI).
Contraindications
Enoxaparin sodium is contraindicated in patients with: Active major bleeding History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies [see Warnings and Precautions (5.4) ] Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/anaphylactoid reactions) [see Adverse Reactions (6.2) ] Known hypersensitivity to heparin or pork products Known hypersensitivity to benzyl alcohol (which is in only the multiple-dose formulation of enoxaparin sodium) [see Warnings and Precautions (5.8) ] Active major bleeding ( 4 ) History of heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies ( 4 ) Hypersensitivity to enoxaparin sodium ( 4 ) Hypersensitivity to heparin or pork products ( 4 ) Hypersensitivity to benzyl alcohol (for multiple-dose formulation only) ( 4 )
Warnings and precautions
Increased Risk of Hemorrhage: Monitor for signs of bleeding. ( 5.1 , 5.2 , 5.3 ) Risk of Heparin-Induced Thrombocytopenia with or without Thrombosis. ( 5.4 ) Thrombocytopenia: Monitor platelet count closely. ( 5.5 ) Interchangeability with other heparins: Do not exchange with heparin or other LMWHs. ( 5.6 ) Increased Risk of Thrombosis in Pregnant Women with Mechanical Prosthetic Heart Valves: Women and their fetuses may be at increased risk.
Monitor more frequently and adjust dosage as needed. ( 5.7 )
5.1Increased Risk of Hemorrhage Cases
of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of enoxaparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture procedures, resulting in long-term or permanent paralysis. The risk of these events is higher with the use of postoperative 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 enoxaparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of enoxaparin [see Clinical Pharmacology (12.3) ] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (30 mg once or twice daily or 40 mg once daily) of enoxaparin sodium and at least 24 hours after the administration of higher doses (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily) of enoxaparin sodium. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided.
Patients receiving the 0.75 mg/kg twice-daily dose or the 1 mg/kg twice-daily dose should not receive the second enoxaparin dose in the twice-daily regimen to allow a longer delay before catheter placement or removal. Likewise, although a specific recommendation for timing of a subsequent enoxaparin sodium dose after catheter removal cannot be made, consider delaying this next dose for at least four 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 enoxaparin is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin sodium (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day) [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), and 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 enoxaparin sodium with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.
Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal. Bleeding can occur at any site during therapy with enoxaparin sodium. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.
5.2 Increased Risk of Bleeding following Percutaneous Coronary Revascularization Procedures To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non–Q-wave myocardial infarction and acute ST-segment elevation myocardial infarction, adhere precisely to the intervals recommended between enoxaparin sodium doses. It is important to achieve hemostasis at the puncture site after PCI.
In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last intravenous/subcutaneous enoxaparin sodium. If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation [see Dosage and Administration (2.1) ] .
5.3Increased Risk of Bleeding in Patients with Concomitant Medical Conditions
Enoxaparin sodium should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage.
5.4Risk of Heparin-Induced Thrombocytopenia with or without Thrombosis
Enoxaparin sodium may cause heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia with thrombosis (HITTS). HITTS may lead to organ infarction, limb ischemia, or death. Monitor thrombocytopenia of any degree closely. Use of enoxaparin sodium in patients with a history of immune-mediated HIT within the past 100 days or in the presence of circulating antibodies is contraindicated [see Contraindications (4) ].
Circulating antibodies may persist for several years. Only use enoxaparin sodium in patients with a history of HIT if more than 100 days have elapsed since the prior HIT episode and no circulating antibodies are present. Because HIT may still occur in these circumstances, the decision to use enoxaparin sodium in such a case must be made only after a careful benefit-risk assessment and after non-heparin alternative treatments are considered.
5.5Thrombocytopenia
Thrombocytopenia can occur with the administration of enoxaparin sodium. Moderate thrombocytopenia (platelet counts between 100,000/mm 3 and 50,000/mm 3 ) occurred at a rate of 1.3% in patients given enoxaparin sodium, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials. Platelet counts less than 50,000/mm 3 occurred at a rate of 0.1% in patients given enoxaparin sodium, in 0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm 3 , enoxaparin sodium should be discontinued.
5.6Interchangeability
with other Heparins Enoxaparin sodium cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use.
5.7Increased Risk of Thrombosis in Pregnant Women with Mechanical Prosthetic Heart Valves Use
of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves may result in valve thrombosis. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce
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Interactions
Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If coadministration is essential, conduct close clinical and laboratory monitoring [see Warnings and Precautions (5.1) ] .
Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium or conduct close clinical and laboratory monitoring. ( 2.6 , 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Placental transfer of enoxaparin was observed in the animal studies. Human data from a retrospective cohort study, which included 693 live births, suggest that enoxaparin does not increase the risk of major developmental abnormalities (see Data ) . Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities (see Data ) . Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with thromboembolic disease and certain high risk pregnancy conditions.
While not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6) ] . Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart valves and those with inherited or acquired thrombophilias, have an increased risk of other maternal complications and fetal loss regardless of the type of anticoagulant used.
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Pregnant women receiving enoxaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches [see Boxed Warning ] . Hemorrhage can occur at any site and may lead to death of mother and/or fetus.
Pregnant women should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy. It is not known if monitoring of anti-Factor Xa activity and dose adjustment (by weight or anti-Factor Xa activity) of enoxaparin sodium affect the safety and the efficacy of the drug during pregnancy. Cases of "gasping syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99–405 mg/kg/day).
The multiple-dose vial of enoxaparin sodium contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions (5.8) ] . Data Human data There are no adequate and well-controlled studies in pregnant women. A retrospective study reviewed the records of 604 women who used enoxaparin during pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic events (11 serious) in 63 women.
There were 14 cases of neonatal hemorrhage. Major congenital anomalies in live births occurred at rates (2.5%) similar to background rates. There have been postmarketing reports of fetal death when pregnant women received enoxaparin sodium. Causality for these cases has not been determined. Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases.
A clinical study using enoxaparin in pregnant women with mechanical prosthetic heart valves has been conducted [see Warnings and Precautions (5.7) ] . Animal data Teratology studies have been conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2 mg/kg as the maximum recommended daily dose). There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Adverse reactions
The following serious adverse reactions are also discussed in other sections of the labeling: Spinal/epidural hematomas [see Boxed Warning and Warnings and Precautions (5.1) ] Increased Risk of Hemorrhage [see Warnings and Precautions (5.1) ] Thrombocytopenia [see Warnings and Precautions (5.5) ] 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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 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. Dosing Regimen Indications 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%) Table 3: Major Bleeding Episodes following Hip or Knee Replacement Surgery 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. Dosing Regimen Indications Enoxaparin Sodium 40 mg daily subcutaneously Enoxaparin Sodium 30 mg q12h subcutaneously Heparin 15,000 U/24h subcutaneously Hip Replacement Surgery without Extended Prophylaxis Enoxaparin sodium 30 mg every 12 hours subcutaneously initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery - n=786 31 (4%) n=541 32 (6%) Hip Replacement Surgery with Extended Prophylaxis - - - Peri-operative Period 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 n=288 4 (2%) - - Extended Prophylaxis Period Enoxaparin sodium 40 mg subcutaneously once a day for up to 21 days after discharge n=221 0 (0%) - - Knee Replacement Surgery without Extended Prophylaxis - n=294 3 (1%) n=225 3 (1%) 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 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. Dosing Regimen Indication Enoxaparin Sodium The rates represent major bleeding on study medication up to 24 hours after last dose. 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%) Table 5: Major Bleeding Episodes in Deep Vein Thrombosis with or without Pulmonary Embolism Treatment 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. Dosing Regimen 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. Indication 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%) Table 6: Major Bleeding Episodes in Unstable Angina and Non–Q-Wave Myocardial Infarction Dosing Regimen Indication Enoxaparin Sodium The rates represent major bleeding on study medication up to 12 hours after dose. 1 mg/kg q12h subcutaneously Heparin aPTT Adjusted Intravenous Therapy Unstable Angina and Non–Q-Wave MI 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. n=1578 17 (1%) n=1529 18 (1%) Table 7: Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction Dosing Regimen Indication Enoxaparin Sodium The rates represent major bleeding (including ICH) up to 30 days. Initial 30 mg intravenous bolus followed by 1 mg/kg q12h subcutaneously Heparin aPTT Adjusted Intravenous Therapy Acute ST-Segment Elevation Myocardial Infarction n=10176 n (%) n=10151 n (%) Major bleeding (including ICH) 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. 211 (2.1) 138 (1.4) Intracranial hemorrhages (ICH) 84 (0.8) 66 (0.7) 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 trea
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Composition
Active ingredients
ENOXAPARIN SODIUM 90MG/0.6ML (150MG/ML) **Federal Register determination that product was not discontinued or withdrawn for safety or effectiveness reasons**
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
ENOXAPARIN SODIUM 90MG/0.6ML (150MG/ML) **Federal Register determination that product was not discontinued or withdrawn for safety or effectiveness reasons** · InjectableThis page
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