Enoxaparin: uses, appearance and warnings

Enoxaparin sodium injection 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 ) 1.1 Prophylaxis of Deep Vein Thrombosis Enoxaparin sodium injection 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 1.2 Treatment of Acute Deep Vein Thrombosis Enoxaparin sodium injection 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 1.3 Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave Myocardial Infarction Enoxaparin sodium injection is indicated for the prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin. 1.4 Treatment of Acute ST-Segment Elevation Myocardial Infarction Enoxaparin sodium injection, 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).

Enoxaparin sodium injection, USP is a clear, colorless to pale-yellow sterile solution available in two concentrations. 100 mg/mL Concentration - Single-dose Prefilled Syringes 30 mg/0.3 mL, 40 mg/0.4 mL - Single-dose Graduated Prefilled Syringes 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL 150 mg/mL Concentration - Single-dose Graduated Prefilled Syringes 120 mg/0.8 mL, 150 mg/mL 100 mg/mL concentration ( 3 ): • Single-dose prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL • Single-dose graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL 150 mg/mL concentration ( 3 ): • Single-dose graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/mL

Enoxaparin sodium injection, USP is available in two concentrations [see Tables 26 and 27 ]: Table 26 100 mg/mL Concentration * Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Enoxaparin sodium injection, USP 30 and 40 mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes each contain 10 mg enoxaparin sodium per 0.1 mL Water for Injection. †Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard. ‡ Each enoxaparin sodium injection, USP prefilled syringe is for single, one-time use only and is affixed with a 27 gauge × 1/2 inch needle. Dosage Unit / Strength * Anti-Xa Activity † Unit of Sale Syringe Label Color Each Prefilled Syringes ‡ 30 mg/0.3 mL 3000 IU NDC# 63323-559-65 10 syringes per carton Medium Blue NDC# 63323-559-63 40 mg/0.4 mL 4000 IU NDC# 63323-564-65 10 syringes per carton Yellow NDC# 63323-564-63 Graduated Prefilled Syringes ‡ 60 mg/0.6 mL 6000 IU NDC# 63323-566-65 10 syringes per carton Orange NDC# 63323-566-63 80 mg/0.8 mL 8000 IU NDC# 63323-584-65 10 syringes per carton Brown NDC# 63323-584-63 100 mg/mL 10,000 IU NDC# 63323-586-65 10 syringes per carton Black NDC# 63323-586-63 Table 27 150 mg/mL Concentration * Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Enoxaparin sodium injection, USP 120 and 150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per 0.1 mL Water for Injection . † Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard. ‡ Each enoxaparin sodium injection, USP graduated prefilled syringe is for single, one-time use only and is affixed with a 27 gauge × 1/2 inch needle. Dosage Unit / Strength * Anti-Xa Activity † Unit of Sale Syringe Label Color Each Graduated Prefilled Syringes ‡ 120 mg/0.8 mL 12,000 IU NDC# 63323-655-56 10 syringes per carton Purple NDC# 63323-655-31 150 mg/mL 15,000 IU NDC# 63323-589-54 10 syringes per carton Navy Blue NDC# 63323-589-31 Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Store in the original carton or packaging until ready to use. Keep out of reach of children

Enoxaparin sodium injection 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 • 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 )

• Increased Risk of Hemorrhage: Monitor for sign 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 ) 5.1 Increased Risk of Hemorrhage Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of enoxaparin sodium injection 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 post-operative 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 injection 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 injection 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 injection. 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 injection 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 injection (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 injection 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 injection. 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 injection 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 injection. 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 ) ]. 5.3 Increased Risk of Bleeding in Patients with Concomitant Medical Conditions Enoxaparin sodium injection 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. 5.4 Risk of Heparin-Induced Thrombocytopenia with or without Thrombosis Enoxaparin sodium injection may cause heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia with thrombosis (HITTS). …

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 6.1 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 …

Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium injection 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 injection or conduct close clinical and laboratory monitoring ( 2.6 , 7 )