WARNINGS AND PRECAUTIONS
Increased Risk of Hemorrhage
Cases of epidural or spinal hematomas have been reported with the associated use of Lovenox and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or by the concomitant use of additional drugs affecting hemostasis such as NSAIDs [see Boxed Warning, Adverse Reactions and Drug Interactions (7) ].
Lovenox should be used 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 Lovenox. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.
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 Lovenox 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 IV/SC Lovenox. 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 ].
Use of Lovenox with Concomitant Medical Conditions
Lovenox 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.
History of Heparin-Induced Thrombocytopenia
Lovenox should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia.
Thrombocytopenia can occur with the administration of Lovenox.
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 1.3% in patients given Lovenox, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials.
Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given Lovenox, 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/mm3, Lovenox should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death [ see Warnings and Precautions ].
Interchangeability with Other Heparins
Lovenox 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.
Pregnant Women with Mechanical Prosthetic Heart Valves
The use of Lovenox for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death. Although a causal relationship has not been established these deaths may have been due to therapeutic failure or inadequate anticoagulation. No patients in the heparin/warfarin group (0 of 4 women) died. There also have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore, frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be needed [see Use in Specific Populations ].
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 ].
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 ].
USE IN SPECIFIC POPULATIONS
Pregnancy Category B
All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of Lovenox to increase the risk of developmental abnormalities above the background risk.
Fetal Risk Summary
Lovenox does not cross the placenta, and is not expected to result in fetal exposure to the drug. Human data from a retrospective cohort study, which included 693 live births, suggest that Lovenox does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities (see Data ).
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 and Use in Specific Populations ]. 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 Lovenox 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 (99405 mg/kg/day). The multiple-dose vial of Lovenox contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions ].
- 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 Lovenox. 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 ].
- Animal Data - Teratology studies have been conducted in pregnant rats and rabbits at SC 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.
It is not known whether Lovenox is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Lovenox, a decision should be made whether to discontinue nursing or discontinue Lovenox, taking into account the importance of Lovenox to the mother and the known benefits of nursing.
Safety and effectiveness of Lovenox in pediatric patients have not been established.
Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave Myocardial Infarction
Over 2800 patients, 65 years and older, have received Lovenox in pivotal clinical trials. The efficacy of Lovenox in the geriatric (≥65 years) was similar to that seen in younger patients (<65 years). The incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when Lovenox was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of Lovenox-associated bleeding increased with age. Serious adverse events increased with age for patients receiving Lovenox. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of Lovenox between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Lovenox should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered [see Warnings and Precautions and Clinical Pharmacology ].
Treatment of Acute ST-Segment Elevation Myocardial Infarction
In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age (n=9015). Patients ≥75 years of age did not receive a 30 mg IV bolus prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours [see Dosage and Administration ]. The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).
Patients with Mechanical Prosthetic Heart Valves
The use of Lovenox has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves and has not been adequately studied for long-term use in this patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin for thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism [see Warnings and Precautions ].
In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients with moderate (creatinine clearance 3050 mL/min) and mild (creatinine clearance 5080 mL/min) renal impairment [see Dosage and Administration and Clinical Pharmacology ]. In patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia [see Adverse Reactions ].
The impact of hepatic impairment on enoxaparin's exposure and antithrombotic effect has not been investigated. Caution should be exercised when administering enoxaparin to patients with hepatic impairment.
An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such patients should be observed carefully for signs and symptoms of bleeding [see Clinical Pharmacology ].