Source: FDA, National Drug Code (US) Revision Year: 2020
Lovenox is contraindicated in patients with:
Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of Lovenox 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 Lovenox and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of Lovenox [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of Lovenox 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 Lovenox 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 Lovenox. 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 Lovenox 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 Lovenox 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 Lovenox is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of Lovenox (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 Lovenox 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.
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 intravenous/subcutaneous Lovenox. If the treatment with Lovenox 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)].
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.
Lovenox 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 Lovenox 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 Lovenox 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 Lovenox in such a case must be made only after a careful benefit-risk assessment and after non-heparin alternative treatments are considered.
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.
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.
Use of Lovenox 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 Lovenox (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. 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 Lovenox 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 (8.6)].
Lovenox multiple-dose vials are not approved for use in neonates or infants.
Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs, including Lovenox multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Lovenox multiple-dose vials contain 15 mg of benzyl alcohol per mL) [see Use in Specific Populations (8.4)].
Because benzyl alcohol may cross the placenta, if anticoagulation with Lovenox is needed during pregnancy, use the preservative-free formulations where possible [see Use in Specific Populations (8.1)].
The following serious adverse reactions are also discussed in other sections of the labeling:
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 Lovenox. 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. Lovenox 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 Lovenox doses were a 30 mg intravenous bolus followed by 1 mg/kg every 12 hours subcutaneously.
The following rates of major bleeding events have been reported during clinical trials with Lovenox (see Tables 2 to 7).
Table 2. Major Bleeding Episodes Following Abdominal and Colorectal Surgery*:
| Dosing Regimen | ||
|---|---|---|
| Indications | Lovenox 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: (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 Surgery*:
| Dosing Regimen | |||
|---|---|---|---|
| Indications | Lovenox 40 mg daily subcutaneously | Lovenox 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‡ | n=288 4 (2%) | ||
| Extended Prophylaxis Period§ | n=221 0 (0%) | ||
| Knee Replacement Surgery without Extended Prophylaxis† | n=294 3 (1%) | n=225 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 and intracranial hemorrhages were always considered major. In the knee replacement surgery trials, intraocular hemorrhages were also considered major hemorrhages.
† Lovenox 30 mg every 12 hours subcutaneously initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery
‡ Lovenox 4 0 mg subcutaneously once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery
§ Lovenox 4 0 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 Lovenox patients versus 1.8% of the placebo patients.
Table 4. Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility During Acute Illness*:
| Dosing Regimen | |||
|---|---|---|---|
| Indication | Lovenox† 20 mg daily subcutaneously | Lovenox† 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: (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.
† 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*:
| Dosing Regimen† | |||
|---|---|---|---|
| Indication | Lovenox 1.5 mg/kg daily subcutaneously | Lovenox 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: (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.
† 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 | ||
|---|---|---|
| Indication | Lovenox* 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: (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 | ||
|---|---|---|
| Indication | Lovenox* 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)† | 211 (2.1) | 138 (1.4) |
| Intracranial hemorrhages (ICH) | 84 (0.8) | 66 (0.7) |
* 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.
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.
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 irritation, pain, hematoma, ecchymosis, and erythema may follow subcutaneous injection of Lovenox.
Other adverse reactions 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 Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing Abdominal or Colorectal Surgery:
| Dosing Regimen | ||||
|---|---|---|---|---|
| Lovenox 40 mg daily subcutaneously n=1228 % | Heparin 5000 U q8h subcutaneously n=1234 % | |||
| Adverse Reaction | 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 Lovenox-Treated Patients Undergoing Hip or Knee Replacement Surgery:
| Dosing Regimen | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Lovenox 40 mg daily subcutaneously | Lovenox 30 mg q12h subcutaneously | Heparin 15,000 U/24h subcutaneously | Placebo q12h subcutaneously | |||||||
| Peri-operative Period | Extended Prophylaxis Period | |||||||||
| n=288* % | n=131† % | n=1080 % | n=766 % | n=115 % | ||||||
| Adverse Reaction | 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 Lovenox 4 0 mg subcutaneously once a day initiated up to 12 hours prior to surgery in 288 hip replacement surgery patients who received Lovenox peri-operatively in an unblinded fashion in one clinical trial.
† Data represent Lovenox 4 0 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 Lovenox-Treated Medical Patients with Severely Restricted Mobility During Acute Illness:
| Dosing Regimen | ||
|---|---|---|
| Adverse Reaction | Lovenox 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 Lovenox-Treated Patients Undergoing Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism:
| Dosing Regimen | ||||||
|---|---|---|---|---|---|---|
| Lovenox 1.5 mg/kg daily subcutaneously n=298 % | Lovenox 1 mg/kg q12h subcutaneously n=559 % | Heparin aPTT Adjusted Intravenous Therapy n=544 % | ||||
| Adverse Reaction | 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 |
Non-hemorrhagic clinical events reported to be related to Lovenox therapy occurred at an incidence of ≤1%.
Non-major hemorrhagic events, primarily injection site ecchymosis and hematomas, were more frequently reported in patients treated with subcutaneous Lovenox than in patients treated with intravenous heparin.
Serious adverse events with Lovenox 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 Lovenox group are provided below (see Table 12).
Table 12. Serious Adverse Events Occurring at ≥0.5% Incidence in Lovenox-Treated Patients with Unstable Angina or Non–Q-Wave Myocardial Infarction:
| Dosing Regimen | ||
|---|---|---|
| Lovenox 1 mg/kg q12h subcutaneously | Heparin aPTT Adjusted Intravenous Therapy | |
| Adverse Event | n=1578 n (%) | n=1529 n (%) |
| Atrial fibrillation | 11 (0.70) | 3 (0.20) |
| Heart failure | 15 (0.95) | 11 (0.72) |
| Lung edema | 11 (0.70) | 11 (0.72) |
| Pneumonia | 13 (0.82) | 9 (0.59) |
In a clinical trial in patients with acute ST-segment elevation myocardial infarction, thrombocytopenia occurred at a rate of 1.5%.
The following adverse reactions have been identified during postapproval use of Lovenox. 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 Lovenox 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 [see Warnings and Precautions (5.5)] 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.
Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of Lovenox 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)].
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, Lovenox 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.
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 Lovenox 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 Lovenox 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 (99–405 mg/kg/day). The multiple-dose vial of Lovenox contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions (5.8)].
There are no adequate and well-controlled studies in pregnant women. A retrospective study reviewed the records of 604 women who used Lovenox 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 Lovenox in pregnant women with mechanical prosthetic heart valves has been conducted [see Warnings and Precautions (5.7)].
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.
It is unknown whether Lovenox is excreted in human milk. In lactating rats, the passage of enoxaparin or its metabolites in the milk is very limited. There is no information available on the effect of enoxaparin or its metabolites on the breastfed child, or on the milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lovenox and any potential adverse effects on the breastfed child from Lovenox or from the underlying maternal condition.
Safety and effectiveness of Lovenox in pediatric patients have not been established.
Lovenox is not approved for use in neonates or infants.
Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth-weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.
Lovenox multiple-dose vials contain 15 mg/mL of benzyl alcohol (at the dose of 1.5 mg/kg twice a day, benzyl alcohol exposure in patients is 0.45 mg/kg daily) [see Warnings and Precautions (5.8)].
Over 2800 patients, 65 years and older, have received Lovenox in 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 (2.6) and Clinical Pharmacology (12.3)].
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 intravenous bolus prior to the normal dosage regimen and had their subcutaneous dose adjusted to 0.75 mg/kg every 12 hours [see Dosage and Administration (2.4)]. The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).
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 creatinine clearance 30 to <50 mL/min and creatinine clearance 50 to 80 mL/min [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. In patients with renal failure, treatment with Lovenox has been associated with the development of hyperkalemia [see Adverse Reactions (6.2)].
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 Lovenox 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 (5.7)].
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). Observe low-weight patients frequently for signs and symptoms of bleeding [see Clinical Pharmacology (12.3)].
Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses of Lovenox in obese patients (BMI >30 kg/m²) has not been fully determined and there is no consensus for dose adjustment. Observe these patients carefully for signs and symptoms of thromboembolism.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
