Lovenox Information
Company Name Physicians Total Care, Inc.
Lovenox (Enoxaparin sodium) Dosage And Administration
These highlights do not include all the information needed to use Lovenox safely and effectively. See full prescribing information for Lovenox. Lovenox (enoxaparin sodium injection) for subcutaneous and intravenous useInitial U.S. Approval: 1993
All patients should be evaluated for a bleeding disorder before administration of Lovenox, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring Lovenox activity, routine monitoring of coagulation parameters is not required [see ].
For subcutaneous use, Lovenox should not be mixed with other injections or infusions. For intravenous use ( for treatment of acute STEMI), Lovenox can be mixed with normal saline solution (0.9%) or 5% dextrose in water.
Lovenox is not intended for intramuscular administration.
Lovenox (Enoxaparin sodium) Dosage Forms And Strengths
Lovenox is available in two concentrations:
Lovenox (Enoxaparin sodium) Warnings And Precautions
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, 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 and ].
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.
Thrombocytopenia can occur with the administration of Lovenox.
Moderate thrombocytopenia (platelet counts between 100,000/mm and 50,000/mm) 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/mm 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/mm, 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 [].
Lovenox (Enoxaparin sodium) Adverse Reactions
The following serious adverse reactions are also discussed in other sections of the labeling:
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in 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 SC once daily to 30 mg SC 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 IV bolus followed by 1 mg/kg every 12 hours SC.
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 post-operative 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 ( nodules, inflammation, oozing), systemic allergic reactions ( pruritus, urticaria anaphylactic/anaphylactoid reactions), vesiculobullous rash, rare 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 ] 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 ( 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.
Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate reliably their frequency or to establish a causal relationship to drug exposure.
Lovenox (Enoxaparin sodium) Drug Interactions
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 co-administration is essential, conduct close clinical and laboratory monitoring [see ].
Lovenox (Enoxaparin sodium) Overdosage
Accidental overdosage following administration of Lovenox may lead to hemorrhagic complications. Injected Lovenox may be largely neutralized by the slow IV injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of Lovenox injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg of Lovenox may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged.
If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information consult the labeling of protamine sulfate injection products.
Lovenox (Enoxaparin sodium) Description
Lovenox is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight heparin. The pH of the injection is 5.5 to 7.5.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight distribution is:
2000 to 8000 daltons ≥68%
>8000 daltons ≤18%
STRUCTURAL FORMULA
The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative [see and ].
Lovenox (Enoxaparin sodium) Clinical Studies
Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE).
In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4% Asian and 0.4% others. Lovenox 40 mg SC, administered once a day, beginning 2 hours prior to surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours SC in reducing the risk of DVT. The efficacy data are provided below [see ].
In a second double-blind, parallel group study, Lovenox 40 mg SC once a day was compared to heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hours prior to surgery and continued for approximately 7 to 10 days after surgery. The efficacy data are provided below [see ].
Lovenox has been shown to reduce the risk of post-operative deep vein thrombosis (DVT) following hip or knee replacement surgery.
In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients with hip replacement. A total of 100 patients were randomized in the study and all patients were treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and 55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below [see ].
A double-blind, multicenter study compared three dosing regimens of Lovenox in patients with hip replacement. A total of 572 patients were randomized in the study and 568 patients were treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and 37% women. Patients were 93% Caucasian, 6% Black,
There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens. In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the study and 131 patients were treated of which 99 had total knee replacement and 32 had either unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT after surgery was significantly lower for Lovenox compared to placebo. The efficacy data are provided below [see ].
Additionally, in an open-label, parallel group, randomized clinical study, Lovenox 30 mg every 12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was significantly lower for Lovenox compared to heparin.
Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery for the prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic disease were randomized to a post-discharge regimen of either Lovenox 40 mg (n = 90) once a day SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were randomized in the double-blind phase of the study and all patients were treated. Patients ranged in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this population of patients, the incidence of DVT during extended prophylaxis was significantly lower for Lovenox compared to placebo. The efficacy data are provided below [see ].
In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease were randomized to a post-discharge regimen of either Lovenox 40 mg (n = 131) once a day SC or to placebo (n = 131) for 3 weeks. A total of 262 patients were randomized in the study double-blind phase and all patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended prophylaxis was significantly lower for Lovenox compared to placebo, with a statistically significant difference in both total DVT (Lovenox 21 [16%] versus placebo 45 [34%]; p = 0.001) and proximal DVT (Lovenox 8 [6%] versus placebo 28 [21%]; p =
In a double blind multicenter, parallel group study, Lovenox 20 mg or 40 mg once a day SC was compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with severely restricted mobility during acute illness (defined as walking distance of
At approximately 3 months following enrollment, the incidence of venous thromboembolism remained significantly lower in the Lovenox 40 mg treatment group versus the placebo treatment group.
In a multicenter, parallel group study, 900 patients with acute lower extremity deep vein thrombosis (DVT) with or without pulmonary embolism (PE) were randomized to an inpatient (hospital) treatment of either (i) Lovenox 1.5 mg/kg once a day SC, (ii) Lovenox 1 mg/kg every 12 hours SC, or (iii) heparin IV bolus (5000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted according to PT to achieve an International Normalization Ratio [INR] of 2.0 to 3.0), commencing within 72 hours of initiation of Lovenox or standard heparin therapy, and continuing for 90 days. Lovenox or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both Lovenox regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided below [see ].
Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to Lovenox or heparin. Patients who could not receive outpatient therapy were excluded from entering the study. Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated co-morbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients were randomized to either Lovenox 1 mg/kg every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. Lovenox or standard heparin therapy was administered for a minimum of 5 days. Lovenox was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are provided below [see ].
In a multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non-Q-wave myocardial infarction were randomized to either Lovenox 1 mg/kg every 12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25–94 years (median age 64 years), with 33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Asian, and 3.5% other. patients were also treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent angina was lower for Lovenox compared with heparin therapy at 14 days after initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an analysis of both all-randomized and all-treated patients. The efficacy data are provided below [see ].
The combined incidence of death or myocardial infarction at all time points was lower for Lovenox compared to standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below [see ].
In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence of death, myocardial infarction, or recurrent angina remained lower for Lovenox versus heparin (32.0% vs 35.7%).
Urgent revascularization procedures were performed less frequently in the Lovenox group as compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
In a multicenter, double-blind, double-dummy, parallel group study, patients with acute ST-segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive either Lovenox or unfractionated heparin.
Study medication was initiated between 15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60 U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted according to the patient's age and renal function. For patients younger than 75 years of age, enoxaparin was given as a single 30 mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first). The mean treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated heparin was 54 hours.
When percutaneous coronary intervention was performed during study medication period, patients received antithrombotic support with blinded study drug. For patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies, no additional dosing, if the last SC administration was less than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin if the last SC administration was more than 8 hours before balloon inflation.
All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20% received streptokinase.
Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male. Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56%, and both in 1%.
The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first 30 days after randomization. Total follow-up was one year.
The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative risk, (P=0.000003) [see ].
Lovenox (Enoxaparin sodium) How Supplied/storage And Handling
Lovenox is available in two concentrations [see and ]:
Lovenox (Enoxaparin sodium) Patient Counseling Information
If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, they should be informed to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately.
Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Their use should be discontinued prior to enoxaparin therapy whenever possible; if co-administration is essential, the patient's clinical and laboratory status should be closely monitored.
