Generic Name: ENOXAPARIN SODIUM
Brand Name: Enoxaparin sodium
- Substance Name(s):
- ENOXAPARIN SODIUM
DRUG INTERACTIONS
7 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 (5.9)].
Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium or conduct close clinical and laboratory monitoring (5.9, 7)
OVERDOSAGE
10 Accidental overdosage following administration of enoxaparin sodium may lead to hemorrhagic complications.
Injected enoxaparin sodium may be largely neutralized by the slow intravenous injection of protamine sulfate (1% solution).
The dose of protamine sulfate should be equal to the dose of enoxaparin sodium injected: 1 mg protamine sulfate should be administered to neutralize 1 mg enoxaparin sodium, 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 enoxaparin sodium 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.
DESCRIPTION
11 Enoxaparin sodium injection 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: 8000 daltons ≤18% STRUCTURAL FORMULA R XX = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end.=15 to 25% n=0 to 20 100-X H n=1 to 21 Enoxaparin sodium injection 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1000 IU [with reference to the W.H.O.
First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
Enoxaparin sodium injection 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1500 IU [with reference to the W.H.O.
First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
The enoxaparin sodium 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 Dosage and Administration (2) and How Supplied (16)].
Chemical Structure Chemical Structure
CLINICAL STUDIES
14 14.1 Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications 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.
Enoxaparin sodium 40 mg subcutaneously, 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 subcutaneously in reducing the risk of DVT.
The efficacy data are provided below (see Table 14).
Table 14: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery Indication Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n (%) Heparin 5000 U q8h subcutaneously n (%) All Treated Abdominal Surgery Patients 555 (100) 560 (100) Treatment Failures Total VTEVTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin (%) 56 (10.1) (95% CICI = Confidence Interval: 8 to 13) 63 (11.3) (95% CI: 9 to 14) DVT Only (%) 54 (9.7) (95% CI: 7 to 12) 61 (10.9) (95% CI: 8 to 13) In a second double-blind, parallel group study, enoxaparin sodium 40 mg subcutaneously once a day was compared to heparin 5000 U every 8 hours subcutaneously 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 Table 15).
Table 15: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Colorectal Surgery Indication Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n (%) Heparin 5000 U q8h subcutaneously n (%) All Treated Colorectal Surgery Patients 673 (100) 674 (100) Treatment Failures Total VTEVTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin (%) 48 (7.1) (95% CICI = Confidence Interval: 5 to 9) 45 (6.7) (95% CI: 5 to 9) DVT Only (%) 47 (7.0) (95% CI: 5 to 9) 44 (6.5) (95% CI: 5 to 8) 14.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Enoxaparin sodium has been shown to reduce the risk of postoperative deep vein thrombosis (DVT) following hip or knee replacement surgery.
In a double-blind study, enoxaparin sodium 30 mg every 12 hours subcutaneously 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 Table 16).
Table 16: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery Indication Dosing Regimen Enoxaparin Sodium 30 mg q12h subcutaneously n (%) Placebo q12h subcutaneously n (%) All Treated Hip Replacement Patients 50 (100) 50 (100) Treatment Failures Total DVT (%) 5 (10)p value versus placebo = 0.0002 23 (46) Proximal DVT (%) 1 (2)p value versus placebo = 0.0134 11 (22) A double-blind, multicenter study compared three dosing regimens of enoxaparin sodium 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, <1% Asian, and 1% others.
Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery.
The efficacy data are provided below (see Table 17).
Table 17: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery Indication Dosing Regimen 10 mg daily subcutaneously n (%) 30 mg q12h subcutaneously n (%) 40 mg daily subcutaneously n (%) All Treated Hip Replacement Patients 161 (100) 208 (100) 199 (100) Treatment Failures Total DVT (%) 40 (25) 22 (11)p value versus enoxaparin sodium 10 mg once a day = 0.0008 27 (14) Proximal DVT (%) 17 (11) 8 (4)p value versus enoxaparin sodium 10 mg once a day = 0.0168 9 (5) There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens.
In a double-blind study, enoxaparin sodium 30 mg every 12 hours subcutaneously 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 enoxaparin sodium compared to placebo.
The efficacy data are provided below (see Table 18).
Table 18: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Total Knee Replacement Surgery Indication Dosing Regimen Enoxaparin Sodium 30 mg q12h subcutaneously n (%) Placebo q12h subcutaneously n (%) All Treated Total Knee Replacement Patients 47 (100) 52 (100) Treatment Failures Total DVT (%) 5 (11)p value versus placebo = 0.0001 (95% CICI = Confidence Interval: 1 to 21) 32 (62) (95% CI: 47 to 76) Proximal DVT (%) 0 (0)p value versus placebo = 0.013 (95% Upper CLCL = Confidence Limit: 5) 7 (13) (95% CI: 3 to 24) Additionally, in an open-label, parallel group, randomized clinical study, enoxaparin sodium 30 mg every 12 hours subcutaneously in patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours subcutaneously.
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 lower for enoxaparin sodium 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 enoxaparin sodium 40 mg subcutaneously, initiated up to 12 hours prior to surgery for the prophylaxis of postoperative 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 enoxaparin sodium 40 mg (n=90) once a day subcutaneously 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 enoxaparin sodium compared to placebo.
The efficacy data are provided below (see Table 19).
Table 19: Efficacy of Enoxaparin Sodium in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery Indication (Post Discharge) Post-discharge Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n (%) Placebo daily subcutaneously n (%) All Treated Extended Prophylaxis Patients 90 (100) 89 (100) Treatment Failures Total DVT (%) 6 (7)p value versus placebo = 0.008 (95% CICI= Confidence Interval: 3 to 14) 18 (20) (95% CI: 12 to 30) Proximal DVT (%) 5 (6)p value versus placebo = 0.537 (95% CI: 2 to 13) 7 (8) (95% CI: 3 to 16) In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with enoxaparin sodium 40 mg subcutaneously, 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 enoxaparin sodium 40 mg (n=131) once a day subcutaneously 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 enoxaparin sodium compared to placebo, with a statistically significant difference in both total DVT (enoxaparin sodium 21 [16%] versus placebo 45 [34%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6%] versus placebo 28 [21%]; p=<0.001).
14.3 Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness In a double blind multicenter, parallel group study, enoxaparin sodium 20 mg or 40 mg once a day subcutaneously 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 <10 meters for ≤3 days).
This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection (excluding septic shock); or acute rheumatic disorder (acute lumbar or sciatic pain, vertebral compression [due to osteoporosis or tumor], acute arthritic episodes of the lower extremities).
A total of 1102 patients were enrolled in the study, and 1073 patients were treated.
Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women.
Treatment continued for a maximum of 14 days (median duration 7 days).
When given at a dose of 40 mg once a day subcutaneously, enoxaparin sodium significantly reduced the incidence of DVT as compared to placebo.
The efficacy data are provided below (see Table 20).
Table 20: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness Indication Dosing Regimen Enoxaparin Sodium 20 mg daily subcutaneously n (%) Enoxaparin Sodium 40 mg daily subcutaneously n (%) Placebo n (%) All Treated Medical Patients During Acute Illness 351 (100) 360 (100) 362 (100) Treatment FailureTreatment failures during therapy, between Days 1 and 14 Total VTEVTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin (%) 43 (12.3) 16 (4.4) 43 (11.9) Total DVT (%) 43 (12.3) (95% CICI = Confidence Interval 8.8 to 15.7) 16 (4.4) (95% CI 2.3 to 6.6) 41 (11.3) (95% CI 8.1 to 14.6) Proximal DVT (%) 13 (3.7) 5 (1.4) 14 (3.9) At approximately 3 months following enrollment, the incidence of venous thromboembolism remained lower in the enoxaparin sodium 40 mg treatment group versus the placebo treatment group.
14.4 Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism 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) enoxaparin sodium 1.5 mg/kg once a day subcutaneously, (ii) enoxaparin sodium 1 mg/kg every 12 hours subcutaneously, or (iii) heparin intravenous 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 enoxaparin sodium or standard heparin therapy, and continuing for 90 days.
Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved.
Both enoxaparin sodium 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 Table 21).
Table 21: Efficacy of Enoxaparin Sodium in Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism Indication Dosing RegimenAll patients were also treated with warfarin sodium commencing within 72 hours of enoxaparin sodium or standard heparin therapy.
Enoxaparin Sodium 1.5 mg/kg daily subcutaneously n (%) Enoxaparin Sodium 1 mg/kg q12h subcutaneously n (%) Heparin aPTT Adjusted Intravenous Therapy n (%) All Treated DVT Patients with or without PE 298 (100) 312 (100) 290 (100) Patient Outcome Total VTEVTE = venous thromboembolic event (DVT and/or PE) (%) 13 (4.4)The 95% Confidence Intervals for the treatment differences for total VTE were: Enoxaparin sodium once a day versus heparin (-3.0 to 3.5) Enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).
9 (2.9) 12 (4.1) DVT Only (%) 11 (3.7) 7 (2.2) 8 (2.8) Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4) PE (%) 2 (0.7) 2 (0.6) 4 (1.4) Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to enoxaparin sodium 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 comorbid 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 enoxaparin sodium 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 enoxaparin sodium 1 mg/kg every 12 hours subcutaneously or heparin intravenous 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.
Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days.
Enoxaparin sodium was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism.
The efficacy data are provided below (see Table 22).
Table 22: Efficacy of Enoxaparin Sodium in Treatment of Deep Vein Thrombosis Indication Dosing RegimenAll patients were also treated with warfarin sodium commencing on the evening of the second day of enoxaparin sodium or standard heparin therapy.
Enoxaparin Sodium 1 mg/kg q12h subcutaneously Heparin aPTT Adjusted Intravenous Therapy n (%) n (%) All Treated DVT Patients 247 (100) 254 (100) Patient Outcome Total VTEVTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]).
(%) 13 (5.3)The 95% Confidence Intervals for the treatment difference for total VTE was: enoxaparin sodium versus heparin (-5.6 to 2.7).
17 (6.7) DVT Only (%) 11 (4.5) 14 (5.5) Proximal DVT (%) 10 (4.0) 12 (4.7) PE (%) 2 (0.8) 3 (1.2) 14.5 Prophylaxis of Ischemic Complications in Unstable Angina and Non–Q-Wave Myocardial Infarction In a multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non–Q-wave myocardial infarction were randomized to either enoxaparin sodium 1 mg/kg every 12 hours subcutaneously or heparin intravenous 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 to 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.
All 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 enoxaparin sodium 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 Table 23).
Table 23: Efficacy of Enoxaparin Sodium in the Prophylaxis of Ischemic Complications in Unstable Angina and Non–Q-Wave Myocardial Infarction (combined endpoint of death, myocardial infarction, or recurrent angina) Indication Dosing RegimenAll patients were also treated with aspirin 100 to 325 mg per day.
Reduction (%) p Value Enoxaparin Sodium 1 mg/kg q12h subcutaneous Heparin aPTT Adjusted Intravenous Therapy n (%) n (%) All Treated Unstable Angina and Non-Q-Wave MI Patients 1578 (100) 1529 (100) TimepointEvaluation timepoints are after initiation of treatment.
Therapy continued for up to 8 days (median duration of 2.6 days).
48 Hours 96 (6.1) 112 (7.3) 1.2 0.120 14 Days 261 (16.5) 303 (19.8) 3.3 0.017 30 Days 313 (19.8) 358 (23.4) 3.6 0.014 The combined incidence of death or myocardial infarction at all time points was lower for enoxaparin sodium compared to standard heparin therapy, but did not achieve statistical significance.
The efficacy data are provided below (see Table 24).
Table 24: Efficacy of Enoxaparin Sodium in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction (Combined endpoint of death or myocardial infarction) Indication Dosing RegimenAll patients were also treated with aspirin 100 to 325 mg per day.
Reduction (%) p Value Enoxaparin Sodium 1 mg/kg q12h subcutaneously n (%) Heparin aPTT Adjusted Intravenous Therapy n (%) All Treated Unstable Angina and Non–Q-Wave MI Patients 1578 (100) 1529 (100) TimepointEvaluation timepoints are after initiation of treatment.
Therapy continued for up to 8 days (median duration of 2.6 days).
48 Hours 16 (1.0) 20 (1.3) 0.3 0.126 14 Days 76 (4.8) 93 (6.1) 1.3 0.115 30 Days 96 (6.1) 118 (7.7) 1.6 0.069 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 enoxaparin sodium versus heparin (32.0% vs 35.7%).
Urgent revascularization procedures were performed less frequently in the enoxaparin sodium group as compared to the heparin group, 6.3% compared to 8.2% at 30 days (p=0.047).
14.6 Treatment of Acute ST-Segment Elevation Myocardial Infarction 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 enoxaparin sodium 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 intravenous 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 intravenous 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 subcutaneous dose followed by a subcutaneous injection of 1 mg/kg every 12 hours.
For patients at least 75 years of age, the intravenous bolus was not given and the subcutaneous 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 subcutaneous 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, i.e.
no additional dosing, if the last subcutaneous administration was less than 8 hours before balloon inflation, intravenous bolus of 0.3 mg/kg enoxaparin if the last subcutaneous 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 Table 25).
Table 25: Efficacy of Enoxaparin Sodium in the Treatment of Acute ST-Segment Elevation Myocardial Infarction Enoxaparin (N=10,256) UFH (N=10,223) Relative Risk (95% CI) P Value Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the clinical decision to perform coronary revascularization during the same hospitalization.
CI denotes confidence intervals.
Outcome at 48 hours n (%) n (%) Death or Myocardial Re-infarction 478 (4.7) 531 (5.2) 0.90 (0.80 to 1.01) 0.08 Death 383 (3.7) 390 (3.8) 0.98 (0.85 to 1.12) 0.76 Myocardial Re-infarction 102 (1.0) 156 (1.5) 0.65 (0.51 to 0.84) <0.001 Urgent Revascularization 74 (0.7) 96 (0.9) 0.77 (0.57 to 1.04) 0.09 Death or Myocardial Re-infarction or Urgent Revascularization 548 (5.3) 622 (6.1) 0.88 (0.79 to 0.98) 0.02 Outcome at 8 Days Death or Myocardial Re-infarction 740 (7.2) 954 (9.3) 0.77 (0.71 to 0.85) <0.001 Death 559 (5.5) 605 (5.9) 0.92 (0.82 to 1.03) 0.15 Myocardial Re-infarction 204 (2.0) 379 (3.7) 0.54 (0.45 to 0.63) <0.001 Urgent Revascularization 145 (1.4) 247 (2.4) 0.59 (0.48 to 0.72) <0.001 Death or Myocardial Re-infarction or Urgent Revascularization 874 (8.5) 1181 (11.6) 0.74 (0.68 to 0.80) <0.001 Outcome at 30 Days Primary efficacy endpoint (Death or Myocardial Re-infarction) 1017 (9.9) 1223 (12.0) 0.83 (0.77 to 0.90) 0.000003 Death 708 (6.9) 765 (7.5) 0.92 (0.84 to 1.02) 0.11 Myocardial Re-infarction 352 (3.4) 508 (5.0) 0.69 (0.60 to 0.79) <0.001 Urgent Revascularization 213 (2.1) 286 (2.8) 0.74 (0.62 to 0.88) <0.001 Death or Myocardial Re-infarction or Urgent Revascularization 1199 (11.7) 1479 (14.5) 0.81 (0.75 to 0.87) <0.001 The beneficial effect of enoxaparin on the primary end point was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1); however, it is necessary to interpret such subgroup analyses with caution.
Figure 1: Relative Risks of and Absolute Event Rates for the Primary End point at 30 Days in Various SubgroupsThe primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first 30 days.
The overall treatment effect of enoxaparin as compared to the unfractionated heparin is shown at the bottom of the figure.
For each subgroup, the circle is proportional to the number and represents the point estimate of the treatment effect and the horizontal lines represent the 95% confidence intervals.
Fibrin-specific fibrinolytic agents included alteplase, tenecteplase, and reteplase.
Time to treatment indicates the time from the onset of symptoms to the administration of study drug (median: 3.2 hours).
The beneficial effect of enoxaparin on the primary end point observed during the first 30 days was maintained over a 12 month follow-up period (see Figure 2).
Figure 2: Kaplan-Meier Plot — Death or Myocardial Re-infarction at 30 Days — ITT Population There is a trend in favor of enoxaparin during the first 48 hours, but most of the treatment difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen in Figure 2), an effect that is more striking when comparing the event rates just prior to and just subsequent to actual times of discontinuation.
These results provide evidence that UFH was effective and that it would be better if used longer than 48 hours.
There is a similar increase in endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued too soon in this study.
The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30 days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group.
The rates of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the unfractionated heparin group.
The 30-day rate of the composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin group (10.1%) as compared to the heparin group (12.2%).
Figure 1 Figure 2
HOW SUPPLIED
16 /STORAGE AND HANDLING Enoxaparin sodium injection is available in two concentrations (see Tables 26 and 27).
Table 26: 100 mg/mL Concentration Dosage Unit / StrengthStrength represents the number of milligrams of enoxaparin sodium in Water for Injection.
Enoxaparin sodium 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.
Anti-Xa ActivityApproximate anti-Factor Xa activity based on reference to the W.H.O.
First International Low Molecular Weight Heparin Reference Standard.
Package Size (per carton) Label Color NDC # 0955- Prefilled SyringesEach enoxaparin sodium prefilled syringe is for single, one-time use only and is affixed with a 27 gauge × 1/2 inch needle.
30 mg/0.3 mL 3000 IU 10 syringes Medium Blue 1003-10 40 mg/0.4 mL 4000 IU 10 syringes Yellow 1004-10 Graduated Prefilled Syringes 60 mg/0.6 mL 6000 IU 10 syringes Orange 1006-10 80 mg/0.8 mL 8000 IU 10 syringes Brown 1008-10 100 mg/1 mL 10,000 IU 10 syringes Black 1010-10 Multiple-Dose VialEach enoxaparin sodium multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative.
300 mg/3 mL 30,000 IU 1 vial Red 1016-01 Table 27: 150 mg/mL Concentration Dosage Unit / StrengthStrength represents the number of milligrams of enoxaparin sodium in Water for Injection.
Enoxaparin sodium 120 and 150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per 0.1 mL Water for Injection.
Anti-Xa ActivityApproximate anti-Factor Xa activity based on reference to the W.H.O.
First International Low Molecular Weight Heparin Reference Standard.
Package Size (per carton) Syringe Label Color NDC # 0955- Graduated Prefilled SyringesEach enoxaparin sodium graduated prefilled syringe is for single, one-time use only and is affixed with a 27 gauge × 1/2 inch needle.
120 mg / 0.8 mL 12,000 IU 10 syringes Purple 1012-10 150 mg / 1 mL 15,000 IU 10 syringes Navy Blue 1015-10 Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature].
Do not store the multiple-dose vials for more than 28 days after the first use.
Keep out of the reach of children.
RECENT MAJOR CHANGES
Contraindications (4) 10/2017 Warnings and Precautions (5.4, 5.8) 10/2017
GERIATRIC USE
8.5 Geriatric Use 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 enoxaparin sodium in pivotal clinical trials.
The efficacy of enoxaparin sodium 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 enoxaparin sodium were employed.
The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when enoxaparin sodium was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours.
The risk of enoxaparin sodium–associated bleeding increased with age.
Serious adverse events increased with age for patients receiving enoxaparin sodium.
Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of enoxaparin sodium between geriatric and younger patients.
Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised.
Enoxaparin sodium 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 (5.9) and Clinical Pharmacology (12.3)].
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 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 (2.3)].
The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).
DOSAGE FORMS AND STRENGTHS
3 Enoxaparin sodium injection is available in two concentrations.
100 mg/mL concentration (3.1): Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL Multiple-dose vial: 300 mg/3 mL 150 mg/mL concentration (3.2): Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL 3.1 100 mg/mL Concentration -Prefilled Syringes 30 mg/0.3 mL, 40 mg/0.4 mL -Graduated Prefilled Syringes 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL -Multiple-Dose Vials 300 mg/3 mL 3.2 150 mg/mL Concentration -Graduated Prefilled Syringes 120 mg/0.8 mL, 150 mg/1 mL
MECHANISM OF ACTION
12.1 Mechanism of Action Enoxaparin sodium is a low molecular weight heparin which has antithrombotic properties.
INDICATIONS AND USAGE
1 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) 1.1 Prophylaxis 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 1.2 Treatment 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 1.3 Prophylaxis 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.
1.4 Treatment 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).
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of enoxaparin sodium in pediatric patients have not been established.
Enoxaparin sodium 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.
Enoxaparin sodium 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)].
PREGNANCY
8.1 Pregnancy 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 enoxaparin sodium to increase the risk of developmental abnormalities above the background risk.
Fetal Risk Summary Enoxaparin sodium 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 enoxaparin sodium 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].
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.
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether enoxaparin sodium 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 enoxaparin sodium, a decision should be made whether to discontinue nursing or discontinue enoxaparin sodium, taking into account the importance of enoxaparin sodium to the mother and the known benefits of nursing.
BOXED WARNING
WARNING: SPINAL/EPIDURAL HEMATOMAS Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture.
These hematomas may result in long-term or permanent paralysis.
Consider these risks when scheduling patients for spinal procedures.
Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of enoxaparin sodium and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment.
If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug Interactions (7)].
WARNING: SPINAL/EPIDURAL HEMATOMAS See full prescribing information for complete boxed warning.
Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture.
These hematomas may result in long-term or permanent paralysis.
Consider these risks when scheduling patients for spinal procedures.
Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of enoxaparin sodium and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment.
If neurological compromise is noted, urgent treatment is necessary.
(5.1, 7)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Increased risk of hemorrhage: Use with caution in patients at risk (5.1) Percutaneous coronary revascularization: Obtain hemostasis at the puncture site before sheath removal (5.2) Concomitant medical conditions: Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension or history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage (5.3) History of heparin-induced thrombocytopenia: See Contraindications (4).
Use may be considered if previous HIT episode was >100 days prior and no circulating antibodies are present (5.4) Thrombocytopenia: Monitor platelet count closely (5.5) Interchangeability with other heparins: Do not exchange with heparin or other LMWHs (5.6) Pregnant women with mechanical prosthetic heart valves, and their fetuses, may be at increased risk and may need more frequent monitoring and dosage adjustment (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 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), 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 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)].
5.3 Use of Enoxaparin Sodium 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.
5.4 History of Heparin-Induced Thrombocytopenia 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.
In patients with a history of HIT, enoxaparin sodium should only be used 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.
5.5 Thrombocytopenia Thrombocytopenia can occur with the administration of enoxaparin sodium.
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) 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/mm3 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/mm3, enoxaparin sodium 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 (5.4)].
5.6 Interchangeability 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.
5.7 Pregnant Women with Mechanical Prosthetic Heart Valves The use of enoxaparin sodium 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 (8.6)].
5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative Enoxaparin sodium 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 enoxaparin sodium 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 (enoxaparin sodium 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 enoxaparin sodium is needed during pregnancy, use the preservative-free formulations where possible [see Use in Specific Populations (8.1)].
5.9 Laboratory Tests Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin sodium.
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 enoxaparin sodium activity and, therefore, unsuitable for monitoring.
Anti-Factor Xa may be used to monitor the anticoagulant effect of enoxaparin sodium in patients with significant renal impairment.
If during enoxaparin sodium therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin sodium [see Clinical Pharmacology (12.3)].
INFORMATION FOR PATIENTS
17 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, advise them to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness.
Instruct the patient to seek immediate medical attention if any of these symptoms occur.
Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage.
When possible, discontinue their use prior to enoxaparin sodium therapy.
Monitor the patient’s clinical and laboratory status if coadministration is essential [see Drug Interactions (7)].
Inform patients: of the instructions for injecting enoxaparin sodium if they continue enoxaparin sodium therapy after discharge from the hospital.
that it may take them longer than usual to stop bleeding.
that they may bruise and/or bleed more easily when they use enoxaparin sodium.
that they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician [see Warnings and Precautions (5.1, 5.5)].
that risks are associated with the use of benzyl alcohol, a preservative in enoxaparin sodium multidose vials, in neonates, infants, and pregnant women.
to tell their physicians and dentists they are taking enoxaparin sodium and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken [see Warnings and Precautions (5.3)].
to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs [see Drug Interactions (7)].
DOSAGE AND ADMINISTRATION
2 All patients should be evaluated for a bleeding disorder before administration of enoxaparin sodium, unless the medication is needed urgently.
Since coagulation parameters are unsuitable for monitoring enoxaparin sodium activity, routine monitoring of coagulation parameters is not required [see Warnings and Precautions (5.9)].
For subcutaneous use, enoxaparin sodium should not be mixed with other injections or infusions.
For intravenous use (i.e., for treatment of acute STEMI), enoxaparin sodium can be mixed with normal saline solution (0.9%) or 5% dextrose in water.
Enoxaparin sodium is not intended for intramuscular administration.
Indication Dose DVT prophylaxis in abdominal surgery 40 mg subcutaneously once daily DVT prophylaxis in knee replacement surgery 30 mg subcutaneously every 12 hours DVT prophylaxis in hip replacement surgery 30 mg subcutaneously every 12 hours or 40 mg subcutaneously once daily DVT prophylaxis in medical patients 40 mg subcutaneously once daily Inpatient treatment of acute DVT with or without pulmonary embolism 1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg subcutaneously once daily* Outpatient treatment of acute DVT without pulmonary embolism 1 mg/kg subcutaneously every 12 hours* Unstable angina and non–Q-wave MI 1 mg/kg subcutaneously every 12 hours (with aspirin) Acute STEMI in patients <75 years of age [For dosing in subsequent PCI, see Dosage and Administration (2.1)] 30 mg single intravenous bolus plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg subcutaneously every 12 hours (with aspirin) Acute STEMI in patients ≥75 years of age 0.75 mg/kg subcutaneously every 12 hours (no bolus) (with aspirin) See recommended durations for enoxaparin sodium therapy (2.1) *See recommendations regarding transitioning to warfarin therapy (2.1) Adjust the dose for patients with severe renal impairment (2.2, 8.7) 2.1 Adult Dosage Abdominal Surgery In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of enoxaparin sodium is 40 mg once a day administered by subcutaneous injection with the initial dose given 2 hours prior to surgery.
The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials.
Hip or Knee Replacement Surgery In patients undergoing hip or knee replacement surgery, the recommended dose of enoxaparin sodium is 30 mg every 12 hours administered by subcutaneous injection.
Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery.
For hip replacement surgery, a dose of 40 mg once a day subcutaneously, given initially 12 (±3) hours prior to surgery, may be considered.
Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with enoxaparin sodium 40 mg once a day be administered by subcutaneous injection for 3 weeks.
The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials.
Medical Patients During Acute Illness In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of enoxaparin sodium is 40 mg once a day administered by subcutaneous injection.
The usual duration of administration is 6 to 11 days; up to 14 days of enoxaparin sodium has been administered in the controlled clinical trial.
Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours administered subcutaneously.
In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours administered subcutaneously or 1.5 mg/kg once a day administered subcutaneously at the same time every day.
In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of enoxaparin sodium).
Enoxaparin sodium should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2 to 3).
The average duration of administration is 7 days; up to 17 days of enoxaparin sodium administration has been administered in controlled clinical trials.
Unstable Angina and Non–Q-Wave Myocardial Infarction In patients with unstable angina or non–Q-wave myocardial infarction, the recommended dose of enoxaparin sodium is 1 mg/kg administered subcutaneously every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily).
Treatment with enoxaparin sodium should be prescribed for a minimum of 2 days and continued until clinical stabilization.
The usual duration of treatment is 2 to 8 days; up to 12.5 days of enoxaparin sodium has been administered in clinical trials [see Warnings and Precautions (5.2) and Clinical Studies (14.5)].
Treatment of Acute ST-Segment Elevation Myocardial Infarction In patients with acute ST-segment elevation myocardial infarction, the recommended dose of enoxaparin sodium is a single intravenous bolus of 30 mg plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg administered subcutaneously every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses).
Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and Administration (2.3)].
All patients should receive aspirin as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated.
When administered in conjunction with a thrombolytic (fibrin specific or non–fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy.
In the pivotal clinical study, the enoxaparin sodium treatment duration was 8 days or until hospital discharge, whichever came first.
An optimal duration of treatment is not known, but it is likely to be longer than 8 days.
For patients managed with percutaneous coronary intervention (PCI), if the last enoxaparin sodium subcutaneous administration was given less than 8 hours before balloon inflation, no additional dosing is needed.
If the last enoxaparin sodium subcutaneous administration was given more than 8 hours before balloon inflation, an intravenous bolus of 0.3 mg/kg of enoxaparin sodium should be administered [see Warnings and Precautions (5.2)].
2.2 Renal Impairment Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.
The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Table 1: Dosage Regimens for Patients with Severe Renal Impairment (creatinine clearance <30 mL/minute) Indication Dosage Regimen Prophylaxis in abdominal surgery 30 mg administered subcutaneously once daily Prophylaxis in hip or knee replacement surgery 30 mg administered subcutaneously once daily Prophylaxis in medical patients during acute illness 30 mg administered subcutaneously once daily Inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered subcutaneously once daily Outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered subcutaneously once daily Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin 1 mg/kg administered subcutaneously once daily Treatment of acute ST-segment elevation myocardial infarction in patients <75 years of age, when administered in conjunction with aspirin 30 mg single intravenous bolus plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg administered subcutaneously once daily.
Treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, when administered in conjunction with aspirin 1 mg/kg administered subcutaneously once daily (no initial bolus) 2.3 Geriatric Patients with Acute ST-Segment Elevation Myocardial Infarction For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, do not use an initial intravenous bolus.
Initiate dosing with 0.75 mg/kg subcutaneously every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses) [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired [see Dosage and Administration (2.2)].
2.4 Administration Enoxaparin sodium injection is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.
The use of a tuberculin syringe or equivalent is recommended when using enoxaparin sodium multiple-dose vials to assure withdrawal of the appropriate volume of drug.
Enoxaparin sodium must not be administered by intramuscular injection.
Enoxaparin sodium is intended for use under the guidance of a physician.
For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary.
Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided.
Subcutaneous Injection Technique Patients should be lying down and enoxaparin sodium administered by deep subcutaneous injection.
To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not expel the air bubble from the syringe before the injection.
Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall.
The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection.
To minimize bruising, do not rub the injection site after completion of the injection.
Enoxaparin sodium prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection.
Remove the prefilled syringe from the blister packaging by peeling at the arrow as directed on the blister.
Do not remove by pulling on the plunger as this may damage the syringe.
Remove the needle shield by pulling it straight off the syringe (see Figure A).
If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient.
Figure A Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B).
Figure B Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C).
Figure C Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod.
The protective sleeve will automatically cover the needle and an audible “click” will be heard to confirm shield activation (see Figure D).
Figure D Immediately dispose of the syringe in the nearest sharps container (see Figure E).
Figure E NOTE: The safety system can only be activated once the syringe has been emptied.
Activation of the safety system must be done only after removing the needle from the patient’s skin.
Do not replace the needle shield after injection.
The safety system should not be sterilized.
Activation of the safety system may cause minimal splatter of fluid.
For optimal safety, activate the system while orienting it downwards away from yourself and others.
Figure A Figure B Figure C Figure D Figure E Intravenous (Bolus) Injection Technique For intravenous injection, the multiple-dose vial should be used.
Enoxaparin sodium should be administered through an intravenous line.
Enoxaparin sodium should not be mixed or coadministered with other medications.
To avoid the possible mixture of enoxaparin sodium with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of enoxaparin sodium to clear the port of drug.
Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.