Enoxaparin Sodium Injection
Dosage Form: injection, solution
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 Injection 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.
[see Warnings
and Precautions (5.1) and Drug
Interactions (7)].
Indications and Usage for Enoxaparin
Sodium Injection
Prophylaxis of Deep Vein Thrombosis
Enoxaparin Sodium Injection is indicated for the
prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism
(PE):
in patients undergoing abdominal
surgery who are at risk for thromboembolic complications [see
Clinical Studies 14.1].in patients undergoing hip
replacement surgery, during and following hospitalization.in patients undergoing knee
replacement surgery.in medical patients who are at risk
for thromboembolic complications due to severely restricted mobility during
acute illness.
Treatment of Acute Deep Vein
Thrombosis
Enoxaparin Sodium Injection is indicated for:
the inpatient
treatment of acute
deep vein thrombosis with or without pulmonary embolism, when administered in
conjunction with warfarin sodium.the outpatient
treatment of acute
deep vein thrombosis without pulmonary embolism when administered in
conjunction with warfarin sodium.
Prophylaxis of Ischemic Complications
of Unstable Angina and Non-Q-Wave Myocardial Infarction
Enoxaparin Sodium Injection is indicated for the
prophylaxis of ischemic complications of unstable angina and non-Q-wave
myocardial infarction, when concurrently administered with aspirin.
Treatment of Acute ST-Segment
Elevation Myocardial Infarction
Enoxaparin Sodium Injection, when administered
concurrently with aspirin, has been shown to reduce the rate of the combined
endpoint of recurrent myocardial infarction or death in patients with acute
ST-segment elevation myocardial infarction (STEMI) receiving thrombolysis and
being managed medically or with percutaneous coronary intervention (PCI).
Enoxaparin Sodium Injection Dosage
and Administration
All patients should be evaluated for a bleeding
disorder before administration of Enoxaparin Sodium Injection, unless the
medication is needed urgently. Since coagulation parameters are unsuitable for
monitoring Enoxaparin Sodium Injection activity, routine monitoring of
coagulation parameters is not required [see Warnings and Precautions (5.9)].
For subcutaneous use, Enoxaparin Sodium Injection
should not be mixed with other injections or infusions.
For intravenous use (i.e., for treatment of acute
STEMI), Enoxaparin Sodium Injection can be mixed with normal saline solution
(0.9%) or 5% dextrose in water.
Enoxaparin Sodium Injection is not intended for
intramuscular administration.
Adult Dosage
Abdominal Surgery: In patients
undergoing abdominal surgery who are at risk for thromboembolic complications,
the recommended dose of Enoxaparin Sodium Injection is 40 mg
once a dayadministered
by SC 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 Injection is 30 mg every 12 hours administered by SC
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 SC, 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 Injection 40 mg once a day be
administered by SC 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 Injection is 40 mg
once a day administered
by SC injection. The usual duration of administration is 6 to 11 days; up to 14
days of Enoxaparin Sodium Injection 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 Injection is 1
mg/kg every 12 hours administered SC. 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 Injection is 1
mg/kg every 12 hours administered SC or
1.5 mg/kg once a day administered SC 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 Injection). Enoxaparin Sodium Injection should be continued for a
minimum of 5 days and until a therapeutic oral anticoagulant effect has been
achieved (International Normalization Ratio 2.0 to 3.0). The average duration
of administration is 7 days; up to 17 days of Enoxaparin Sodium Injection
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
Injection is 1 mg/kgadministered SC every
12 hours in
conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment
with Enoxaparin Sodium Injection 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 Injection 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 Injection is
a single IV bolus of 30 mg plus a 1 mg/kg SC
dose followed by 1 mg/kg administered SC 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
Injection should be given between 15 minutes before and 30 minutes after the
start of fibrinolytic therapy. In the pivotal clinical study, the Enoxaparin
Sodium Injection 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 Injection SC administration
was given less than 8 hours before balloon inflation, no additional dosing is
needed. If the last Enoxaparin Sodium Injection SC administration was given
more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of
Enoxaparin Sodium Injection should be administered [see Warnings and Precautions (5.2)].
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 (8.6) and Clinical Pharmacology (12.3)].
|
|
|
Dosage Regimens for Patients with Severe Renal Impairment
(creatinine clearance <30 mL/minute)
|
|
Indication
|
Dosage Regimen
|
|
Prophylaxis
in abdominal surgery
|
30
mg administered SC once daily
|
|
Prophylaxis
in hip or knee replacement surgery
|
30
mg administered SC once daily
|
|
Prophylaxis
in medical patients during acute illness
|
30
mg administered SC 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 SC once daily
|
|
Outpatient
treatment of acute deep vein thrombosis without pulmonary embolism, when
administered in conjunction with warfarin sodium
|
1
mg/kg administered SC once daily
|
|
Prophylaxis
of ischemic complications of unstable angina and non-Q-wave myocardial
infarction, when concurrently administered with aspirin
|
1
mg/kg administered SC 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 IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC
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 SC once daily (no initial
bolus)
|
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 IV bolus. Initiate dosing with 0.75
mg/kg SC 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 Phamacology (12.3)].
No dose adjustment is necessary for other
indications in geriatric patients unless kidney function is impaired [see Dosage and Administration (2.2)].
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.
Enoxaparin Sodium Injection must not be
administered by intramuscular injection.
Enoxaparin Sodium Injection 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 Injection administered by deep SC 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 Injection 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 needle cover by pulling
straight off of needle (see
Figure
1). If adjusting the dose is required, the adjustment must be done
prior to injecting the prescribed dose into the patient.
See
Administration:
Subcutaneous Injection Technique for a description of the Standard
Protocol for administration.
Depress the plunger while grasping
the finger flange
until the entire dose has been
given. The Passive
needle guard should not activate unless the entire dose has been given.
Remove needle from patient, then
let go of the plunger and allow syringe to move up until the entire needle
is guarded.
Dispose of syringe/needle guard
assembly in approved sharps container.
NOTE:
The safety system should only
activate 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.
Intravenous (Bolus) Injection
Technique
For intravenous injection, the multiple-dose vial
should be used. Enoxaparin Sodium Injection should be administered through an
intravenous line. Enoxaparin Sodium Injection should not be mixed or
co-administered with other medications. To avoid the possible mixture of
Enoxaparin Sodium Injection 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
Injection to clear the port of drug. Enoxaparin Sodium Injection may be safely
administered with normal saline solution (0.9%) or 5% dextrose in water.
Dosage Forms and Strengths
Enoxaparin Sodium Injection is available in two
concentrations:
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
|
150 mg/mL Concentration
|
-Graduated Prefilled Syringes
|
120
mg / 0.8 mL, 150 mg / 1 mL
|
Contraindications
Active major bleedingThrombocytopenia associated with a
positive in vitro test for anti-platelet
antibody in the presence of enoxaparin sodiumKnown hypersensitivity to
enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/
anaphylactoid reactions) [see
Adverse Reactions (6.2)]Known hypersensitivity to heparin
or pork products
Warnings and Precautions
Increased Risk of Hemorrhage
Cases of epidural or spinal hemorrhage and subsequent
hematomas have been reported with the use of Enoxaparin Sodium Injection and
epidural or spinal anesthesia/analgesia or spinal puncture procedures,
resulting in long-term or permanent paralysis. The risk of these events is
higher with the use of post-operative indwelling epidural catheters, with the
concomitant use of additional drugs affecting hemostasis such as NSAIDs, with
traumatic or repeated epidural or spinal puncture, or in patients with a
history of spinal surgery or spinal deformity [see Boxed Warning, Adverse Reactions (6.2)and Drug Interactions (7)].
To reduce the potential risk of bleeding associated
with the concurrent use of enoxaparin sodium and epidural or spinal
anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile
of enoxaparin [see Clinical Pharmacology (12.3)]. Placement or removal of
an epidural catheter or lumbar puncture is best performed when the
anticoagulant effect of enoxaparin is low; however, the exact timing to reach a
sufficiently low anticoagulant effect in each patient is not known.
Placement or removal of a catheter should be
delayed for at least 12 hours after administration of lower doses (30 mg once
or twice daily or 40 mg once daily) of Enoxaparin Sodium Injection, and at
least 24 hours after the administration of higher doses (0.75 mg/kg twice
daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily) of Enoxaparin Sodium Injection.
Anti-Xa levels are still detectable at these time points, and these delays are
not a guarantee that neuraxial hematoma will be avoided. Patients receiving the
0.75 mg/kg twice daily dose or the 1 mg/kg twice daily dose should not receive
the second enoxaparin dose in the twice daily regimen to allow a longer delay
before catheter placement or removal. Likewise, although a specific
recommendation for timing of a subsequent Enoxaparin Sodium Injection dose
after catheter removal cannot be made, consider delaying this next dose for at
least four hours, based on a benefit-risk assessment considering both the risk
for thrombosis and the risk for bleeding in the context of the procedure and
patient risk factors. For patients with creatinine clearance <30mL/minute,
additional considerations are necessary because elimination of enoxaparin is
more prolonged; consider doubling the timing of removal of a catheter, at least
24 hours for the lower prescribed dose of Enoxaparin Sodium Injection (30 mg
once daily) and at least 48 hours for the higher dose (1 mg/kg/day) [see Clinical Pharmacology (12.3)].
Should the physician decide to administer
anticoagulation in the context of epidural or spinal anesthesia/analgesia or
lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and
motor deficits (numbness or weakness in lower limbs), 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.
Enoxaparin Sodium Injection 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
Enoxaparin Sodium Injection. An unexplained fall in hematocrit or blood
pressure should lead to a search for a bleeding site.
Percutaneous Coronary
Revascularization Procedures
To minimize the risk of bleeding following the
vascular instrumentation during the treatment of unstable angina, non-Q-wave
myocardial infarction, and acute ST-segment elevation myocardial infarction,
adhere precisely to the intervals recommended between Enoxaparin Sodium
Injection doses. It is important to achieve hemostasis at the puncture site
after PCI.
In case a closure device is used, the sheath can be
removed immediately. If a manual compression method is used, sheath should be
removed 6 hours after the last IV/SC Enoxaparin Sodium Injection. If the
treatment with enoxaparin sodium is to be continued, the next scheduled dose
should be given no sooner than 6 to 8 hours after sheath removal. The site of
the procedure should be observed for signs of bleeding or hematoma formation [see Dosage and Administration (2.1)].
Use of Enoxaparin Sodium Injection
with Concomitant Medical Conditions
Enoxaparin Sodium Injection should be used with
care in patients with a bleeding diathesis, uncontrolled arterial hypertension
or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal
dysfunction and hemorrhage.
History of Heparin-Induced
Thrombocytopenia
Enoxaparin Sodium Injection should be used with
extreme caution in patients with a history of heparin-induced thrombocytopenia.
Thrombocytopenia
Thrombocytopenia can occur with the administration
of Enoxaparin Sodium Injection.
Moderate thrombocytopenia (platelet counts between
100,000/mm3 and 50,000/mm3) occurred at a rate of 1.3% in
patients given Enoxaparin Sodium Injection, 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 Injection, 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 Injection 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)].
Interchangeability with Other
Heparins
Enoxaparin Sodium Injection cannot be used interchangeably
(unit for unit) with heparin or other low molecular weight heparins as they
differ in manufacturing process, molecular weight distribution, anti-Xa and
anti-IIa activities, units, and dosage. Each of these medicines has its own
instructions for use.
Pregnant Women with Mechanical
Prosthetic Heart Valves
The use of Enoxaparin Sodium Injection 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)].
Laboratory Tests
Periodic complete blood counts, including platelet
count, and stool occult blood tests are recommended during the course of
treatment with Enoxaparin Sodium Injection. 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 Injection activity and, therefore, unsuitable for
monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of
Enoxaparin Sodium Injection in patients with significant renal impairment. If during Enoxaparin
Sodium Injection therapy abnormal coagulation parameters or bleeding should
occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects
of Enoxaparin Sodium Injection [see Clinical Pharmacology (12.3)].
Adverse Reactions
Clinical Trials Experience
The following serious adverse reactions are also
discussed in other sections of the labeling:
Spinal/epidural hematoma [see
Boxed Warning and
Warnings and Precautions (5.1)]Increased Risk of Hemorrhage
[see
Warnings and Precautions (5.1)]Thrombocytopenia [see
Warnings and Precautions (5.5)]
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice.
During clinical development for the approved
indications, 15,918 patients were exposed to 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.
Hemorrhage
The incidence of major hemorrhagic complications
during Enoxaparin Sodium Injection treatment has been low.
The following rates of major bleeding events have
been reported during clinical trials with Enoxaparin Sodium Injection
[see Tables 2 to 7].
Table 2 Major Bleeding Episodes Following Abdominal and Colorectal
Surgery*
|
|
|
Indications
|
Dosing Regimen
|
|
|
Enoxaparin Sodium Inj.
|
Heparin
|
|
|
40 mg q.d. SC
|
5000 U q8h SC
|
|
|
*
Bleeding complications were considered major: (1)
if the hemorrhage caused a significant clinical event, or (2) if accompanied
by a hemoglobin decrease ≥2
g/dL or transfusion of 2 or more units of blood products. Retroperitoneal,
intraocular, and intracranial hemorrhages were always considered major.
|
|
|
Abdominal Surgery
|
n=555
|
n=560
|
|
|
|
23 (4%)
|
16 (3%)
|
|
|
Colorectal Surgery
|
n=673
|
n=674
|
|
|
|
28 (4%)
|
21 (3%)
|
|
Table 3 Major Bleeding Episodes Following Hip or Knee Replacement
Surgery*
|
|
|
|
Dosing Regimen
|
|
|
Indications
|
Enoxaparin Sodium
Inj.
40 mg q.d. SC
|
Enoxaparin Sodium
Inj.
30 mg q12h SC
|
Heparin
15,000 U/24h SC
|
|
|
NOTE:
At no time point were the 40 mg once a day pre-operative and the 30 mg every
12 hours post-operative hip replacement surgery prophylactic regimens
compared in clinical trials. Injection site hematomas during the extended
prophylaxis period after hip replacement surgery occurred in 9% of the
Enoxaparin Sodium Injection patients versus 1.8% of the placebo patients.
|
|
|
*
Bleeding
complications were considered major: (1) if the hemorrhage caused a
significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood
products. Retroperitoneal and intracranial hemorrhages were always considered
major. In the knee replacement surgery trials, intraocular hemorrhages were
also considered major hemorrhages.
†
Enoxaparin
Sodium Injection 30 mg every 12 hours SC initiated 12 to 24 hours after
surgery and continued for up to 14 days after surgery.
‡
Enoxaparin
Sodium Injection 40 mg SC once a day initiated up to 12 hours prior to
surgery and continued for up to 7 days after surgery.
§
Enoxaparin Sodium Injection 40 mg SC once a day
for up to 21 days after discharge.
|
|
|
Hip Replacement Surgery without Extended
Prophylaxis†
|
|
n = 786
31 (4%)
|
n = 541
32 (6%)
|
|
|
Hip Replacement Surgery with Extended
Prophylaxis
|
|
|
|
|
|
Peri-operative
Period‡
|
n = 288
|
|
|
|
|
|
4 (2%)
|
|
|
|
|
Extended
Prophylaxis Period§
|
n = 221
0 (0%)
|
|
|
|
|
Knee Replacement Surgery without Extended
Prophylaxis†
|
|
n = 294
3 (1%)
|
n = 225
3 (1%)
|
|
|
|
|
|
|
|
|
Table 4 Major Bleeding Episodes in Medical Patients with Severely
Restricted Mobility During Acute Illness*
|
|
|
Dosing Regimen
|
|
Indications
|
Enoxaparin Sodium
Inj.†
|
Enoxaparin Sodium
Inj.†
|
Placebo†
|
|
20 mg q.d. SC
|
40 mg q.d. SC
|
|
|
*
Bleeding
complications were considered major: (1) if the hemorrhage caused a
significant clinical event, (2) if the hemorrhage caused a decrease in
hemoglobin of ≥ 2 g/dL or transfusion of 2
or more units of blood products. Retroperitoneal and intracranial hemorrhages
were always considered major although none were reported during the trial.
†
The rates represent major bleeding on study
medication up to 24 hours after last dose.
|
|
Medical Patients During Acute Illness
|
n = 351
1 (<1%)
|
n = 360
3 (<1%)
|
n = 362
2 (<1%)
|
Table 5 Major Bleeding Episodes in Deep Vein Thrombosis with or
without Pulmonary Embolism Treatment*
|
|
|
Dosing Regimen†
|
|
Indication
|
Enoxaparin Sodium
Inj.
1.5 mg/kg q.d. SC
|
Enoxaparin Sodium
Inj.
1 mg/kg q12h SC
|
Heparin
aPTT Adjusted IV Therapy
|
|
*
Bleeding
complications were considered major: (1) if the hemorrhage caused a
significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood
products. Retroperitoneal, intraocular, and intracranial hemorrhages were
always considered major.
†
All patients also received warfarin sodium
(dose-adjusted according to PT to achieve an INR of 2.0 to 3.0) commencing
within 72 hours of Enoxaparin Sodium Injection or standard heparin therapy
and continuing for up to 90 days.
|
|
Treatment of DVT and PE
|
n = 298
5 (2%)
|
n = 559
9 (2%)
|
n = 554
9 (2%)
|
Table 6 Major Bleeding Episodes in Unstable Angina and Non-Q-Wave
Myocardial Infarction
|
|
|
Dosing Regimen
|
|
Indication
|
Enoxaparin Sodium
Inj.*
1 mg/kg q12h SC
|
Heparin*
aPTT Adjusted IV Therapy
|
|
*
The rates
represent major bleeding on study medication up to 12 hours after dose.
†
Aspirin
therapy was administered concurrently (100 to 325 mg per day).
‡
Bleeding complications were considered major: (1)
if the hemorrhage caused a significant clinical event, or (2) if accompanied
by a hemoglobin decrease by ≥ 3
g/dL or transfusion of 2 or more units of blood products. Intraocular,
retroperitoneal, and intracranial hemorrhages were always considered major.
|
|
Unstable Angina and Non-Q-Wave MI †,‡
|
n = 1578
17 (1%)
|
n = 1529
18 (1%)
|
Table 7 Major Bleeding Episodes in Acute ST-Segment Elevation
Myocardial Infarction
|
|
|
Dosing Regimen
|
|
Indication
|
Enoxaparin Sodium
Inj.*
Initial 30 mg IV bolus
followed by 1 mg/kg q12h SC
|
Heparin*
aPTT Adjusted IV Therapy
|
|
*
The rates
represent major bleeding (including ICH) up to 30 days
†
Bleedings were considered major if the hemorrhage
caused a significant clinical event associated with a hemoglobin decrease by ≥ 5 g/dL. ICH were always considered major.
|
|
Acute ST-Segment Elevation
|
n = 10176
|
n = 10151
|
|
Myocardial Infarction
|
n (%)
|
n (%)
|
|
-Major
bleeding (including ICH)†
|
211 (2.1)
|
138 (1.4)
|
|
-Intracranial
hemorrhages (ICH)
|
84 (0.8)
|
66 (0.7)
|
Elevations of Serum Aminotransferases
Asymptomatic increases in aspartate (AST [SGOT])
and alanine (ALT [SGPT]) aminotransferase levels greater than three times the
upper limit of normal of the laboratory reference range have been reported in
up to 6.1% and 5.9% of patients, respectively, during treatment with Enoxaparin
Sodium Injection. Similar significant increases in aminotransferase levels have
also been observed in patients and healthy volunteers treated with heparin and
other low molecular weight heparins. Such elevations are fully reversible and
are rarely associated with increases in bilirubin.
Since aminotransferase determinations are important
in the differential diagnosis of myocardial infarction, liver disease, and
pulmonary emboli, elevations that might be caused by drugs like Enoxaparin
Sodium Injection should be interpreted with caution.
Local Reactions
Mild local irritation, pain, hematoma, ecchymosis,
and erythema may follow SC injection of Enoxaparin Sodium Injection.
Adverse Reactions in Patients
Receiving Enoxaparin Sodium Injection for Prophylaxis or Treatment ofDVT,PE:
Other adverse reactions that were thought to be
possibly or probably related to treatment with Enoxaparin Sodium Injection,
heparin, or placebo in clinical trials with patients undergoing hip or knee
replacement surgery, abdominal or colorectal surgery, or treatment for DVT and
that occurred at a rate of at least 2% in the Enoxaparin Sodium Injection
group, are provided below [see Tables 8 to 11].
Table 8 Adverse Reactions Occurring at ≥ 2% Incidence in Enoxaparin Sodium Injection-Treated Patients
Undergoing Abdominal or Colorectal Surgery
|
|
|
Dosing Regimen
|
|
|
Enoxaparin Sodium
Inj.
40 mg q.d. SC
n = 1228
%
|
Heparin
5000 U q8h SC
n = 1234
%
|
|
Adverse Reaction
|
Severe
|
Total
|
Severe
|
Total
|
|
Hemorrhage
|
<1
|
7
|
<1
|
6
|
|
Anemia
|
<1
|
3
|
<1
|
3
|
|
Ecchymosis
|
0
|
3
|
0
|
3
|
Table 9 Adverse Reactions Occurring at ≥ 2% Incidence in Enoxaparin Sodium Injection-Treated Patients
Undergoing Hip or Knee Replacement Surgery
|
|
|
Dosing Regimen
|
|
|
Enoxaparin Sodium
Inj.
40 mg q.d. SC
|
Enoxaparin
Sodium
Inj.
30 mg q12h SC
|
Heparin
15,000 U/24h SC
|
Placebo
q12h SC
|
|
|
Peri-operative
Period
|
Extended Prophylaxis
Period
|
|
|
|
|
|
n = 288*
%
|
n = 131†
%
|
n = 1080
%
|
n = 766
%
|
n = 115
%
|
|
Adverse Reaction
|
Severe
|
Total
|
Severe
|
Total
|
Severe
|
Total
|
Severe
|
Total
|
Severe
|
Total
|
|
*
Data
represent Enoxaparin Sodium Injection 40 mg SC once a day initiated up to 12
hours prior to surgery in 288 hip replacement surgery patients who received
Enoxaparin Sodium Injection peri-operatively in an unblinded fashion in one
clinical trial.
†
Data represent Enoxaparin Sodium Injection 40 mg
SC once a day given in a blinded fashion as extended prophylaxis at the end
of the peri-operative period in 131 of the original 288 hip replacement
surgery patients for up to 21 days in one clinical trial.
|
|
Fever
|
0
|
8
|
0
|
0
|
<1
|
5
|
<1
|
4
|
0
|
3
|
|
Hemorrhage
|
<1
|
13
|
0
|
5
|
<1
|
4
|
1
|
4
|
0
|
3
|
|
Nausea
|
|
|
|
|
<1
|
3
|
<1
|
2
|
0
|
2
|
|
Anemia
|
0
|
16
|
0
|
<2
|
<1
|
2
|
2
|
5
|
<1
|
7
|
|
Edema
|
|
|
|
|
<1
|
2
|
<1
|
2
|
0
|
2
|
|
Peripheral
edema
|
0
|
6
|
0
|
0
|
<1
|
3
|
<1
|
4
|
0
|
3
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Table 10 Adverse Reactions Occurring at ≥ 2% Incidence in Enoxaparin Sodium
Injection-Treated Medical Patients with Severely Restricted Mobility During
Acute Illness
|
|
|
Adverse Reaction
|
Dosing Regimen
|
|
|
Enoxaparin Sodium
Inj.
40 mg q.d. SC
n = 360
%
|
Placebo
q.d. SC
n = 362
%
|
|
|
Dyspnea
|
3.3
|
5.2
|
|
|
Thrombocytopenia
|
2.8
|
2.8
|
|
|
Confusion
|
2.2
|
1.1
|
|
|
Diarrhea
|
2.2
|
1.7
|
|
|
Nausea
|
2.5
|
1.7
|
|
Table 11 Adverse Reactions Occurring at ≥ 2% Incidence in Enoxaparin Sodium
Injection-Treated Patients Undergoing Treatment of Deep Vein Thrombosis with
or without Pulmonary Embolism
|
|
|
Adverse Event
|
Dosing Regimen
|
|
|
Enoxaparin Sodium
Inj.
1.5 mg/kg q.d. SC
n = 298
%
|
Enoxaparin Sodium
Inj.
1 mg/kg q12h SC
n = 559
%
|
Heparin
aPTT Adjusted IV Therapy
n = 544
%
|
|
|
Severe
|
Total
|
Severe
|
Total
|
Severe
|
Total
|
|
|
Injection
Site Hemorrhage
|
0
|
5
|
0
|
3
|
<1
|
<1
|
|
|
Injection
Site Pain
|
0
|
2
|
0
|
2
|
0
|
0
|
|
|
Hematuria
|
0
|
2
|
0
|
<1
|
<1
|
2
|
|
|
|
|
|
|
|
|
|
|
|
|
Adverse Events in Enoxaparin Sodium
Injection-Treated Patients with Unstable Angina or Non-Q-Wave Myocardial
Infarction:
Non-hemorrhagic clinical events reported to be
related to Enoxaparin Sodium Injection therapy occurred at an incidence of ≤
1%.
Non-major hemorrhagic events, primarily injection
site ecchymoses and hematomas, were more frequently reported in patients
treated with SC Enoxaparin Sodium Injection than in patients treated with IV
heparin.
Serious adverse events with Enoxaparin Sodium
Injection or heparin in a clinical trial in patients with unstable angina or
non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in
the Enoxaparin Sodium Injection group are provided below [see Table 12].
Table 12 Serious Adverse Events Occurring at ≥ 0.5% Incidence in Enoxaparin Sodium
Injection-Treated Patients with Unstable Angina or Non-Q-Wave Myocardial
Infarction
|
|
|
Adverse Event
|
Dosing Regimen
|
|
|
Enoxaparin Sodium
Inj.
1 mg/kg q12h SC
n =1578
n (%)
|
Heparin
aPTT Adjusted IV Therapy
n =1529
n (%)
|
|
|
Atrial
fibrillation
|
11 (0.70)
|
3 (0.20)
|
|
|
Heart
failure
|
15 (0.95)
|
11 (0.72)
|
|
|
Lung
edema
|
11 (0.70)
|
11 (0.72)
|
|
|
Pneumonia
|
13 (0.82)
|
9 (0.59)
|
|
Adverse Reactions in Enoxaparin
Sodium Injection-Treated Patients with Acute ST-Segment Elevation Myocardial
Infarction:
In a clinical trial in patients with acute
ST-segment elevation myocardial infarction, the only adverse reaction that
occurred at a rate of at least 0.5% in the Enoxaparin Sodium Injection group
was thrombocytopenia (1.5%).
Postmarketing Experience
The following adverse reactions have been
identified during postapproval use of Enoxaparin Sodium Injection. Because
these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
There have been reports of epidural or spinal
hematoma formation with concurrent use of Enoxaparin Sodium Injection 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 (e.g., nodules,
inflammation, oozing including shock), systemic allergic reactions (e.g., 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 Warnings
and Precautions (5.5)] have been reported.
Cases of hyperkalemia have been reported. Most of
these reports occurred in patients who also had conditions that tend toward the
development of hyperkalemia (e.g., renal dysfunction, concomitant
potassium-sparing drugs, administration of potassium, hematoma in body
tissues). Very rare cases of hyperlipidemia have also been reported, with one
case of hyperlipidemia, with marked hypertriglyceridemia, reported in a
diabetic pregnant woman; causality has not been determined.
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.
Cases of headache, hemorrhagic anemia,
eosinophilia, alopecia, hepatocellular and cholestatic liver injury have been
reported. Osteoperosis has also been reported following long-term
therapy.
Drug Interactions
Whenever possible, agents which may enhance the
risk of hemorrhage should be discontinued prior to initiation of Enoxaparin
Sodium Injection therapy. These agents include medications such as:
anticoagulants, platelet inhibitors including acetylsalicylic acid,
salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or
sulfinpyrazone. If co-administration is essential, conduct close clinical and
laboratory monitoring [see Warnings
and Precautions (5.9)].
USE IN SPECIFIC POPULATIONS
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 Injection to
increase the risk of developmental abnormalities above the background risk.
Fetal Risk Summary
Enoxaparin Sodium Injection 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 Injection 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 Injection affect the safety and the efficacy of the drug
during pregnancy.
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 Injection. 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 SC
doses of enoxaparin up to 15 times the recommended human dose (by
comparison with 2 mg/kg as the maximum recommended daily dose). There was
no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly
needed.
Nursing Mothers
It is not known whether Enoxaparin Sodium Injection
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 Injection, a decision should be made whether to discontinue
nursing or discontinue Enoxaparin Sodium Injection, taking into account the
importance of Enoxaparin Sodium Injection to the mother and the known benefits of
nursing.
Pediatric Use
Safety and effectiveness of Enoxaparin Sodium
Injection in pediatric patients have not been established.
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 Injection in pivotal clinical trials. The efficacy
of Enoxaparin Sodium Injection 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 Injection were
employed. The incidence of bleeding complications was higher in geriatric
patients as compared to younger patients when Enoxaparin Sodium Injection was
administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The
risk of Enoxaparin Sodium Injection-associated bleeding increased with age.
Serious adverse events increased with age for patients receiving Enoxaparin
Sodium Injection. Other clinical experience (including postmarketing
surveillance and literature reports) has not revealed additional differences in
the safety of Enoxaparin Sodium Injection between geriatric and younger
patients. Careful attention to dosing intervals and concomitant medications
(especially antiplatelet medications) is advised. Enoxaparin Sodium Injection
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
IV bolus prior to the normal dosage regimen and had their SC dose adjusted to
0.75 mg/kg every 12 hours [see Dosage
and Administration (2.3)]. The incidence of bleeding
complications was higher in patients ≥65 years of age as compared to younger
patients (<65 years).
Patients with Mechanical Prosthetic
Heart Valves
The use of Enoxaparin Sodium Injection has not been
adequately studied for thromboprophylaxis in patients with mechanical
prosthetic heart valves and has not been adequately studied for long-term use
in this patient population. Isolated cases of prosthetic heart valve thrombosis
have been reported in patients with mechanical prosthetic heart valves who have
received enoxaparin for thromboprophylaxis. Some of these cases were pregnant
women in whom thrombosis led to maternal and fetal deaths. Insufficient data,
the underlying disease and the possibility of inadequate anticoagulation complicate
the evaluation of these cases. Pregnant women with mechanical prosthetic heart
valves may be at higher risk for thromboembolism [see Warnings
and Precautions (5.7)].
Renal Impairment
In patients with renal impairment, there is an
increase in exposure of enoxaparin sodium. All such patients should be observed
carefully for signs and symptoms of bleeding. Because exposure of enoxaparin
sodium is significantly increased in patients with severe renal impairment
(creatinine clearance <30 mL/min), a dosage adjustment is recommended for
therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended
in patients with moderate (creatinine clearance 30–50 mL/min) and mild
(creatinine clearance 50–80 mL/min) renal impairment [see Dosage
and Administration (2.2) and Clinical
Pharmacology (12.3)]. In patients with renal failure,
treatment with enoxaparin has been associated with the development of
hyperkalemia [see Adverse
Reactions (6.2)].
Hepatic Impairment
The impact of hepatic impairment on enoxaparin's
exposure and antithrombotic effect has not been investigated. Caution should be
exercised when administering enoxaparin to patients with hepatic impairment.
Low-Weight Patients
An increase in exposure of enoxaparin sodium with
prophylactic dosages (non-weight adjusted) has been observed in low-weight
women (<45 kg) and low-weight men (<57 kg). All such patients should be
observed carefully for signs and symptoms of bleeding [see Clinical
Pharmacology (12.3)].
Obese Patients
Obese patients are at higher risk for
thromboembolism. The safety and efficacy of prophylactic doses of Enoxaparin
Sodium Injection in obese patients (BMI >30 kg/m2) has not been fully determined and
there is no consensus for dose adjustment. These patients should be observed
carefully for signs and symptoms of thromboembolism.
Overdosage
Accidental overdosage following administration of
Enoxaparin Sodium Injection may lead to hemorrhagic complications. Injected
Enoxaparin Sodium Injection 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 Enoxaparin Sodium Injection injected: 1 mg protamine
sulfate should be administered to neutralize 1 mg Enoxaparin Sodium Injection,
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 Injection 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.
Enoxaparin Sodium Injection
Description
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:
|
<2000
daltons
|
≤20%
|
|
2000 to
8000 daltons
|
≥68%
|
|
>8000
daltons
|
≤18%
|
|
*
X = Percent of polysaccharide chain containing
1,6 anhydro derivative on the reducing end.
|
|
STRUCTURAL FORMULA
|
|
|
R
|
X*=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. Second 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. Second International Low
Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
The Enoxaparin Sodium Injection prefilled syringes
and graduated prefilled syringes are preservative-free and intended for use
only as a single-dose injection [see
Dosage and Administration (2) and How
Supplied (16)].
Enoxaparin Sodium Injection -
Clinical Pharmacology
Mechanism of Action
Enoxaparin is a low molecular weight heparin, which
has antithrombotic properties.
Pharmacodynamics
In humans, enoxaparin given at a dose of 1.5 mg/kg
subcutaneously (SC) is characterized by a higher ratio of anti-Factor Xa to
anti-Factor IIa activity (mean±SD, 14.0±3.1) (based on areas under anti-Factor
activity versus time curves) compared to the ratios observed for heparin
(mean±SD, 1.22±0.13). Increases of up to 1.8 times the control values were seen
in the thrombin time (TT) and the activated partial thromboplastin time (aPTT).
Enoxaparin at a 1 mg/kg dose (100 mg/mL concentration), administered SC every
12 hours to patients in a large clinical trial resulted in aPTT values of 45
seconds or less in the majority of patients (n =1607). A 30 mg IV bolus
immediately followed by a 1 mg/kg SC administration resulted in aPTT
post-injection values of 50 seconds. The average aPTT prolongation value on Day
1 was about 16% higher than on Day 4.
Pharmacokinetics
Absorption: Pharmacokinetic
trials were conducted using the 100 mg/mL formulation. Maximum anti-Factor Xa
and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after SC
injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58
mcg/mL) and 0.38 IU/mL (3.83 mcg/mL) after the 20 mg and the 40 mg clinically
tested SC doses, respectively. Mean (n = 46) peak anti-Factor Xa activity was
1.1 IU/mL at steady state in patients with unstable angina receiving 1 mg/kg SC
every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, after
1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100% in
healthy subjects.
A 30 mg IV bolus immediately followed by a 1 mg/kg
SC every 12 hours provided initial peak anti-Factor Xa levels of 1.16 IU/mL
(n=16) and average exposure corresponding to 84% of steady-state levels. Steady
state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear
over the recommended dosage ranges [see Dosage
and Administration (2)]. After repeated subcutaneous administration
of 40 mg once daily and 1.5 mg/kg once-daily regimens in healthy volunteers,
the steady state is reached on day 2 with an average exposure ratio about 15%
higher than after a single dose. Steady-state enoxaparin activity levels are
well predicted by single-dose pharmacokinetics. After repeated subcutaneous
administration of the 1 mg/kg twice daily regimen, the steady state is reached
from day 4 with mean exposure about 65% higher than after a single dose and
mean peak and trough levels of about 1.2 and 0.52 IU/mL, respectively. Based on
enoxaparin sodium pharmacokinetics, this difference in steady state is expected
and within the therapeutic range.
Although not studied clinically, the 150 mg/mL
concentration of enoxaparin sodium is projected to result in anticoagulant
activities similar to those of 100 mg/mL and 200 mg/mL concentrations at the
same enoxaparin dose. When a daily 1.5 mg/kg SC injection of enoxaparin sodium
was given to 25 healthy male and female subjects using a 100 mg/mL or a 200
mg/mL concentration the following pharmacokinetic profiles were obtained
[see Table
13].
Table 13 Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg SC Once Daily Doses of Enoxaparin Sodium
Using 100 mg/mL or 200 mg/mL Concentrations
|
|
|
Concentration
|
Anti-Xa
|
Anti-IIa
|
Heptest
|
aPTT
|
|
*
Means ± SD at Day 5 and 90% Confidence Interval (CI) of the
ratio
†
Median (range)
|
|
Amax
(IU/mL or Δ sec)
|
100 mg/mL
|
1.37 (±0.23)
|
0.23 (±0.05)
|
105 (±17)
|
19 (±5)
|
|
200 mg/mL
|
1.45 (±0.22)
|
0.26 (±0.05)
|
111 (±17)
|
22 (±7)
|
|
90% CI
|
102–110%
|
|
102–111%
|
|
|
tmax†(h)
|
100 mg/mL
|
3 (2–6)
|
4 (2–5)
|
2.5 (2–4.5)
|
3 (2–4.5)
|
|
200 mg/mL
|
3.5 (2–6)
|
4.5 (2.5–6)
|
3.3 (2–5)
|
3 (2–5)
|
|
AUC (ss)
(h*IU/mL or h*Δ sec)
|
100 mg/mL
|
14.26 (±2.93)
|
1.54 (±0.61)
|
1321 (±219)
|
|
|
200 mg/mL
|
15.43 (±2.96)
|
1.77 (±0.67)
|
1401 (±227)
|
|
|
90% CI
|
105–112%
|
|
103–109%
|
|
Distribution: The volume of
distribution of anti-Factor Xa activity is about 4.3 L.
Elimination: Following
intravenous (IV) dosing, the total body clearance of enoxaparin is 26 mL/min.
After IV dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 40% of radioactivity
and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours.
Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a
single SC dose to about 7 hours after repeated dosing. Significant anti-Factor
Xa activity persists in plasma for about 12 hours following a 40 mg SC once a
day dose.
Following SC dosing, the apparent clearance (CL/F)
of enoxaparin is approximately 15 mL/min.
Metabolism: Enoxaparin sodium is
primarily metabolized in the liver by desulfation and/or depolymerization to
lower molecular weight species with much reduced biological potency. Renal
clearance of active fragments represents about 10% of the administered dose and
total renal excretion of active and non-active fragments 40% of the dose.
Special Populations
Gender: Apparent clearance and Amax derived from
anti-Factor Xa values following single SC dosing (40 mg and 60 mg) were
slightly higher in males than in females. The source of the gender difference
in these parameters has not been conclusively identified; however, body weight
may be a contributing factor.
Geriatric: Apparent clearance
and Amax derived from
anti-Factor Xa values following single and multiple SC dosing in geriatric
subjects were close to those observed in young subjects. Following once a day
SC dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor Xa
activity versus time curve (AUC) was approximately 15% greater than the mean Day
1 AUC value [see Dosage
and Administration (2.3) and Use
in Specific Populations (8.5)].
Renal Impairment: A linear
relationship between anti-Factor Xa plasma clearance and creatinine clearance
at steady-state has been observed, which indicates decreased clearance of
enoxaparin sodium in patients with reduced renal function. Anti-Factor Xa exposure
represented by AUC, at steady-state, is marginally increased in mild
(creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–50
mL/min) renal impairment after repeated subcutaneous 40 mg once-daily doses. In
patients with severe renal impairment (creatinine clearance <30 mL/min), the
AUC at steady-state is significantly increased on average by 65% after repeated
subcutaneous 40 mg once-daily doses [see Dosage
and Administration (2.2) and Use
in Specific Populations (8.7)].
Hemodialysis: In a single study,
elimination rate appeared similar but AUC was two-fold higher than control
population, after a single 0.25 or 0.5 mg/kg intravenous dose.
Hepatic Impairment: Studies with
enoxaparin in patients with hepatic impairment have not been conducted and the
impact of hepatic impairment on the exposure to enoxaparin is unknown [see Use
in Specific Populations (8.8)].
Weight: After repeated subcutaneous 1.5
mg/kg once daily dosing, mean AUC of anti-Factor Xa activity is marginally
higher at steady-state in obese healthy volunteers (BMI 30–48 kg/m2) compared to non-obese
control subjects, while Amax is not increased. When non-weight adjusted
dosing was administered, it was found after a single-subcutaneous 40 mg dose,
that anti-Factor Xa exposure is 52% higher in low-weight women (<45 kg) and
27% higher in low-weight men (< 57 kg) when compared to normal weight
control subjects [see Use
in Specific Populations (8.9)].
Pharmacokinetic interaction: No pharmacokinetic
interaction was observed between enoxaparin and thrombolytics when administered
concomitantly.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis,
Impairment of Fertility
No long-term studies in animals have been performed
to evaluate the carcinogenic potential of enoxaparin. Enoxaparin was not
mutagenic in in vitro tests, including the Ames test,
mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal
aberration test, and the in vivo rat bone marrow chromosomal
aberration test. Enoxaparin was found to have no effect on fertility or
reproductive performance of male and female rats at SC doses up to 20 mg/kg/day
or 141 mg/m2/day. The maximum human dose in clinical trials was
2.0 mg/kg/day or 78 mg/m2/day (for an average body weight of
70 kg, height of 170 cm, and body surface area of 1.8 m2).
Animal Toxicology and/or Pharmacology
A single SC dose of 46.4 mg/kg enoxaparin was
lethal to rats. The symptoms of acute toxicity were ataxia, decreased motility,
dyspnea, cyanosis, and coma.
Reproductive and Developmental
Toxicology
Teratology studies have been conducted in pregnant
rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day corresponding to
211 mg/m2/day and 410 mg/m2/day in rats and rabbits
respectively. There was no evidence of teratogenic effects or fetotoxicity due
to enoxaparin.
Clinical Studies
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 Injection 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 Table
14].
Table 14 Efficacy of Enoxaparin Sodium Injection in the Prophylaxis
of Deep Vein Thrombosis Following Abdominal Surgery
|
|
|
Indication
|
Dosing Regimen
|
|
|
Enoxaparin Sodium
Inj.
40 mg q.d. SC
n (%)
|
Heparin
5000 U q8h SC
n (%)
|
|
|
*
VTE =
Venous thromboembolic events which included DVT, PE, and death considered to
be thromboembolic in origin.
†
CI = Confidence Interval
|
|
|
All
Treated Abdominal Surgery Patients
|
555 (100)
|
560 (100)
|
|
|
Treatment
Failures
|
|
|
|
|
Total VTE* (%)
|
56 (10.1)
(95% CI†: 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 Injection 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 Table
15].
Table 15 Efficacy of Enoxaparin Sodium Injection in the Prophylaxis
of Deep Vein Thrombosis Following Colorectal Surgery
|
|
|
Dosing Regimen
|
|
|
Enoxaparin Sodium
Inj.
|
Heparin
|
|
Indication
|
40 mg q.d. SC
n (%)
|
5000 U q8h SC
n (%)
|
|
*
VTE =
Venous thromboembolic events which included DVT, PE, and death considered to
be thromboembolic in origin.
†
CI = Confidence Interval
|
|
All
Treated Colorectal Surgery Patients
|
673 (100)
|
674 (100)
|
|
Treatment
Failures
Total VTE* (%)
|
48 (7.1)
(95% CI† : 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)
|
Prophylaxis of Deep Vein Thrombosis
Following Hip or Knee Replacement Surgery
Enoxaparin Sodium Injection 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, Enoxaparin Sodium
Injection 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 Table
16].
Table 16 Efficacy of Enoxaparin Sodium Injection in the Prophylaxis
of Deep Vein Thrombosis Following Hip Replacement Surgery
|
|
Indication
|
Dosing Regimen
|
|
Enoxaparin Sodium
Inj.
30 mg q12h SC
n (%)
|
Placebo
q12h SC
n (%)
|
|
|
|
|
*
p value
versus placebo = 0.0002
†
p value versus placebo = 0.0002
|
|
All
Treated Hip Replacement Patients
|
50 (100)
|
50 (100)
|
|
Treatment
Failures
|
|
|
|
Total DVT
(%)
|
5 (10)*
|
23 (46)
|
|
Proximal
DVT (%)
|
1 (2)†
|
11 (22)
|
A double-blind, multicenter study compared three
dosing regimens of Enoxaparin Sodium Injection 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 Injection in the Prophylaxis
of Deep Vein Thrombosis Following Hip Replacement Surgery
|
|
Indication
|
Dosing Regimen
|
|
10 mg q.d. SC
n (%)
|
30 mg q12h SC
n (%)
|
40 mg q.d. SC
n (%)
|
|
|
|
|
|
*
p value
versus placebo = 0.0002
†
p value versus placebo = 0.0002
|
|
All
Treated Hip Replacement Patients
|
161 (100)
|
208 (100)
|
199 (100)
|
|
Treatment
Failures
|
|
|
|
|
Total DVT
(%)
|
40 (25)
|
22 (11)*
|
27 (14)
|
|
Proximal
DVT (%)
|
17 (11)
|
8 (4)†
|
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 Injection 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 Enoxaparin Sodium Injection compared
to placebo. The efficacy data are provided below [see Table
18].
Table 18 Efficacy of Enoxaparin Sodium Injection in the Prophylaxis
of Deep Vein Thrombosis Following Total Knee Replacement Surgery
|
|
Indication
|
Dosing Regimen
|
|
Enoxaparin Sodium
Inj.
30 mg q12h SC
n (%)
|
Placebo
q12h SC
n (%)
|
|
|
|
|
*
p value
versus placebo = 0.0002
†
p value
versus placebo = 0.0002
‡
p value
versus placebo = 0.0002
§
p value versus placebo = 0.0002
|
|
All
Treated Total Knee Replacement Patients
|
47 (100)
|
52 (100)
|
|
Treatment
Failures
|
5 (11)*
|
32 (62)
|
|
Total DVT
(%)
|
(95% CI†: 1
to 21)
|
(95% CI: 47 to 76)
|
|
Proximal
DVT (%)
|
0 (0)‡
(95% Upper CL§: 5)
|
7 (13)
(95% CI: 3 to 24)
|
Additionally, in an open-label, parallel group,
randomized clinical study, Enoxaparin Sodium Injection 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 Enoxaparin Sodium Injection 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 Injection 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 Enoxaparin Sodium Injection 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 Enoxaparin
Sodium Injection compared to placebo. The efficacy data are provided below
[see Table
19].
Table 19 Efficacy of Enoxaparin Sodium Injection in the Extended
Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery
|
|
Indication (Post-Discharge)
|
Post-Discharge Dosing Regimen
|
|
Enoxaparin Sodium
Inj.
40 mg q.d. SC
n (%)
|
Placebo
q.d. SC
n (%)
|
|
|
|
|
*
p value
versus placebo = 0.0002
†
p value versus
placebo = 0.0002
‡
p value versus placebo = 0.0002
|
|
All
Treated Extended Prophylaxis Patients
|
90 (100)
|
89 (100)
|
|
Treatment
Failures
Total DVT (%)
|
6 (7)*
(95% CI†: 3
to 14)
|
18 (20)
(95% CI: 12 to 30)
|
|
Proximal
DVT (%)
|
5 (6)‡
(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
Injection 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 Enoxaparin
Sodium Injection 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
Enoxaparin Sodium Injection compared to placebo, with a statistically
significant difference in both total DVT (Enoxaparin Sodium Injection 21 [16%]
versus placebo 45 [34%]; p = 0.001) and proximal DVT (Enoxaparin Sodium
Injection 8 [6%] versus placebo 28 [21%]; p = <0.001).
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 Injection 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 <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 SC, Enoxaparin Sodium Injection
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 Injection in the Prophylaxis
of Deep Vein Thrombosis in Medical Patients with Severely Restricted
Mobility During Acute Illness
|
|
|
Indication
|
Dosing Regimen
|
|
|
Enoxaparin Sodium
Inj.
20 mg q.d. SC
|
Enoxaparin Sodium
Inj.
40 mg q.d. SC
|
Placebo
|
|
|
n (%)
|
n (%)
|
n (%)
|
|
|
*
Treatment
failures during therapy, between Days 1 and 14.
†
VTE =
Venous thromboembolic events which included DVT, PE, and death considered to
be thromboembolic in origin.
‡
CI = Confidence Interval
|
|
|
All
Treated Medical Patients During Acute Illness
|
351 (100)
|
360 (100)
|
362 (100)
|
|
|
Treatment
Failure*
Total VTE† (%)
|
43 (12.3)
|
16 (4.4)
|
43 (11.9)
|
|
|
Total DVT
(%)
|
43 (12.3)
(95% CI‡ 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 significantly lower in the
Enoxaparin Sodium Injection 40 mg treatment group versus the placebo treatment
group.
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 Injection 1.5 mg/kg once a day SC, (ii) Enoxaparin
Sodium Injection 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 Enoxaparin
Sodium Injection or standard heparin therapy, and continuing for 90 days.
Enoxaparin Sodium Injection or standard heparin therapy was administered for a
minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both
Enoxaparin Sodium Injection 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 Injection in Treatment of Deep
Vein Thrombosis with or without Pulmonary Embolism
|
|
|
Indication
|
Dosing Regimen*
|
|
|
Enoxaparin Sodium
Inj.
1.5 mg/kg q.d. SC
n (%)
|
Enoxaparin Sodium
Inj.
1 mg/kg q12h SC
n (%)
|
Heparin
aPTT Adjusted
IV Therapy
n (%)
|
|
|
*
All
patients were also treated with warfarin sodium commencing within 72 hours of
Enoxaparin Sodium Injection or standard heparin therapy.
†
VTE =
venous thromboembolic event (DVT and/or PE).
‡
The 95% Confidence Intervals for the treatment
differences for total VTE were: Enoxaparin Sodium Injection once a day versus
heparin (-3.0 to 3.5) Enoxaparin Sodium Injection every 12 hours versus
heparin (-4.2 to 1.7).
|
|
|
All
Treated DVT Patients with or without PE
|
298 (100)
|
312 (100)
|
290 (100)
|
|
|
Patient
Outcome
Total VTE† (%)
|
13 (4.4)‡
|
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 Injection 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 Enoxaparin Sodium
Injection 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 Injection 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. Enoxaparin Sodium Injection or standard heparin therapy was
administered for a minimum of 5 days. Enoxaparin Sodium Injection 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 Injection in Treatment of Deep
Vein Thrombosis
|
|
|
Indication
|
Dosing Regimen*
|
|
|
Enoxaparin Sodium
Inj.
1 mg/kg q12h SC
n (%)
|
Heparin
aPTT Adjusted
IV Therapy
n (%)
|
|
|
*
All
patients were also treated with warfarin sodium commencing on the evening of
the second day of Enoxaparin Sodium Injection or standard heparin therapy.
†
VTE =
venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary
embolism [PE]).
‡
The 95% Confidence Intervals for the treatment
difference for total VTE was: Enoxaparin Sodium Injection versus heparin
(-5.6 to 2.7).
|
|
|
All
Treated DVT Patients
|
247 (100)
|
254 (100)
|
|
|
Patient
Outcome
Total VTE† (%)
|
13 (5.3)‡
|
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)
|
|
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 Injection 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. 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
Injection 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 Injection 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 Regimen*
|
|
|
|
|
Enoxaparin Sodium
Inj.
1 mg/kg q12h SC
n (%)
|
Heparin
aPTT Adjusted
IV Therapy
n (%)
|
Reduction
(%)
|
p Value
|
|
|
*
All
patients were also treated with aspirin 100 to 325 mg per day.
†
Evaluation timepoints are after initiation of
treatment. Therapy continued for up to 8 days (median duration of 2.6 days).
|
|
|
All
Treated Unstable Angina and Non-Q-Wave MI Patients
|
1578 (100)
|
1529 (100)
|
|
|
|
|
Timepoint †
|
|
|
|
|
|
|
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 Injection
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 Injection in the Prophylaxis
of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial
Infarction (Combined Endpoint of Death or Myocardial Infarction)
|
|
|
Dosing Regimen*
|
|
|
|
Indication
|
Enoxaparin Sodium
Inj.
1 mg/kg q12h SC
n (%)
|
Heparin
aPTT Adjusted
IV Therapy
n (%)
|
Reduction
(%)
|
p Value
|
|
*
All
patients were also treated with aspirin 100 to 325 mg per day.
†
Evaluation timepoints are after initiation of
treatment. Therapy continued for up to 8 days (median duration of 2.6 days).
|
|
All
Treated Unstable Angina and Non-Q-Wave MI Patients
|
1578 (100)
|
1529 (100)
|
|
|
|
Timepoint †
|
|
|
|
|
|
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 Injection versus heparin (32.0% vs 35.7%).
Urgent revascularization procedures were performed
less frequently in the Enoxaparin Sodium Injection group as compared to the
heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
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 Injection 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, i.e. 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 Table
25].
Table 25 Efficacy of Enoxaparin Sodium Injection 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 Subgroups *
|
|
*
The 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 percent 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%).
How Supplied/Storage and Handling
Enoxaparin Sodium Injection is available in two
concentrations [see Tables
26 and 27]:
Table 26 100 mg/mL Concentration
|
|
Dosage Unit/Strength *
|
Anti-Xa Activity †
|
Package Size
(per carton)
|
Syringe Label Color
|
NDC# 0548-
|
|
|
|
|
|
|
|
|
|
|
|
|
|
*
Strength
represents the number of milligrams of enoxaparin sodium in Water for
Injection. Enoxaparin Sodium Injection, 30 and 40 mg prefilled syringes, and
60, 80, and 100 mg graduated prefilled syringes each contain
†
Strength
represents the number of milligrams of enoxaparin sodium in Water for
Injection. Enoxaparin Sodium Injection, 30 and 40 mg prefilled syringes, and
60, 80, and 100 mg graduated prefilled syringes each contain
‡
Each Enoxaparin Sodium Injection prefilled
syringe is for single, one-time use only and is affixed with a 27 gauge × 1/2 inch needle.
|
|
Prefilled Syringes‡
30 mg/0.3 mL
|
3000
IU
|
10
syringes
|
Medium
Blue
|
5631-00
|
|
40
mg/0.4 mL
|
4000
IU
|
10
syringes
|
Yellow
|
5632-00
|
|
Graduated Prefilled Syringes‡
|
|
|
|
|
|
60
mg/0.6 mL
|
6000
IU
|
10
syringes
|
Orange
|
5633-00
|
|
80
mg/0.8 mL
|
8000
IU
|
10
syringes
|
Brown
|
5634-00
|
|
100
mg/1 mL
|
10,000
IU
|
10
syringes
|
Black
|
5635-00
|
Table 27 150 mg/mL Concentration
|
|
Dosage Unit /Strength *
|
Anti-Xa Activity †
|
Package Size
(per carton)
|
Syringe Label Color
|
NDC # 0548-
|
|
|
|
|
|
|
|
|
|
|
|
|
|
*
Strength
represents the number of milligrams of enoxaparin sodium in Water for
Injection. Enoxaparin Sodium Injection, 30 and 40 mg prefilled syringes, and
60, 80, and 100 mg graduated prefilled syringes each contain
†
Strength
represents the number of milligrams of enoxaparin sodium in Water for
Injection. Enoxaparin Sodium Injection, 30 and 40 mg prefilled syringes, and
60, 80, and 100 mg graduated prefilled syringes each contain
‡
Strength represents the number of milligrams of
enoxaparin sodium in Water for Injection. Enoxaparin Sodium Injection, 30 and
40 mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes
each contain
|
|
Graduated Prefilled Syringes ‡
|
|
|
|
|
|
120
mg/0.8 mL
|
12,000
IU
|
10
syringes
|
Purple
|
5636-00
|
|
150
mg/1 mL
|
15,000
IU
|
10
syringes
|
Navy
Blue
|
5637-00
|
|
|
|
|
|
|
|
Store at 25°C (77°F); excursions permitted to
15–30°C (59–86°F) [See USP Controlled Room Temperature].
Keep out of the reach of children.
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 NSAID's
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 [see Drug
Interactions (7)].
Patients should also be informed:
of the instructions for injecting
Enoxaparin Sodium Injection if their therapy is to continue after
discharge from the hospitals.it may take them longer than usual
to stop bleeding.they may bruise and/or bleed more
easily when they are treated with Enoxaparin Sodium Injection.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)].to tell their physicians and
dentists they are taking Enoxaparin Sodium Injection 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 NSAID's [see
Drug
Interactions (7)].
Manufactured for Amerinet Choice by
Amphastar Pharmaceuticals, Inc.
Rancho Cucamonga, CA 91730 U.S.A.
