Endosa Syringes is indicated in adults for:
• Prophylaxis of venous thromboembolic disease in moderate and high risk
surgical patients, in particular those undergoing orthopaedic or general surgery
including cancer surgery.
• Prophylaxis of venous thromboembolic disease in medical patients with an
acute illness (such as acute heart failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased risk of
venous thromboembolism.
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE),
excluding PE likely to require thrombolytic therapy or surgery.
• Prevention of thrombus formation in extra corporeal circulation during
haemodialysis.
• Acute coronary syndrome:
- Treatment of unstable angina and Non ST-segment elevation myocardial
infarction (NSTEMI), in combination with oral acetylsalicylic acid.
- Treatment of acute ST-segment elevation myocardial infarction (STEMI)
including patients to be managed medically or with subsequent percutaneous
coronary intervention (PCI).

Posology
Prophylaxis of venous thromboembolic disease in moderate and high risk
surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk
stratification model.
• In patients at moderate risk of thromboembolism, the recommended dose of
enoxaparin sodium is 2,000 IU (20 mg) once daily by subcutaneous (SC)
injection. Preoperative initiation (2 hours before surgery) of enoxaparin sodium
2,000 IU (20 mg) was proven effective and safe in moderate risk surgery.
In moderate risk patients, enoxaparin sodium treatment should be maintained for
a minimal period of 7-10 days whatever the recovery status (e.g. mobility).
Prophylaxis should be continued until the patient no longer has significantly
reduced mobility.
• In patients at high risk of thromboembolism, the recommended dose of
enoxaparin sodium is 4,000 IU (40 mg) once daily given by SC injection
preferably started 12 hours before surgery. If there is a need for earlier than 12
hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk
patient waiting for a deferred orthopaedic surgery), the last injection should be
administered no later than 12 hours prior to surgery and resumed 12 hours after
surgery.
o For patients who undergo major orthopaedic surgery an extended
thromboprophylaxis up to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo
abdominal or pelvic surgery for cancer an extended thromboprophylaxis up to 4
weeks is recommended.
Prophylaxis of venous thromboembolism in medical patients
The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by
SC injection. Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days
whatever the recovery status (e.g. mobility). The benefit is not established for a
treatment longer than 14 days.
Treatment of DVT and PE
Enoxaparin sodium can be administered SC either as a once daily injection of
150 IU/kg (1.5 mg/kg) or as twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual
assessment including evaluation of the thromboembolic risk and of the risk of
bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg) administered once daily
should be used in uncomplicated patients with low risk of VTE recurrence. The
dose regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in
all other patients such as those with obesity, with symptomatic PE, cancer,
recurrent VTE or proximal (vena iliaca) thrombosis.
Enoxaparin sodium treatment is prescribed for an average period of 10 days.
Oral anticoagulant therapy should be initiated when appropriate (see “Switch
between enoxaparin sodium and oral anticoagulants” at the end of section 4.2).
Prevention of thrombus formation during haemodialysis
The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50
IU/kg (0.5 mg/kg) for double vascular access or 75 IU/kg (0.75 mg/kg) for single
vascular access.
During haemodialysis, enoxaparin sodium should be introduced into the arterial
line of the circuit at the beginning of the dialysis session. The effect of this dose
is usually sufficient for a 4-hour session; however, if fibrin rings are found, for
example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.
No data are available in patients using enoxaparin sodium for prophylaxis or
treatment and during haemodialysis sessions.
Acute coronary syndrome: treatment of unstable angina and NSTEMI and
treatment of acute STEMI
• For treatment of unstable angina and NSTEMI, the recommended dose of
enoxaparin sodium is 100 IU/kg (1 mg/kg) every 12 hours by SC injection
administered in combination with antiplatelet therapy. Treatment should be
maintained for a minimum of 2 days and continued until clinical stabilization. The
usual duration of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at
an initial oral loading dose of 150–300 mg (in acetylsalicylic acid-naive patients)
and a maintenance dose of 75–325 mg/day long-term regardless of treatment
strategy.
• For treatment of acute STEMI, the recommended dose of enoxaparin sodium is
a single intravenous (IV) bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg)
SC dose followed by 100 IU/kg (1 mg/kg) administered SC every 12 hours
(maximum 10,000 IU (100 mg) for each of the first two SC doses). Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg to 325 mg once daily)
should be administered concomitantly unless contraindicated. The recommended
duration of treatment is 8 days or until hospital discharge, whichever comes first.
When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin
specific), enoxaparin sodium should be given between 15 minutes before and 30
minutes after the start of fibrinolytic therapy.
o For dosage in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last dose of enoxaparin sodium SC was
given less than 8 hours before balloon inflation, no additional dosing is needed. If
the last SC administration was given more than 8 hours before balloon inflation,
an IV bolus of 30 IU/kg (0.3 mg/kg) enoxaparin sodium should be administered.
Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not
been established.
Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly
patients, unless kidney function is impaired (see below “renal impairment” and
section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial IV
bolus must not be used. Initiate dosing with 75 IU/kg (0.75 mg/kg) SC every 12
hours (maximum 7,500 IU (75 mg) for each of the first two SC doses only,
followed by 75 IU/kg (0.75 mg/kg) SC dosing for the remaining doses). For
dosage in elderly patients with impaired kidney function, see below “renal
impairment” and section 4.4.
Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1
and 5.2) and caution should be used in these patients (see section 4.4).
Renal impairment (see sections 4.4 and 5.2)
• Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal
disease (creatinine clearance <15 ml/min) due to lack of data in this population
outside the prevention of thrombus formation in extra corporeal circulation during
haemodialysis.
Dosage table for patients with severe renal impairment (creatinine clearance [15-
30] ml/min): 

Indication	Dosing regimen
Prophylaxis of venous thromboembolic disease	2,000 IU (20 mg) SC once daily
Treatment of DVT and PE	100 IU/kg (1 mg/kg) body weight SC once daily
Treatment of unstable angina and NSTEMI	100 IU/kg (1 mg/kg) body weight SC once daily
Treatment of acute STEMI (patients under 75) Treatment of acute STEMI (patients over 75)	1 x 3,000 IU (30 mg) IV bolus plus 100 IU/kg (1 mg/kg) body weight SC and then 100 IU/kg (1 mg/kg) body weight SC every 24 hours No IV initial bolus, 100 IU/kg (1 mg/kg) body weight SC and then 100 IU/kg (1 mg/kg) body weight SC every 24 hours

The recommended dosage adjustments do not apply to the haemodialysis
indication.
• Moderate and mild 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, careful clinical monitoring is advised.
Method of administration
Endosa Syringes should not be administered by the intramuscular route.
For the prophylaxis of venous thrombo-embolic disease following surgery,
treatment of DVT and PE, treatment of unstable angina and NSTEMI, enoxaparin
sodium should be administered by SC injection.
• For acute STEMI, treatment is to be initiated with a single IV bolus injection
immediately followed by a SC injection.
• For the prevention of thrombus formation in the extra corporeal circulation
during haemodialysis, it is administered through the arterial line of a dialysis
circuit.
The pre-filled disposable syringe is ready for immediate use.
• SC injection technique:
Injection should be made preferably when the patient is lying down. Enoxaparin
sodium is administered by deep SC injection.
Do not expel the air bubble from the syringe before the injection to avoid the loss
of drug when using pre-filled syringes. When the quantity of drug to be injected
requires to be adjusted based on the patient's body weight, use the graduated
pre-filled syringes to reach the required volume by discarding the excess before
injection. Please be aware that in some cases it is not possible to achieve an
exact dose due to the graduations on the syringe, and in such case the volume
shall be rounded up to the nearest graduation.
The administration should be alternated between the left and right anterolateral
or posterolateral abdominal wall.
The whole length of the needle should be introduced vertically into a skin fold
gently held between the thumb and index finger. The skin fold should not be
released until the injection is complete. Do not rub the injection site after
administration. Note for the pre-filled syringes fitted with an automatic safety system: The safety
system is triggered at the end of the injection (see instructions in section 6.6).
In case of self-administration, patient should be advised to follow instructions
provided in the patient information leaflet included in the pack of this medicine.
• IV (bolus) injection (for acute STEMI indication only):
For acute STEMI, treatment is to be initiated with a single IV bolus injection
immediately followed by a SC injection.
For IV injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an IV line. It should not be
mixed or co-administered with other medications. To avoid the possible mixture
of enoxaparin sodium with other drugs, the IV access chosen should be flushed
with a sufficient amount of saline or dextrose solution prior to and following the IV
bolus administration of enoxaparin sodium to clear the port of drug. Enoxaparin
sodium may be safely administered with normal saline solution (0.9%) or 5%
dextrose in water.
o Initial 3,000 IU (30 mg) bolus
For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated
pre-filled syringe, expel the excessive volume to retain only 3,000 IU (30 mg) in
the syringe. The 3,000 IU (30 mg) dose can then be directly injected into the IV
line.
o Additional bolus for PCI when last SC administration was given more than 8
hours before balloon inflation
For patients being managed with PCI, an additional IV bolus of 30 IU/kg (0.3
mg/kg) is to be administered if last SC administration was given more than 8
hours before balloon inflation.
In order to assure the accuracy of the small volume to be injected, it is
recommended to dilute the drug to 300 IU/ml (3 mg/ml).
To obtain a 300 IU/ml (3 mg/ml) solution, using a 6,000 IU (60 mg) enoxaparin
sodium pre-filled syringe, it is recommended to use a 50 ml infusion bag (i.e.
using either normal saline solution (0.9%) or 5% dextrose in water) as follows:
Withdraw 30 ml from the infusion bag with a syringe and discard the liquid. Inject
the complete contents of the 6,000 IU (60 mg) enoxaparin sodium pre-filled
syringe into the 20 ml remaining in the bag. Gently mix the contents of the bag.
Withdraw the required volume of diluted solution with a syringe for administration
into the IV line.
After dilution is completed, the volume to be injected can be calculated using the
following formula [Volume of diluted solution (ml) = Patient weight (kg) x 0.1] or
using the table below. It is recommended to prepare the dilution immediately
before use.
Volume to be injected through IV line after dilution is completed at a
concentration of 300 IU (3 mg) /ml.

Weight	Required dose 30 IU/kg (0.3 mg/kg)		Volume to inject when diluted to a final concentration of 300 IU (3 mg) / ml
[Kg]	IU	[mg]	[ml]
45	1350	13.5	4.5
50	1500	15	5
55	1650	16.5	5.5
60	1800	18	6
65	1950	19.5	6.5
70	2100	21	7
75	2250	22.5	7.5
80	2400	24	8
85	2550	25.5	8.5
90	2700	27	9
95	2850	28.5	9.5
100	3000	30	10
105	3150	31.5	10.5
110	3300	33	11
115	3450	34.5	11.5
120	3600	36	12
125	3750	37.5	12.5
130	3900	39	13
135	4050	40.5	13.5
140	4200	42	14
145	4350	43.5	14.5
150	4500	45	15

• Arterial line injection:
It is administered through the arterial line of a dialysis circuit for the prevention of
thrombus formation in the extra corporeal circulation during haemodialysis.
Switch between enoxaparin sodium and oral anticoagulants
• Switch between enoxaparin sodium and vitamin K antagonists (VKA)
Clinical monitoring and laboratory tests [prothrombin time expressed as the
International Normalized
Ratio (INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin
sodium therapy should be continued at a constant dose for as long as necessary
in order to maintain the INR within the desired therapeutic range for the indication
in two successive tests.

For patients currently receiving a VKA, the VKA should be discontinued and the
first dose of enoxaparin sodium should be given when the INR has dropped
below the therapeutic range.
• Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)
For patients currently receiving enoxaparin sodium, discontinue enoxaparin
sodium and start the DOAC 0 to 2 hours before the time that the next scheduled
administration of enoxaparin sodium would be due as per DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium
should be given at the time the next DOAC dose would be taken.
Administration in spinal/epidural anaesthesia or lumbar puncture
Should the physician decide to administer anticoagulation in the context of
epidural or spinal anaesthesia/analgesia or lumbar puncture, careful neurological
monitoring is recommended due to the risk of neuraxial haematomas (see
section 4.4).

- At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of
enoxaparin sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before
removing the catheter.
For patients with creatinine clearance [15-30] ml/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible
with neuraxial anaesthesia.
- At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of
enoxaparin sodium at curative doses and the needle or catheter placement (see also section
4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] ml/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.
Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg (1
mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a
guarantee that neuraxial hematoma will be avoided.
Likewise, consider not using enoxaparin sodium until at least 4 hours after the
spinal/epidural puncture or after the catheter has been removed. The delay must
be 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.

Enoxaparin sodium is contraindicated in patients with: • Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins (LMWH) or to any of the excipients listed in section 6.1; • History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies (see also section 4.4 ); • Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding, recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities; • Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for treatment in the previous 24 hours (see section 4.4).

• General
Enoxaparin sodium cannot be used interchangeably (unit for unit) with other
LMWHs. These medicinal products differ in their manufacturing process,
molecular weights, specific anti-Xa and anti-IIa activities, units, dosage and
clinical efficacy and safety. This results in differences in pharmacokinetics and
associated biological activities (e.g. anti-thrombin activity, and platelet
interactions). Special attention and compliance with the instructions for use
specific to each proprietary medicinal product are therefore required.
• History of HIT (>100 days)
Use of enoxaparin sodium in patients with a history of immune mediated HIT
within the past 100 days or in the presence of circulating antibodies is
contraindicated (see section 4.3). Circulating antibodies may persist several
years.
Enoxaparin sodium is to be used with extreme caution in patients with a history
(>100 days) of heparin-induced thrombocytopenia without circulating antibodies.
The decision to use enoxaparin sodium in such a case must be made only after a
careful benefit risk assessment and after non-heparin alternative treatments are
considered (e.g. danaparoid sodium or lepirudin).
• Monitoring of platelet counts
The risk of antibody-mediated HIT also exists with LMWHs. Should
thrombocytopenia occur, it usually appears between the 5th and the 21st day
following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac
surgery and in patients with cancer.
Therefore, it is recommended that the platelet counts be measured before the
initiation of therapy with enoxaparin sodium and then regularly thereafter during
the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial
and/or venous thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), platelet count should be
measured. Patients must be aware that these symptoms may occur and if so,
that they should inform their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed
(30 to 50 % of the initial value), enoxaparin sodium treatment must be
immediately discontinued and the patient switched to another non-heparin
anticoagulant alternative treatment.
• Haemorrhage
As with other anticoagulants, bleeding may occur at any site. If bleeding occurs,
the origin of the haemorrhage should be investigated and appropriate treatment
instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with
caution in conditions with increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medications affecting haemostasis (see section 4.5).
• Laboratory tests
At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium
does not influence bleeding time and global blood coagulation tests significantly,
nor does it affect platelet aggregation or binding of fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and
activated clotting time (ACT) may occur. Increases in aPTT and ACT are not
linearly correlated with increasing enoxaparin sodium antithrombotic activity and
therefore are unsuitable and unreliable for monitoring enoxaparin sodium activity.
• Spinal/Epidural anaesthesia or lumbar puncture
Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24
hours of administration of enoxaparin sodium at therapeutic doses (see also
section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent
use of enoxaparin sodium and spinal/epidural anaesthesia or spinal puncture
procedures resulting in long term or permanent paralysis. These events are rare
with enoxaparin sodium dosage regimens 4,000 IU (40 mg) once daily or lower.
The risk of these events is higher with the use of post-operative indwelling
epidural catheters, with the concomitant use of additional drugs affecting
haemostasis such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), with
traumatic or repeated epidural or spinal puncture, or in patients with a history of
spinal surgery or spinal deformity. To reduce the potential risk of bleeding associated with the concurrent use of
enoxaparin sodium and epidural or spinal anaesthesia/analgesia or spinal
puncture, consider the pharmacokinetic profile of enoxaparin sodium (see section
5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however,
the exact timing to reach a sufficiently low anticoagulant effect in each patient is
not known. For patients with creatinine clearance [15-30 ml/minute], additional
considerations are necessary because elimination of enoxaparin sodium is more
prolonged (see section 4.2).
Should the physician decide to administer anticoagulation in the context of
epidural or spinal anaesthesia/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.
• Skin necrosis / cutaneous vasculitis
Skin necrosis and cutaneous vasculitis have been reported with LMWHs and
should lead to prompt treatment discontinuation.
• Percutaneous coronary revascularization procedures
To minimize the risk of bleeding following the vascular instrumentation during the
treatment of unstable angina, NSTEMI and acute STEMI, adhere precisely to the
intervals recommended between enoxaparin sodium injection doses. It is
important to achieve haemostasis 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.
• Acute infective endocarditis
Use of heparin is usually not recommended in patients with acute infective
endocarditis due to the risk of cerebral haemorrhage. If such use is considered
absolutely necessary, the decision must be made only after a careful individual
benefit risk assessment.
• Mechanical prosthetic heart valves
The use of enoxaparin sodium has not been adequately studied for
thromboprophylaxis in patients with mechanical prosthetic heart valves. Isolated
cases of prosthetic heart valve thrombosis have been reported in patients with
mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit the evaluation of these cases. Some of these cases
were pregnant women in whom thrombosis led to maternal and foetal death.
• Pregnant women with mechanical prosthetic heart valves
The use of enoxaparin sodium for thromboprophylaxis in pregnant women with
mechanical prosthetic heart valves has not been adequately studied. In a clinical
study of pregnant women with mechanical prosthetic heart valves given
enoxaparin sodium (100 IU/kg (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 foetal death. There have been isolated postmarketing
reports of valve thrombosis in pregnant women with mechanical
prosthetic heart valves while receiving enoxaparin sodium for
thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves
may be at higher risk for thromboembolism.
• Elderly
No increased bleeding tendency is observed in the elderly with the prophylactic
dosage ranges. Elderly patients (especially patients eighty years of age and
older) may be at an increased risk for bleeding complications with the therapeutic
dosage ranges. Careful clinical monitoring is advised and dose reduction might
be considered in patients older than 75 years treated for STEMI (see sections 4.2
and 5.2).
• Renal impairment
In patients with renal impairment, there is an increase in exposure of enoxaparin
sodium which increases the risk of bleeding. In these patients, careful clinical
monitoring is advised, and biological monitoring by anti-Xa activity measurement
might be considered (see sections 4.2 and 5.2).
Enoxaparin sodium is not recommended for patients with end stage renal
disease (creatinine clearance <15 ml/min) due to lack of data in this population
outside the prevention of thrombus formation in extra corporeal circulation during
haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 ml/min),
since exposure of enoxaparin sodium is significantly increased, a dosage
adjustment is recommended for therapeutic and prophylactic dosage ranges (see
section 4.2).
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.
• Hepatic impairment
Enoxaparin sodium should be used with caution in patients with hepatic
impairment due to an increased potential for bleeding. Dose adjustment based
on monitoring of anti-Xa levels is unreliable in patients with liver cirrhosis and not
recommended (see section 5.2).
• Low weight 

An increase in exposure of enoxaparin sodium with prophylactic dosages (nonweight
adjusted) has been observed in low-weight women (<45 kg) and lowweight
men (<57 kg), which may lead to a higher risk of bleeding. Therefore,
careful clinical monitoring is advised in these patients (see section 5.2).
• Obese Patients
Obese patients are at higher risk for thromboembolism. The safety and efficacy
of prophylactic doses 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.
• Hyperkalaemia
Heparins can suppress adrenal secretion of aldosterone leading to
hyperkalaemia (see section 4.8), particularly in patients such as those with
diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, taking
medicinal products known to increase potassium (see section 4.5). Plasma
potassium should be monitored regularly especially in patients at risk.
• Traceability
LMWHs are biological medicinal products. In order to improve the LMWH
traceability, it is recommended that health care professionals record the trade
name and batch number of the administered product in the patient file.

Concomitant use not recommended:
• Medicinal products affecting haemostasis (see section 4.4)
It is recommended that some agents which affect haemostasis should be
discontinued prior to enoxaparin sodium therapy unless strictly indicated. If the
combination is indicated, enoxaparin sodium should be used with careful clinical
and laboratory monitoring when appropriate. These agents include medicinal
products such as:
- Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and
NSAIDs including ketorolac,
- Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase,
urokinase) and anticoagulants (see section 4.2).
Concomitant use with caution:
The following medicinal products may be administered with caution
concomitantly with enoxaparin sodium:
• Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at
antiaggregant dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein
IIb/IIIa antagonists indicated in acute coronary syndrome due to the risk of
bleeding,
- Dextran 40,
- Systemic glucocorticoids.

• Medicinal products increasing potassium levels:
Medicinal products that increase serum potassium levels may be administered
concurrently with enoxaparin sodium under careful clinical and laboratory
monitoring (see sections 4.4 and 4.8).

Pregnancy
In humans, there is no evidence that enoxaparin crosses the placental barrier
during the second and third trimester of pregnancy. There is no information
available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity
(see section 5.3). Animal data have shown that enoxaparin passage through the
placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has
established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for
evidence of bleeding or excessive anticoagulation and should be warned of the
haemorrhagic risk. Overall, the data suggest that there is no evidence for an
increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to
the risk observed in non-pregnant women, other than that observed in pregnant
women with prosthetic heart valves (see section 4.4).
If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin
sodium treatment before (see section 4.4).
Breastfeeding
It is not known whether unchanged enoxaparin is excreted in human breast milk.
In lactating rats, the passage of enoxaparin or its metabolites in milk is very low.
The oral absorption of enoxaparin sodium is unlikely. Endosa Syringes can be
used during breastfeeding.
Fertility
There are no clinical data for enoxaparin sodium in fertility. Animal studies did not
show any effect on fertility (see section 5.3).

Enoxaparin sodium has no or negligible influence on the ability to drive and use
machines.

Summary of the safety profile
Enoxaparin sodium has been evaluated in more than 15,000 patients who
received enoxaparin sodium in clinical trials. These included 1,776 for
prophylaxis of deep vein thrombosis following orthopaedic or abdominal surgery
in patients at risk for thromboembolic complications, 1,169 for prophylaxis of
deep vein thrombosis in acutely ill medical patients with severely restricted
mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment
of acute STEMI.
Enoxaparin sodium regimen administered during these clinical trials varies
depending on indications. The enoxaparin sodium dose was 4,000 IU (40 mg)
SC once daily for prophylaxis of deep vein thrombosis following surgery or in
acutely ill medical patients with severely restricted mobility. In treatment of DVT
with or without PE, patients receiving enoxaparin sodium were treated with either
a 100 IU/kg (1 mg/kg) SC dose every 12 hours or a 150 IU/kg (1.5 mg/kg) SC
dose once a day. In the clinical studies for treatment of unstable angina and non-
Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) SC every 12
hours, and in the clinical study for treatment of acute STEMI enoxaparin sodium
regimen was a 3,000 IU (30 mg) IV bolus followed by 100 IU/kg (1 mg/kg) SC
every 12 hours.
In clinical studies, haemorrhages, thrombocytopenia and thrombocytosis were
the most commonly reported reactions (see section 4.4 and 'Description of
selected adverse reactions' below).
Tabulated summary list of adverse reactions
Other adverse reactions observed in clinical studies and reported in postmarketing
experience (* indicates reactions from post-marketing experience) are
detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to
< 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very
rare (< 1/10,000) or not known (cannot be estimated from available data). Within
each system organ class, adverse reactions are presented in order of decreasing
seriousness.
Blood and the lymphatic system disorders
• Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia,
thrombocytosis
• Rare: Eosinophilia*
• Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of
them thrombosis was complicated by organ infarction or limb ischaemia (see
section 4.4).
Immune system disorders
• Common: Allergic reaction
• Rare: Anaphylactic/Anaphylactoid reactions including shock*
Nervous system disorders
• Common: Headache*
Vascular disorders
• Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have
resulted in varying degrees of neurologic injuries including long-term or
permanent paralysis (see section 4.4).

Hepato-biliary disorders
• Very common: Hepatic enzyme increases (mainly transaminases > 3 times the
upper limit of normality)
• Uncommon: Hepatocellular liver injury *
• Rare: Cholestatic liver injury*
Skin and subcutaneous tissue disorders
• Common: Urticaria, pruritus, erythema
• Uncommon: Bullous dermatitis
• Rare: Alopecia*
• Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site
(these phenomena have been usually preceded by purpura or erythematous
plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of
enoxaparin). They resolve after a few days and should not cause treatment
discontinuation.
Musculoskeletal, connective tissue and bone disorders
• Rare: Osteoporosis* following long term therapy (greater than 3 months)
General disorders and administration site conditions
• Common: Injection site haematoma, injection site pain, other injection site
reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass,
pain, or reaction)
• Uncommon: Local irritation, skin necrosis at injection site
Investigations
• Rare: Hyperkalaemia* (see sections 4.4 and 4.5).
Description of selected adverse reactions
Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients
(surgical patients). Some of these cases have been fatal. In surgical patients,
haemorrhage complications were considered major: (1) if the haemorrhage
caused a significant clinical event, or (2) if accompanied by haemoglobin
decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products.
Retroperitoneal and intracranial haemorrhages were always considered major.
As with other anticoagulants, haemorrhage may occur in the presence of
associated risk factors such as: organic lesions liable to bleed, invasive
procedures or the concomitant use of medications affecting haemostasis (see
sections 4.4 and 4.5).

System Organ Class	Prophylaxis in surgical patients	Prophylaxis in medical patients	Treatment in patients with DVT with or without PE	Treatment in patients with unstable angina and non-Q-wave MI	Treatment in patients with acute STEMI
Blood and lymphatic system disorders	Very common: Haemorrhage α Rare: Retroperitoneal haemorrhage	Common: Haemorrhage α	Very common: Haemorrhage α Uncommon: Intracranial haemorrhage, Retroperitoneal haemorrhage	Common: Haemorrhage α Rare: Retroperitoneal haemorrhage	Common: Haemorrhage α Uncommon: Intracranial haemorrhage, Retroperitoneal haemorrhage

α: such as haematoma, ecchymosis other than at injection site, wound
haematoma, haematuria, epistaxis and gastro-intestinal haemorrhage.
Thrombocytopenia and thrombocytosis

System Organ Class	Prophylaxis in surgical patients	Prophylaxis in medical patients	Treatment in patients with DVT with or without PE	Treatment in patients with unstable angina and non-Q-wave MI	Treatment in patients with acute STEMI
Blood and lymphatic system disorders	Very common: Thrombocytosisβ Common: Thrombocytopenia	Uncommon: Thrombocytopenia	Very common: Thrombocytosis β Common: Thrombocytopenia	Uncommon: Thrombocytopenia	Common: Thrombocyto sisβThrombo cytopenia Very rare: Immunoallergic thrombocyto penia

β: Platelet increased >400 G/L

Paediatric population
The safety and efficacy of enoxaparin sodium in children have not been
established (see section 4.2).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance of
the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard

To report any side effect(s): • The National Pharmacovigilance and Drug Safety Centre (NPC) Fax: +966-11-205-7662 Call NPC at: +966-11-2038222 Exts: 2317-2356-2353-2354-2334-2340. Toll free phone: 8002490000 E-mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc

Signs and symptoms
Accidental overdose with enoxaparin sodium after IV, extracorporeal or SC
administration may lead to haemorrhagic complications. Following oral
administration of even large doses, it is unlikely that enoxaparin sodium will be
absorbed.
Management
The anticoagulant effects can be largely neutralized by the slow IV injection of
protamine. The dose of protamine depends on the dose of enoxaparin sodium
injected; 1 mg protamine neutralizes the anticoagulant effect of 100 IU (1 mg) of
enoxaparin sodium, if enoxaparin sodium was administered in the previous 8
hours. An infusion of 0.5 mg protamine per 100 IU (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. After 12 hours of the enoxaparin sodium
injection, protamine administration may not be required. However, even with high
doses of protamine, the anti-Xa activity of enoxaparin sodium is never completely
neutralized (maximum about 60%) (see the prescribing information for protamine
salts).

Pharmacotherapeutic group: Antithrombotic agent, heparin group, ATC code:
B01A B05
Pharmacodynamic effects
Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500
daltons, in which the antithrombotic and anticoagulant activities of standard
heparin have been dissociated. The drug substance is the sodium salt.
In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity
(approximately 100 IU/mg) and low anti-IIa or anti thrombin activity
(approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant activities are
mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in
humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory
properties of enoxaparin have been identified in healthy subjects and patients as
well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor
VIIa, induction of endogenous Tissue Factor Pathway Inhibitor (TFPI) release as
well as a reduced release of von Willebrand factor (vWF) from the vascular
endothelium into the blood circulation. These factors are known to contribute to
the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly
affect the aPTT. When used as curative treatment, aPTT can be prolonged by
1.5-2.2 times the control time at peak activity.
Clinical efficacy and safety
Prevention of venous thromboembolic disease associated with surgery
• Extended prophylaxis of VTE following orthopaedic surgery
In a double blind study of extended prophylaxis for patients undergoing hip
replacement surgery, 179 patients with no venous thromboembolic disease
initially treated, while hospitalized, with enoxaparin sodium 4,000 IU (40 mg) SC,
were randomized to a post-discharge regimen of either enoxaparin sodium 4,000
IU (40 mg) (n=90) once a day SC or to placebo (n=89) for 3 weeks. The
incidence of DVT during extended prophylaxis was significantly lower for
enoxaparin sodium compared to placebo, no PE was reported. No major
bleeding occurred.

*p value versus placebo =0.008 #p value versus placebo =0.537

	Enoxaparin sodium 4,000 IU (40 mg) once a day SC n (%)	Placebo once a day SC n (%)
All Treated Extended Prophylaxis Patients	90 (100)	89 (100)
Total VTE	6 (6.6)	18 (20.2)
• Total DVT (%)	6 (6.6)*	18 (20.2)
• Proximal DVT (%)	5 (5.6)#	7 (8.8)

In a second double-blind study, 262 patients without VTE disease and
undergoing hip replacement surgery initially treated, while hospitalized, with
enoxaparin sodium 4,000 IU (40 mg) SC were randomized to a post-discharge
regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day SC or
to placebo (n=131) for 3 weeks. Similar to the first study the incidence of VTE during extended prophylaxis was significantly lower for enoxaparin sodium
compared to placebo for both total VTE (enoxaparin sodium 21 [16%] versus
placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6.1%]
versus placebo 28 [21.4%]; p=<0.001). No difference in major bleeding was
found between the enoxaparin sodium and the placebo group.
• Extended prophylaxis of DVT following cancer surgery
A double-blind, multicenter trial, compared a four-week and a one-week regimen
of enoxaparin sodium prophylaxis in terms of safety and efficacy in 332 patients
undergoing elective surgery for abdominal or pelvic cancer. Patients received
enoxaparin sodium (4,000 IU (40 mg) SC) daily for 6 to 10 days and were then
randomly assigned to receive either enoxaparin sodium or placebo for another 21
days. Bilateral venography was performed between days 25 and 31, or sooner if
symptoms of venous thromboembolism occurred. The patients were followed for
three months. Enoxaparin sodium prophylaxis for four weeks after surgery for
abdominal or pelvic cancer significantly reduced the incidence of venographically
demonstrated thrombosis, as compared with enoxaparin sodium prophylaxis for
one week. The rates of venous thromboembolism at the end of the double-blind
phase were 12.0 % (n=20) in the placebo group and 4.8% (n=8) in the
enoxaparin sodium group; p=0.02. This difference persisted at three months
[13.8% vs. 5.5% (n=23 vs 9), p=0.01]. There were no differences in the rates of
bleeding or other complications during the double-blind or follow-up periods.
Prophylaxis of venous thromboembolic disease in medical patients with an acute
illness expected to induce limitation of mobility
In a double blind multicenter, parallel group study, enoxaparin sodium 2,000 IU
(20 mg) or 4,000 IU (40 mg) once a day SC was compared to placebo in the
prophylaxis of 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, and acute infection or
acute rheumatic; if associated with at least one VTE risk factor (age ≥75 years,
cancer, previous VTE, obesity, varicose veins, hormone therapy, and chronic
heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were
treated. Treatment continued for 6 to 14 days (median duration 7 days). When
given at a dose of 4,000 IU (40 mg) once a day SC, enoxaparin sodium
significantly reduced the incidence of VTE as compared to placebo. The efficacy
data are provided in the table below.

 

	Enoxaparin sodium 2,000 IU (20 mg) once a day SC n (%)	Enoxaparin sodium 4,000 IU (40 mg) once a day SC n (%)	Placebo n (%)
All Treated Medical Patients During Acute Illness	287 (100)	291(100)	288 (100)
Total VTE (%)	43 (15.0)	16 (5.5)*	43 (14.9)
• Total DVT (%)	43 (15.0)	16 (5.5)	40 (13.9)
• Proximal DVT (%)	13 (4.5)	5 (1.7)	14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin * p value versus placebo =0.0002

 

At approximately 3 months following enrolment, the incidence of VTE remained
significantly lower in the enoxaparin sodium 4,000 IU (40 mg) treatment group
versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in
the placebo group, 11.7% and 0.3% in the enoxaparin sodium 2,000 IU (20 mg)
group and 12.6% and 1.7% in the enoxaparin sodium 4,000 IU (40 mg) group.
Treatment of deep vein thrombosis with or without pulmonary embolism
In a multicenter, parallel group study, 900 patients with acute lower extremity
DVT with or without PE were randomized to an inpatient (hospital) treatment of
either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day SC, (ii)
enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours SC, or (iii) heparin IV
bolus (5,000 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. All patients also received warfarin sodium (dose
adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0),
commencing within 72 hours of initiation of enoxaparin sodium or standard
heparin therapy, and continuing for 90 days. Enoxaparin sodium or standard
heparin therapy was administered for a minimum of 5 days and until the targeted
warfarin sodium INR was achieved. Both enoxaparin sodium regimens were
equivalent to standard heparin therapy in reducing the risk of recurrent venous
thromboembolism (DVT and/or PE). The efficacy data are provided in the table
below.

	Enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day SC n (%)	Enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day SC n (%)	Heparin aPTT Adjusted IV Therapy n (%)
All Treated DVT Patients with or without PE	298 (100)	312 (100)	290 (100)
Total VTE (%)	13 (4.4)*	9 (2.9)*	12 (4.1)
• Total DVT (%)	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)
VTE = venous thromboembolic event (DVT and/or PE) *The 95% Confidence Intervals for the treatment differences for total VTE were: - enoxaparin sodium once a day versus heparin (-3.0 to 3.5) - enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

 

 

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5
mg/kg) once a day group, 1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg)
twice a day group and 2.1% in the heparin group.
Treatment of unstable angina and non ST elevation myocardial infarction
In a large multicenter study, 3,171 patients enrolled at the acute phase of
unstable angina or non-Q-wave myocardial infarction were randomized to receive
in association with acetylsalicylic acid (100 to 325 mg once daily), either SC
enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated
heparin adjusted based on aPTT. Patients had to be treated in hospital for a
minimum of 2 days and a maximum of 8 days, until clinical stabilization,
revascularization procedures or hospital discharge. The patients had to be
followed up to 30 days. In comparison with heparin, enoxaparin sodium
significantly reduced the combined incidence of angina pectoris, myocardial
infarction and death, with a decrease of 19.8 to 16.6% (relative risk reduction of
16.2%) on day 14. This reduction in the combined incidence was maintained
after 30 days (from 23.3 to 19.8%; relative risk reduction of 15%).
There were no significant differences in major haemorrhages, although a
haemorrhage at the site of the SC injection was more frequent.
Treatment of acute ST-segment elevation myocardial infarction
In a large multicenter study, 20,479 patients with STEMI eligible to receive
fibrinolytic therapy were randomized to receive either enoxaparin sodium in a
single 3,000 IU (30 mg) IV bolus plus a 100 IU/kg (1 mg/kg) SC dose followed by
an SC injection of 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated
heparin adjusted based on aPTT for 48 hours. All patients were also treated with
acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing
strategy was adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin sodium were given until
hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving
antithrombotic support with blinded study drug. Therefore, for patients on
enoxaparin sodium, the PCI was to be performed on enoxaparin sodium (no
switch) using the regimen established in previous studies i.e. no additional
dosing, if last SC administration given less than 8 hours before balloon inflation,
IV bolus of 30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last SC administration
given more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased
the incidence of the primary end point, a composite of death from any cause or
myocardial re-infarction in the first 30 days after randomization [9.9 percent in the
enoxaparin sodium group, as compared with 12.0 percent in the unfractionated
heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy
outcomes, emerged at 48 hours, at which time there was a 35 percent reduction
in the relative risk of myocardial re-infarction, as compared with treatment with
unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was
consistent across key subgroups including age, gender, infarct location, history of
diabetes, history of prior myocardial infarction, type of fibrinolytic administered,
and time to treatment with study drug.
There was a significant treatment benefit of enoxaparin sodium, as compared
with unfractionated heparin, in patients who underwent percutaneous coronary
intervention within 30 days after randomization (23 percent reduction in relative
risk) or who were treated medically (15 percent reduction in relative risk, p=0.27
for interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or
intracranial haemorrhage (a measure of net clinical benefit) was significantly
lower (p<0.0001) in the enoxaparin sodium group (10.1%) as compared to the
heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in
the enoxaparin sodium group (2.1%) versus the heparin group (1.4%). There was
a higher incidence of gastrointestinal bleeding in the enoxaparin sodium group
(0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus
0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed
during the first 30 days was maintained over a 12 month follow-up period.
Hepatic impairment
Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in
cirrhotic patients (Child-Pugh class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the literature studies
may have limitations. Caution should be used in patients with hepatic impairment
as these patients have an increased potential for bleeding (see section 4.4) and
no formal dose finding studies have been performed in cirrhotic patients (Child
Pugh class A, B nor C).

 

General characteristics
The pharmacokinetic parameters of enoxaparin sodium have been studied
primarily in terms of the time course of plasma anti-Xa activity and also by anti-IIa
activity, at the recommended dosage ranges after single and repeated SC
administration and after single IV administration. The quantitative determination
of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated
amidolytic methods.
Absorption
The absolute bioavailability of enoxaparin sodium after SC injection, based on
anti-Xa activity, is close to 100%.
Different doses and formulations and dosing regimens can be used.
The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after
SC injection and achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/ml
following single SC administration of 2,000 IU, 4,000 IU, 100 IU/kg and 150 IU/kg
(20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.
A 3,000 IU (30 mg) IV bolus immediately followed by a 100 IU/kg (1 mg/kg) SC
every 12 hours provided initial maximum anti-Xa activity level of 1.16 IU/ml
(n=16) and average exposure corresponding to 88% of steady-state levels.
Steady-state is achieved on the second day of treatment.
After repeated SC administration of 4,000 IU (40 mg) once daily and 150 IU/kg
(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. After repeated SC administration of the 100 IU/kg (1 mg/kg) twice
daily regimen, the steady-state is reached from day 3 to 4 with mean exposure
about 65% higher than after a single dose and mean maximum and trough anti-
Xa activity levels of about 1.2 and 0.52 IU/ml, respectively.
Injection volume and dose concentration over the range 100-200 mg/ml does not
affect pharmacokinetic parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the
recommended dosage ranges.
Intra-patient and inter-patient variability is low. Following repeated SC
administration no accumulation takes place.
Plasma anti-IIa activity after SC administration is approximately ten-fold lower
than anti-Xa activity. The mean maximum anti-IIa activity level is observed
approximately 3 to 4 hours following SC injection and reaches 0.13 IU/ml and 0.19 IU/ml following repeated administration of 100 IU/kg (1 mg/kg) twice daily
and 150 IU/kg (1.5 mg/kg) once daily, respectively.
Distribution
The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres
and is close to the blood volume.
Biotransformation
Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or
depolymerization to lower molecular weight species with much reduced biological
potency.
Elimination
Enoxaparin sodium is a low clearance drug with a mean anti-Xa plasma
clearance of 0.74 L/h after a 150 IU /kg (1.5 mg/kg) 6-hour IV infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single
SC dose to about 7 hours after repeated dosing.
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
Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin
sodium kinetic profile is not different in elderly subjects compared to younger
subjects when renal function is normal. However, since renal function is known to
decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).
Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin
sodium 4,000 IU (40 mg) once daily, a decrease in maximum anti-Xa activity was
associated with an increase in the severity of hepatic impairment (assessed by
Child-Pugh categories). This decrease was mainly attributed to a decrease in
ATIII level secondary to a reduced synthesis of ATIII in patients with hepatic
impairment.
Renal impairment
A linear relationship between anti-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-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 SC 4,000 IU (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 SC 4,000 IU
(40 mg) once daily doses (see sections 4.2 and 4.4).
Haemodialysis 

Enoxaparin sodium pharmacokinetics appeared similar than control population,
after a single 25 IU, 50 IU or 100 IU/kg (0.25, 0.50 or 1.0 mg/kg) IV dose
however, AUC was two-fold higher than control.
Weight
After repeated SC 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa
activity is marginally higher at steady state in obese healthy volunteers (BMI 30-
48 kg/m2) compared to non-obese control subjects, while maximum plasma anti-
Xa activity level is not increased. There is a lower weight-adjusted clearance in
obese subjects with SC dosing.
When non-weight adjusted dosing was administered, it was found after a single-
SC 4,000 IU (40 mg) dose, that anti-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 section 4.4).
Pharmacokinetic interactions
No pharmacokinetic interactions were observed between enoxaparin sodium and
thrombolytics when administered concomitantly.

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence
of adverse effects at 15 mg/kg/day in the 13-week SC toxicity studies both in rats
and dogs and at 10 mg/kg/day in the 26-week SC and IV toxicity studies both in
rats, and monkeys.
Enoxaparin sodium has shown no mutagenic activity based on in vitro tests,
including the Ames test, mouse lymphoma cell forward mutation test, and no
clastogenic activity based on an in vitro human lymphocyte chromosomal
aberration test, and the in vivo rat bone marrow chromosomal aberration test.
Studies conducted in pregnant rats and rabbits at SC doses of enoxaparin
sodium up to 30 mg/kg/day did not reveal any evidence of teratogenic effects or
foetotoxicity. Enoxaparin sodium 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.

Water for Injections.

SC injection
Do not mix with other products.
IV (Bolus) Injection (for acute STEMI indication only): Enoxaparin sodium may be safely administered with normal saline solution
(0.9%) or 5% dextrose in water (see section 4.2).

2 years.

Do not store in a refrigerator or freezer. Do not store above 30°C. Store in the
original container.
Do not use this medicine if you notice any visible change in the appearance of
the solution.

A clear, colourless type I neutral glass syringe barrel with fixed needle and
needle shield closed by chlorobutyl rubber stopper and polypropylene plunger
rod.
Each pack contains 2 pre-filled syringes

See section 4.2 Posology and method of administration.
The pre-filled syringes are for single dose use only. Discard any unused
medicine.
.
Do not throw away any medicines via wastewater or household waste. Ask your
pharmacist how to throw away medicines you no longer use. These measures
will help protect the environment.