SPC 350 0715-03

SUMMARY OF PRODUCT CHARACTERISTICS
SPC 350 0715-03
1. NAME OF THE MEDICINAL PRODUCT
NOXPRIN®
Enoxaparin sodium
20 mg, 40 mg, 60 mg and 80 mg
Prescription only medicine
2. QUALI-QUANTITIVE FORMULA
Each pre-filled syringe contains:
Raw material Noxprin 20 Noxprin 40 Noxprin 60 Noxprin 80

Enoxaparin sodium 20mg 40mg 60mg 80mg
Sodium hydroxide 1mol/L or
q.s. q.s. q.s. q.s.
Hydrochloric acid 1 mol/L
Water for injection q.s.t. 0.2mL 0.4mL 0.6mL 0.8mL
3. PHARMACEUTICAL FORM
Prefilled syringes with solution for injection.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
• Prophylaxis of deep vein thrombosis which may lead to pulmonary embolism in

patients:
- Undergoing abdominal surgery with risk of thromboembolic complications.

- Undergoing hip replacement surgery during and after hospitalization.
- Undergoing knee replacement surgery.
- Medicated patients at risk of thromboembolic complications due to severely restricted
mobility during acute illness.
- Prophylaxis of ischemic complications of unstable angina and myocardial infarction of non-Q
wave with concurrent administration of acetylsalicylic acid.
It is also indicated in the following cases:

- Hospitalized patients with deep vein thrombosis with or without pulmonary embolism,
together with sodium warfarin administration.
LABORATORIOS CLAUSEN
Laboratorios Clausen S.A. Bulevar Artigas 3896
Tel.: (005982) 2209 09 09*. Fax: (005892) 2209 08 68
Montevideo – Uruguay. www.clausen.com.uy
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- Outpatients with deep vein thrombosis without pulmonary embolism, together with sodium
warfarin administration
4.2 Posology and method of administration
All patients should be evaluated for a bleeding disorder before administration of ENOXAPARIN
SODIUM, unless the medication is needed urgently. Since the coagulation parameters are
unsuitable for monitoring ENOXAPARIN SODIUM activity, routine monitoring of coagulation
parameters is not required.
Adult Dosage:
Abdominal surgery: In patients undergoing abdominal surgery who are at risk of

thromboembolic complications, the recommended dose is of 40 mg once a day administered
by SC injection, being the initial dose given 2 hours prior to the surgery. The usual duration of
administration is 7 to 10 days; up to 12 days administration has been well tolerated in clinical
trials.
Hip or knee replacement surgery: In patients undergoing hip or knee replacement surgery, the
recommended dose is of 20 to 40 mg every 12 hours administered by SC injection. Provided
that haemostasis has been established, the initial dose should be given 12 to 24 hours after
the surgery. For hip replacement surgery, a 40 mg once a day SC dose given initially 12 (± 3)
hours prior to surgery may be considered. Following the initial phase of thromboprophylaxis in
hip replacement surgery patients, it is recommended that continued prophylaxis with
ENOXAPARIN SODIUM, 40 mg once a day be administered by 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 of thromboembolic
complications due to severely restricted mobility during acute illness, the recommended dose
of ENOXAPARIN SODIUM is 40 mg once a day administered by SC injection. The usual duration
of the administration is 6 to 11 days; ENOXAPARIN SODIUM has been well tolerated during up
to 14 days in controlled clinical trials.
Unstable Angina and non-Q-Wave myocardial infarction: In patients with unstable angina or
non-Q-wave myocardial infarction, the recommended dose of ENOXAPARIN SODIUM is of
1mg/kg administered SC every 12 hours in conjunction with oral ASA therapy (100 to 325 mg
once a day). Treatment with ENOXAPARIN SODIUM should be prescribed for a minimum of 2
days and continued until clinical stabilization. To minimize the risk of bleeding after the
vascular instrumentation during the treatment of unstable angina, follow exactly the
recommended intervals between doses of ENOXAPARIN SODIUM. The cover of the vascular
access for instrumentation must be kept in its place for 6 to 8 hours after a dose of
ENOXAPARIN SODIUM. The following programmed dose must be administered not before 6 to
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8 hours after the removal of the cover. The place of the procedure must be observed for
haemorrhage signs or hematoma formation. The usual duration of treatment is 2 to 8 days;
ENOXAPARIN SODIUM was well tolerated for up to 12.5 days in clinical trials.
Treatment of deep vein thrombosis with or without pulmonary embolism: In outpatient
treatment, patients with acute deep vein thrombosis without pulmonary embolism who can
be treated at home, the recommended dose of ENOXAPARIN SODIUM is 1 mg/kg every 12
hours administered SC. In the treatment of inpatients, patients with acute deep vein
thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without
pulmonary embolism (who are not candidates for outpatient treatment), the recommended
dose of ENOXAPARIN SODIUM is of 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once
a day administered SC at the same time every day. Both in outpatient and inpatient
treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72
hours of the administration of ENOXAPARIN SODIUM). ENOXAPARIN SODIUM should be
continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been
achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration
is 7 days; ENOXAPARIN SODIUM has been well tolerated for 17 days in controlled clinical trials.
Renal impairment: Although no dose adjustment is recommended in patients with moderate
(creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mg/min) renal
impairment, all such patients should be observed carefully for signs and symptoms of bleeding.
To avoid the formation of clots during haemodialysis, ENOXAPARIN SODIUM must be
incorporated to the arterial line of the circuit at the beginning of the dialysis session. The
recommended dose is of 1 mg/kg, in patients with high risk of haemorrhages the dose must be
lower; 0.5 mg/kg for double access or 0.75 mg/kg for single access. The effect of such dose is
generally enough for a 4-hour haemodialysis session, the dose may have to be adjusted in case
of longer sessions.
The recommended prophylaxis and treatment dosage regimens for patients with severe renal
impairment (creatinine clearance < 30 mL/min) are described in the following table:
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Dosage regimens for patients with severe renal impairment (creatinine clearance
<30mL/minute)
Indication Dosage Regimen

Prophylaxis in abdominal surgery 30 mg administered SC once daily
Prophylaxis in hip or knee surgery 30 mg administered SC once daily
Prophylaxis in medical patients during acute illness 30 mg administered SC once daily
Prophylaxis of ischemic complications of unstable 1 mg/kg administered SC once
angina and non-Q-wave myocardial infarction, when daily
concurrently administered with aspirin
Inpatient treatment of acute deep vein thrombosis with
1 mg/kg administered SC once
or without pulmonary embolism, when administered in
daily
conjunction with warfarin sodium
Outpatient treatment of acute deep vein thrombosis
1 mg/kg administered SC once
without pulmonary embolism, when administered in
daily
conjunction with warfarin sodium
Administration: NOXPRIN is a clear, colourless to pale yellow sterile solution and, as other
parenteral drug products, should be visually inspected for particles and discoloration prior to
administration. NOXPRIN is administered by SC injection. It must not be administered by
intramuscular injection. NOXPRIN has to be used under medical supervision. Patients may self-
inject only if their physician determines that it is appropriate and with medical follow-up if
necessary. Proper training in SC injection technique (with or without the assistance of an
injection device) should be provided.
Subcutaneous injection technique: Patients should be lying down and NOXPRIN administered
by deep SC injection. Do not expel the air bubbles from the syringe before the injection. The
administration must 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 the forefinger; the skin fold should be held throughout the
injection. To minimize bruising, do not rub the injection site after completion of the injection.
4.3 Contraindications
NOXPRIN is contraindicated in patients with active major bleeding, in patients with

thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the
presence of enoxaparin sodium, or in patients with hypersensitivity to enoxaparin sodium.
Patients with known hypersensitivity to heparin or pork derived products must not be treated
with NOXPRIN or any of its components.
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4.4 Special warnings and precautions for use
Epidural or spinal hematomas may occur in anticoagulated patients with low molecular weight
heparin (LMWH) or heparinoids, during epidural/peridural anaesthesia or spinal puncture.
These hematomas could determine permanent or protracted duration paralysis. These risks
should be considered when such procedures are coordinated in these patients.
The following factors increase spinal or epidural hematoma in these patients: prolonged use of
epidural catheter, concomitant use of other drugs that affect haemostasis (such as NSAIDs),
platelet inhibitors and other anticoagulants, history of traumatic cord puncture or repeated
and spinal deformation or surgery background.
Patients should be checked frequently for signs and symptoms of neurologic involvement. In
case of finding some compromise on this area, treatment must be urgently implemented.
Consider risks and benefits of neuroaxial surgery in anticoagulated patients or in patients
subjected to anticoagulant thromboprophylaxis.
NOXPRIN is not meant for intramuscular use.

NOXPRIN cannot be used interchangeably (unit for unit) with other heparin or other low
molecular weight heparins as they differ in the manufacturing process, molecular weight
distribution, anti-Xa and anti-IIa activities, units and dosage. Each of these medicines has its
own instructions for use.
NOXPRIN must be used with extreme caution in patients with a history of heparin-induced
thrombocytopenia.
Haemorrhage: ENOXAPARIN SODIUM, as well as other anticoagulants, must be used with

extreme caution in conditions of increased risk of haemorrhage, such as bacterial endocarditis,
congenital or acquired bleeding disorders, active ulcerative and angiodysplastic
gastrointestinal disease, haemorrhagic stroke, or shortly after brain, spinal or ophthalmologic
surgery, or in patients treated concomitantly with platelet inhibitors.
Cases of epidural or spinal hematomas have been reported with the associated use of
ENOXAPARIN SODIUM and spinal/epidural anaesthesia or spinal puncture resulting in long-
term or permanent paralysis. The risk of these events is higher with the use of post-operatory
indwelling epidural catheters or by the concomitant use of additional drugs affecting
haemostasis such as NSAIDs.
Major haemorrhages including retroperitoneal and intracranial bleeding have been reported.
Some of these cases have been fatal. Bleeding can occur at any site during therapy with
ENOXAPARIN SODIUM. An unexplained fall in haematocrit or blood pressure should lead to a
search for a bleeding site.
Thrombocytopenia: Thrombocytopenia may occur with the administration of ENOXAPARIN
SODIUM. Moderate thrombocytopenia (platelet count between 100,000/mm3 and
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50,000/mm3) occurred at a rate of 1.3% in patients given ENOXAPARIN SODIUM, 1.2% in

patients given heparin and in 0.7% of patients given placebo in clinical trials.
Platelet counts under 50,000/mm3 occurred at a rate of 0.1% in patients given ENOXAPARIN
SODIUM, in 0.2% of patients given heparin and in 0.4% of patients given placebo in the same
tests. Thrombocytopenia of any type should be closely controlled. If the platelet count falls
below 100,000/mm3, ENOXAPARIN SODIUM must be discontinued. Cases of heparin-induced
thrombocytopenia have been observed in clinical practice. Some of these cases were
complicated by organ infarction, limb ischemia or death.
Pregnant women with heart valves: The use of ENOXAPARIN SODIUM for thromboprophylaxis
in pregnant women with mechanical prosthetic heart valves has not been properly studied. In
a clinical trial of pregnant women with heart valves that received enoxaparin (1 mg/kg bid) to
reduce the risk of thromboembolism, 2 to 8 women developed clots that resulted in blockage
of the valve and lead to maternal and foetal death. Although a causal relationship has not been
established, these deaths may have been due to the therapeutic failure or inadequate
anticoagulation. There were not any fatal cases registered in the heparin/warfarin group (0 of
4 women). There have also been isolated post marketing reports of valve thrombosis in
pregnant women with heart valves while they received enoxaparin for thromboprophylaxis.
Women with mechanical prosthetic heart valves may present a higher risk of having
thromboembolism during pregnancy, and, when pregnant, have a higher number of foetal
loss, spontaneous abortion and premature deliveries. Therefore, it is necessary to have a
frequent control of the peak and stable anti-factor Xa levels.
General precautions:
ENOXAPARIN SODIUM must not be mixed with other injections or infusions.

ENOXAPARIN SODIUM must be used with caution in patients with bleeding diathesis,
uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic
retinopathy, and haemorrhage. ENOXAPARIN SODIUM must be used with caution in advanced
age patients who may develop a delayed elimination of enoxaparin. If thromboembolic cases
occur while using ENOXAPARIN SODIUM for prophylaxis, an appropriate therapy must be
conducted.
Mechanical prosthetic heart valves: The use of ENOXAPARIN SODIUM has been properly
studied for thromboprophylaxis in patients with mechanical prosthetic heart valves and has
not been properly studied for a prolonged use in this group. There has been report of isolated
thrombosis cases of prosthetic valves in patients that had received enoxaparin for
thromboprophylaxis. Some of these cases were pregnant women in which the thrombosis led
to maternal and foetal deaths. The lack of data, the underlying illness and the possibility of
anticoagulation complicate the evaluation of these cases. Pregnant women with mechanical
prosthetic heart valves may have a higher risk of thromboembolism.
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Renal impairment: In patients with renal impairment there is an increase in the exposure of
enoxaparin sodium. All of these patients must be carefully observed for haemorrhage signs
and symptoms. As the exposure to enoxaparin sodium is significantly increased in patients
with severe renal impairment (creatinine clearance < 30 ml/min), it is recommended to adjust
the dose for therapeutic and prophylactic dosing ratios. It is not recommended to adjust the
dose in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine
clearance 50-80 ml/min) impairment.
Low weight patients: An increase in the exposure of enoxaparin sodium in prophylactic doses
(not adjusted by weight) was observed in low weight women (< 45 kg) and low weight men (<
57 kg). Such patients must be carefully observed for haemorrhage signs and symptoms.
Laboratory tests: Periodic complete blood counts, including platelet count, and stool occult
blood tests are recommended during the course of treatment with ENOXAPARIN SODIUM.
When administered at the recommended prophylactic doses, the coagulation routine tests
such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPPT) are relatively
intensive measures of ENOXAPARIN SODIUM activity, and therefore unsuitable for monitoring.
Anti-factor Xa can be used to control the anticoagulant effect of ENOXAPARIN SODIUM in
patients with significant renal impairment. If during the therapy with ENOXAPARIN SODIUM
abnormal coagulation or haemorrhage parameters are detected, anti-Factor Xa levels can be
used to control the anticoagulant effects of ENOXAPARIN SODIUM.
4.5 Interaction with other medicinal products and other forms of interaction
Unless really needed, agents that may enhance the risk of haemorrhage must be discontinued
before starting the therapy with ENOXAPARIN SODIUM. These agents include drugs 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.
4.6 Pregnancy and breastfeeding
All pregnancies have a risk of birth defects, loss or other adverse outcomes regardless of drug
exposure. The following information describes the potential of increasing the risk of
abnormalities in the development above the background risk with the use of ENOXAPARIN
SODIUM.
Foetal risk summary: Enoxaparin sodium is not predicted to increase the risk of abnormalities
in the development. Enoxaparin sodium does not cross the placenta, based on human and
animal studies, and shows no evidence of teratogenic effects or foetotoxicity.
Clinical considerations: It has not been demonstrated if it is necessary to either adjust the dose
or control the ant-Xa activity of enoxaparin during pregnancy. Pregnancy in itself confers an
increased risk of thromboembolism, which is even higher for women with thromboembolic
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disease and certain conditions of high-risk pregnancy. Although it has not been properly
studied, pregnant women with mechanical prosthetic heart valves may present an even higher
risk of thrombosis. Pregnant women with thromboembolic, including those with mechanical
prosthetic heart valves, and those with inherited or acquired thrombophilias, also have an
increased risk of other maternal complications and foetal loss regardless the time of the used
anticoagulant. All patients that receive anticoagulants such as enoxaparin, including pregnant
women, are at risk of suffering haemorrhage. Pregnant women who receive enoxaparin must
be closely controlled for risk of haemorrhage or excessive anticoagulation. As delivery
approaches, the use of a shorter action anticoagulant must be considered. Haemorrhage can
occur at any site and may conduct to the death of the mother and/or the foetus. Pregnant
women should be warned of the potential risk for the foetus and the mother if enoxaparin is
administered during the 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 the
pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72 haemorrhagic
events (11 serious) in 63 women. There were 14 cases of neonatal haemorrhage. Major
congenital anomalies in live births occurred at rates (2.5 %) similar to background rates. There
are post-marketing reports of foetal death in pregnant women who received ENOXAPARIN
SODIUM. The causality for these cases has not been determined. The lack of data, the
underlying disease and the possibility of inadequate anticoagulation complicate the evaluation
of these cases.
• Animal data: Teratology studies have been conducted in pregnant rats and rabbits at SC
doses of enoxaparin up to 30 mg/kg/day or 211 mg/m2/day and 410 mg/m2/day, respectively.
There was no evidence of teratogenic effects or foetotoxicity due to enoxaparin. As the
reproduction studies in animals not always anticipate the response in human beings, this drug
must be used during the pregnancy only if it is strictly necessary.
It is not known if this drug is excreted in human milk. Because many drugs are excreted by
milk, caution should be taken when enoxaparin is administered to breastfeeding women.
4.7 Effects on ability to drive and use machines
The effects on the ability to drive or use machines with the usage of enoxaparin sodium have
not been described.
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4.8 Undesirable effects
Haemorrhage: The incidence of major haemorrhagic complications during the treatment with
ENOXAPARIN SODIUM has been low. The following percentages of major haemorrhagic events
have been reported during clinical trials with ENOXAPARIN SODIUM.
Major haemorrhagic events after abdominal and colorectal surgery1
Dosing regimen
Indications ENOXAPARIN Heparin
SODIUM 5000 U q8h
40 mg q.d. SC SC
Abdominal n = 555 n = 560
surgery 23 (4%) 16 (3%)
Colorectal n = 673 n = 674
surgery 28 (4%) 21 (3%)
1
The haemorrhagic complications were considered major: (1) if the haemorrhage caused a
significant clinical event, or (2) if it was accompanied by a haemoglobin decrease >2 g/dL or
transfusion of 2 or more units of blood products. The intraperitoneal, intraocular or
intracranial haemorrhages were always considered major.
Major haemorrhagic events after hip or knee replacement surgery1
Dose regimen
Indications ENOXAPARIN ENOXAPARIN Heparin
SODIUM INJ SODIUM INJ 15,000 U/24h
40 mg q.d. SC 30 mg q12h SC
SC
Hip replacement surgery with n = 786 n = 541
extended prophylaxis 2 31 (4%) 32 (6%)
Hip replacement surgery without
extended prophylaxis
Peri-operative period3 n = 288
4 (2%)
Extended prophylaxis period4 n = 221
0 (0%)
Hip replacement surgery without n = 294 3 n = 225
extended prophylaxis 2 (1%) 3 (1%)
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1
transfusion of 2 or more units of blood products. The intraperitoneal or intracranial
haemorrhages were always considered major. In the knee replacement surgery trials,
intraocular haemorrhages were always considered major.
2
ENOXAPARIN SODIUM 30 mg every 12 hours SC initiated 12 to 24 hours after the surgery and
continued for up to 14 days after the surgery
3
ENOXAPARIN SODIUM 40 mg SC once a day initiated up to 12 hours before the surgery and
continued 7 days after the surgery
4
ENOXAPARIN SODIUM 40 mg SC once a day up to 21 days after discharge
NOTE: At no point were the 40 mg once a day before the operation and the 30 mg every 12
hours post-operation regimens compared in clinical trials. Hematomas in the injection site
were registered during the extended prophylaxis period after the hip replacement surgery in
9% of the patients with enoxaparin sodium versus 1.8% of the patients that received placebo.
Major haemorrhage episodes in medical patients with severely restricted mobility during acute
illness 1
Dose regimen
ENOXAPARIN SODIUM ENOXAPARIN SODIUM Placebo2
Indications INJ2 INJ 2
20 mg q.d. SC 40 mg q.d. SC
Medical patients n = 351 1 (<1%) n = 360 n = 362
during acute illness 3 (<1%) 2 (<1%)
1
transfusion of 2 or more units of blood products. The intraperitoneal or intracranial
haemorrhages were always considered major although none were reported during the trial.
2
The percentages represent major haemorrhage with the study medication up to 24 hours
after the last dose.
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Major haemorrhage episodes in unstable angina and non-Q-wave myocardial infarction
Dose regimen
ENOXAPARIN SODIUM Heparin1
1
Indication INJ aPTT
1 mg/kg q12h SC Adjusted IV
therapy
Unstable n = 1578 17 (1%) n = 1529
angina and 18 (1%)
non-Q-wave
myocardial
infarction 2,3
1
Percentages represent major haemorrhage with the study medication up to 12 hours after
the dose.
2
ASA therapy was administered concurrently (100 to 325 mg per day)
3
Haemorrhagic complications were considered major: (1) if the haemorrhage caused a
significant clinical event, or (2) if it was accompanied by a haemoglobin decrease of more than
3 g/dL or transfusion of 2 or more units of blood products. The intraperitoneal, intraocular or
Major haemorrhage episodes in deep vein thrombosis with or without pulmonary embolism
treatment 1
Dose regimen2
Indication ENOXAPARIN SODIUM ENOXAPARIN SODIUM Heparin
INJ INJ aPTT
1.5 mg/kg q.d. SC Adjusted
1 mg/kg q12h SC IV therapy
Treatment of n = 298 n = 559 n = 554
DVT and PE 5 (2%) 9 (2%) 9 (2%)
1
transfusion of 2 or more units of blood products. The retroperitoneal, intraocular or
2
All the patients also received warfarin sodium (dose adjustment according to PT to achieve an
INR of 2.0 to 3.0) starting within 72 hours of ENOXAPARIN SODIUM or standard therapy with
heparin and continuing for up to 90 days.
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Thrombocytopenia: see WARNINGS: Thrombocytopenia, Elevations in serum

aminotransferases: There has been report of asymptomatic increases in the levels of aspartate
(AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase greater than three times the upper
limit of the normal laboratory reference in up to 6.1 % and 5.9 % of the patients, respectively,
during the treatment with ENOXAPARIN SODIUM. There have also been similar significant
increases in the levels of aminotransferase in patients and healthy volunteers treated with
heparin and other low molecular weight heparins. Such increases are completely reversible
and are rarely associated to increases in bilirubin.
Since the aminotransferase determinations are important in the differential diagnosis of
myocardial infarction, liver diseases and pulmonary embolism, elevations that might be caused
by drugs such as enoxaparin sodium should be interpreted with caution.
Local reactions: Mild local irritation, pain, hematoma, ecchymosis and erythema may follow SC
injection of ENOXAPARIN SODIUM.
Others: The adverse effects that were thought to be possibly or probably related to the
treatment with ENOXAPARIN SODIUM, 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 group, are
provided below.
Adverse events occurring at ≥2% incidence in patients treated with INJECTABLE ENOXAPARIN
SODIUM 1 undergoing abdominal or colorectal surgery
Dosing regimen
ENOXAPARIN SODIUM Heparin
INJ 5000 U q8h SC
40 mg q.d. SC n = 1234
n = 1228
Adverse Severe Total Severe Total
event
Haemorrhage <1% 7% <1% 6%
Anaemia <1% 3% <1% 3%
Ecchymosis 0% 3% 0% 3%
1
Excluding unrelated adverse events
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Adverse events occurring with an incidence of ≥2% in patients treated with INJECTABLE
ENOXAPARIN SODIUM1 undergoing hip or knee replacement surgery
Dosing regimen
Enoxaparin sodium inj Enoxaparin Heparin Placebo
40 mg q.d. SC sodium inj 15,000 U/24h q12h SC
30 mg q12h SC
SC
Peri- Extended n = 1080 n = 766
n = 115
Operative prophylaxis
period period
n = 288 2 n = 131 3
Adverse Severe Total Severe Total Severe Total Severe Total Severe Total
event
Fever 0% 8% 0% 0% <1% 5% <1% 4% 0% 3%
Haemorrhage <1% 13% 0% 5% < 1% 4% 1% 4% 0% 3%
Nausea <1% 3% <1% 2% 0% 2%
Anaemia 0% 16% 0% <2% <1% 2% 2% 5% <1% 7%
Oedema <1% 2% <1% 2% 0% 2%
Peripheral 0% 6% 0% 0% <1% 3% <1% 4% 0% 3%
Oedema
1
Excluding unrelated adverse events
2
Data represents ENOXAPARIN SODIUM 40 mg SC once a day initiated up to 12 hours prior to
surgery in 288 patients who received ENOXAPARIN SODIUM peri-operativeley in an unblinded
fashion in one clinical trial
3
Data represents ENOXAPARIN SODIUM 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 288 original hip-
replacement surgery patients for up to 21 days in one clinical trial
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Adverse events occurring at ≥2% incidence in ENOXAPARIN SODIUM1 treated medical patients
with severely restricted mobility during acute illness
Dosing regimen
ENOXAPARIN SODIUM Placebo
INJ q.d. SC
40 mg q.d. SC n = 362
Adverse event n = 360 %
%
Dyspnoea 3.3 5.2
Thrombocytopenia 2.8 2.8
Confusion 2.2 1.1
Diarrhoea 2.2 1.7
Nausea 2.5 1.7
1
Excluding unrelated and unlikely adverse events
Adverse events in patients treated with ENOXAPARIN SODIUM with unstable angina or non-
Q-wave myocardial infarction: The non-haemorrhagic clinical events reported to be related to
ENOXAPARIN SODIUM therapy occurred at an incidence of ≤1%. The non-major haemorrhagic
episodes, mainly injection site ecchymosis and hematomas, were more frequently reported in
patients treated with SC ENOXAPARIN SODIUM than in patients treated with IV heparin.
Serious adverse effects with ENOXAPARIN SODIUM or heparin in a clinical trial with patients
with unstable angina or non-Q-wave myocardial infarction that occurred at a rate of at least
0.5% in the ENOXAPARIN SODIUM group are provided below (regardless of the relation with
drug therapy).
Serious adverse events occurring at ≥ 0.5% incidence in ENOXAPARIN SODIUM treated patients
with unstable angina or non-Q-wave myocardial infarction
Dosing regimen
Enoxaparin sodium inj Heparin
Adverse event 1 mg/kg q12h SC aPTT adjusted IV therapy
n = 1578 n = 1529
n (%) n (%)
Atrial fibrillation 11 (0.70) 3 (0.20)
Heart failure 15 (0.95) 11 (0.72)
Lung Oedema 11 (0.70) 11 (0.72)
Pneumonia 13 (0.82) 9 (0.59)
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SPC 350 0715-03
Serious adverse events occurring at ≥2% incidence in patients treated with ENOXAPARIN
SODIUM1 undergoing treatment of deep vein thrombosis with or without pulmonary embolism
Dosing Regimen
Enoxaparin Enoxaparin sodium Heparin
sodium inj inj aPTT Adjusted IV
1.5 mg/kg q.d. SC 1 mg/kg q12h SC therapy
n = 298 n = 559 n = 544
Adverse event Severe Total Severe Total Severe Total
Injection site 0% 5% 0% 3% <1% <1%
haemorrhage
Injection site 0% 2% 0% 2% 0% 0%
pain
Haematuria 0% 2% 0% <1% <1% 2%
1 Excluding unrelated adverse events
4.9 Overdose
Symptoms/Treatment: Accidental overdosage following administration of ENOXAPARIN

SODIUM may lead to haemorrhagic complications. Injected ENOXAPARIN SODIUM can be
largely neutralized by the slow IV injection of protamine sulphate (1% solution). The protamine
sulphate solution should be equal to the dose of injected ENOXAPARIN SODIUM: 1 mg of
protamine sulphate should be administered to neutralize 1 mg of ENOXAPARIN SODIUM. A
second infusion of 0.5 mg of protamine sulphate or 1 mg of ENOXAPARIN SODIUM may be
administered if the aPPT measured 2 to 4 hours after the first infusion remains prolonged. If at
least 12 hours have passed since the last injection of ENOXAPARIN SODIUM, the
administration of protamine may not be necessary. However, even with higher doses of
protamine, the aPPT may remain more prolonged than after the injection of heparin. In all
cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%).
Particular care should be taken to avoid protamine sulphate overdose. The administration of
protamine sulphate may cause severe hypotensive and anaphylactoid reactions. As fatal
reactions have been reported, frequently of anaphylactic type, with protamine sulphate, it
should be administered only when resuscitating techniques and treatment for anaphylactic
shock are readily available. For additional information, consult the PROTAMINE SULFATE
INJECTABLE prospect. A single SC dose of 46.4 mg/kg of enoxaparin was lethal to rats. The
acute toxicity symptoms were ataxia, mobility decrease, dyspnoea, cyanosis and coma.
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SPC 350 0715-03
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamics properties
NOXPRIN, enoxaparin sodium, is a low molecular weight heparin that has antithrombotic
properties. In humans, enoxaparin given at a dose of 1.5 mg/kg SC is characterized by a higher
ratio of anti- Factor Xa or 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), 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).
5.2 Pharmacokinetics (conducted using the 100 mg/mL formula):
Absorption. Maximum anti-factor Xa and anti-thrombin (anti-factor IIa) activities occur 3 to 5

hours after the SC injection of enoxaparin. Mean peak anti-factor Xa activity was 0.16 IU/mL
(1.58 μg/mL) and 0.38 IU/mL (3.83 μg/mL) after the 20 mg and 40 mg clinically tested SC
doses, respectively. Mean (n=46) peak anti-Factor Xa activity was 1.1 IU/mL 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 volunteers. Enoxaparin pharmacokinetics appears to be linear over the
recommended dosage ranges. After repeated SC administration of 40 mg once daily and 1.5
mg/kg regimens in healthy volunteers, stability is reached on day 2 with an average exposure
ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels can be
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 stable 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. When a daily 1.5 mg/kg SC injection of
enoxaparin sodium was given to 25 healthy subjects of both sexes using a 100 mg/ml or 200
mg/ml concentration, the following pharmacokinetic profiles were obtained:
Pharmacokinetic parameters* after 5 days of 1.5 mg/kg SC Once Daily Doses of Enoxaparin
Sodium using 100 or 200 mg/ml concentrations
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SPC 350 0715-03
Concentration Anti-Xa Anti-IIa Heptest aPTT

Amax 100 mg/ mL 1.37 (±0.23) 0.23 104.5 19.3
(IU/mL or Δ (±0.05) (±16.6) (±4.7)
sec)
200 mg/mL 1.45 (±0.22) 0.26 110.9 22 (±6.7)
(±0.05) (±17.1)
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 100 mg/mL 14.26 1.54 1321 (±219)
(ssh*IU/mL (±2.93) (±0.61)
or h* Δ sec)
200 mg/mL 15.43 1.77 1401 (±227)
(±2.96) (±0.67)
90% CI 105-112% 103-109%
*Means ± SD at day 5 and 90% Confidence Interval (CI) of the ratio

**Median (range)
Distribution: The volume of distribution of anti-Factor Xa activity is about 4.3 litres.

Elimination: Following IV dosing, the total body clearance of enoxaparin is 26 mL/min. After IV
dosing of enoxaparin labelled with 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 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 desulphation 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.
5.3. Preclinical safety data
Toxicology
Single-dose toxicity
Acute toxicity was produced in rodents by the iv or sc administration of dose of enoxaparin of
6000-8000 and 2300 mg/kg respectively. Acute toxicity was manifested by ataxia, dyspnoea,
cyanosis, seizures and death.
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SPC 350 0715-03
Repeated dose toxicity

In sub chronic and chronic toxicity studies, bleeding was the main manifestation of drug effect.
Changes in haematology profile and development of extra medullary hemopoiesis were
related to blood loss. The highest non-toxic dose in chronic toxicity studies of 26 weeks was 3
mg/kg/day both in rats and monkeys.
The effect of enoxaparin on calcium metabolism was not observed in rodents or monkeys.
Elevation of serum urea, renal tubular necrosis and renal capsular haemorrhage were
observed in rats given enoxaparin at the dose of 40 mg/kg/day iv for 26 days.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Please see section 2.
6.2 Incompatibilities
Subcutaneous injection: do not administer with other products.
Intravenous bolus injection: the product can be safely administered with normal saline
solution (0.9%) or 5% aqueous dextrose.
6.3 Shelf life
36 months
6.4 Special precautions for storage
KEEP OUT OF THE REACH OF CHILDREN

STORE BELOW 25 ºC
DO NOT REFRIGERATE OR FREEZE. PROTECT FROM LIGHT.
6.5 Nature and contents of container
NOXPRIN 20: Packages with 1, 2, 10 and 100 pre-filled syringes with 0.2 mL
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Page 18 of 19
SPC 350 0715-03
6.6 Special precautions for disposal and handling
The solution for injection in a pre-filled syringe is ready for use.
For single use only. Only solution without particles and without visible signs of deterioration
should be used.
Any unused medicinal product or waste material should be disposed of in accordance with
local requirements.
7. MARKETING AUTHORISATION HOLDER
Tel.: (005982) 2209 09 09*. Fax: (005892) 2209 08 68
Montevideo – Uruguay
8. MARKETING AUTHORISATION NUMBER (S)
In Uruguay Noxprin is registered with the following numbers:
Noxprin 20: 42281

Noxprin 40: 42282
Noxprin 60: 42283
Noxprin 80: 42284
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorization: 29/06/2009

Date of last renewal: 29/06/2014
10. DATE OF REVISON OF THE TEXT
07/2015
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SUMMARY OF PRODUCT CHARACTERISTICS

SPC 350 0715-03

1. NAME OF THE MEDICINAL PRODUCT

Each pre-filled syringe contains:

Raw material Noxprin 20 Noxprin 40 Noxprin 60 Noxprin 80

Prefilled syringes with solution for injection.

4.1 Therapeutic Indications

• Prophylaxis of deep vein thrombosis which may lead to pulmonary embolism in

- Undergoing abdominal surgery with risk of thromboembolic complications.

It is also indicated in the following cases:

4.2 Posology and method of administration

Abdominal surgery: In patients undergoing abdominal surgery who are at risk of

Indication Dosage Regimen

NOXPRIN is contraindicated in patients with active major bleeding, in patients with

4.4 Special warnings and precautions for use

NOXPRIN is not meant for intramuscular use.

Haemorrhage: ENOXAPARIN SODIUM, as well as other anticoagulants, must be used with

50,000/mm3) occurred at a rate of 1.3% in patients given ENOXAPARIN SODIUM, 1.2% in

ENOXAPARIN SODIUM must not be mixed with other injections or infusions.

4.6 Pregnancy and breastfeeding

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

Major haemorrhagic events after abdominal and colorectal surgery1

Major haemorrhagic events after hip or knee replacement surgery1

Major haemorrhage episodes in unstable angina and non-Q-wave myocardial infarction

Thrombocytopenia: see WARNINGS: Thrombocytopenia, Elevations in serum

1 Excluding unrelated adverse events

Symptoms/Treatment: Accidental overdosage following administration of ENOXAPARIN

5.1 Pharmacodynamics properties

5.2 Pharmacokinetics (conducted using the 100 mg/mL formula):

Absorption. Maximum anti-factor Xa and anti-thrombin (anti-factor IIa) activities occur 3 to 5

Concentration Anti-Xa Anti-IIa Heptest aPTT

*Means ± SD at day 5 and 90% Confidence Interval (CI) of the ratio

Distribution: The volume of distribution of anti-Factor Xa activity is about 4.3 litres.

5.3. Preclinical safety data

Repeated dose toxicity

6.1 List of excipients

Please see section 2.

Subcutaneous injection: do not administer with other products.

6.3 Shelf life

6.4 Special precautions for storage

KEEP OUT OF THE REACH OF CHILDREN

6.5 Nature and contents of container

6.6 Special precautions for disposal and handling

The solution for injection in a pre-filled syringe is ready for use.

7. MARKETING AUTHORISATION HOLDER

8. MARKETING AUTHORISATION NUMBER (S)

In Uruguay Noxprin is registered with the following numbers:

Noxprin 20: 42281

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 29/06/2009

10. DATE OF REVISON OF THE TEXT

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