BEMIPARIN: PROPHYLAXIS OF VTE IN SURGICAL AND ORTHOPAEDIC PATIENTS

COMMITMENT TO PREVENTION

Bemiparin 2500 IU/ 0,2 mlBemiparin 3500 IU/ 0,2 ml

Surgical prophylaxis1-7

01Unlike other LMWHs, BEMIPARIN allows the initiation of thromboprophylaxis in the postoperative period1, 2

02BEMIPARIN, thromboprophylactic regimen 6 hours after or 2 hours before surgery3

03The postoperative regimen facilitates neuraxial anaesthesia techniques, minimizing the risk of spinal haematoma without compromising efficacy3, 4, 6

The postoperative initiation of thromboprophylaxis with bemiparin allows the admission of the patient on the same day of the procedure. This could reduce the costs of the hospital stay7

Preoperative Period Surgicalprocedure

Insertionof

catheter

BEMIPARIN3.500IU/day

BEMIPARIN3.500IU/day

Postoperative6 hours

Removal of

catheter

≥ 12 hours ≥ 4 hours

01BEMIPARIN in different situations in the field of orthopaedic surgery in clinical practice8

• Bemiparin was studied in 7,959 patients, of which 84.9% received doses of 3,500 IU/day and 15.1% received 2,500 IU/day8

• Thromboprophylaxis with bemiparin during 3-4 weeks in patients immobilized with plaster casts and other orthopaedic processes was associated to lower rates of VTE, haemorrhages and other adverse effects8

In patients undergoing major orthopaedic surgery, it is recommended that the prophylaxis is extended in the outpatient period until 35 days after surgery, compared with prophylaxis during 10-14 days9

Surgical prophylaxis. Orthopaedics8, 9

Data taken from the 9th edition of the ACCP guidelines 2012

02The initiation of the postoperative prophylaxis with BEMIPARIN in patients undergoing TKR/THR and its subsequent administration during 5-6 weeks was effective and safe3

INCIDENCE (%) OF VTE, DVT AND PE with bemiparin postoperatively in orthopaedic surgery

221,51,5

110,50,5

0,3% 0,3% 0,3% 0,3% 0,3% 0,3%0%

0,3% 0,2% 0%0,3% 0,1%

Total VTE Total DVT Proximal Distal

Knee Arthroplasty (n=653)(TKR)

Hip Arthroplasty (n=356)(THR)

Total events (n=1.009)

Data taken from Abad JL et al3

Surgical prophylaxis: Total knee replacement6, 7

01 efficacy and safetyBEMIPARIN 3,500 IU/day postoperatively is as effective and safe as enoxaparin in the preoperative regimen in the prevention of VTE in total knee replacement (TKR)6

02 cost-efficacyBEMIPARIN is more cost-effective than Enoxaparin in patients undergoing TKR, with savings in the costs per patient7

03 local reactions at the injection siteThe incidence of haematomas and other local reactions at the injection site was significantly minor in the BEMIPARIN group of patients than in the enoxaparin group6

8080606040402020

61 (32,5%)

Nº o

f pat

ient

s (%

)

42 (22,7%)

p=0,03

Enoxaparin BemiparinStart 12 hours before procedure Start 6 hours after procedure

INCIDENCIE of haematomas and ecchymosis at the injection site

Data taken from Navarro-Quilis A et al6

Surgical prophylaxis: Total hip replacement10, 11

01 preoperative regimen10

The incidence of DVT confirmed by phlebography was significantly lower in the group of patients treated with BEMIPARIN 3,500 IU/day (8.9%) than in the group treated with UFH (20.7%, p=0.03)10

The relative risk of developing thrombosis with UFH was two times greater (RR: 2.67, 95% CI 1.18-6.05)10

RandomizationUFH Su

rgic

alpr

oced

ure

12 ±

4 d

ays

-2 hours Monitoring

4 w

eeks

Bemiparin 3500 IU/day149 patients

149 patients298 patients

202015151010

55 0,8% 1,5%Inci

denc

e (%

)

p=0,01 for total VTE

n=125 n=134 n=125 n=134

7,2%

18,7%

PE VTE Totaln=125 n=134

3,0%4,3%

Proximaln=125 n=134

4,0%

11,2%

Distal

Bemiparin UFH

EFFICACY ofBemiparin 3,500 IU/day

preoperatively in the prevention of VTEin hip arthroplasty

Data taken from Kakkar W et al10

Data taken of Kakkar W et al10

There were no significant differences between both treatments in the incidence of major bleeding requiring prophylaxis discontinuation; intraoperative bleeding losses, need for transfusion or wound haematomas10

02 postoperative regimen11

BEMIPARIN 3,500 IU/day in postoperative regimen is effective and safe in preventing VTE in patients undergoing hip replacement11

With BEMIPARIN 3,500 IU/day no major bleeding was observed and a single case of haematoma was detected. Neither ecchymosis was observed at the injection site11

Bemiparin 3,500 IU/day postoperative regimen (n=57)

88664422

7,02%

Nº o

f pat

ient

s (%

)

5,26%

Total DVT Proximal DVT

EFFICACY of Bemiparin 3,500 IU/day in postoperative regimen in the prevention of VTE in hip arthoplasty

Data taken from Planés A et al11

Prophylaxis in major ambulatory surgery

01BEMIPARIN 2,500 IU/day and 3,500 IU/day is the only LMWH licensed for the postoperative initiation of thromboprophylaxis2.

• Starting with the first dose 6 hours after surgery, every 24 hours during 7 days, in patients with moderate and high risk5

No risk

Moderate risk

High risk

Riskassessment

Surg

ical

proc

edur

e

10 d

ays

Bemiparin2.500 IU/day

6 h

Bemiparin3.500 IU/day

6 h

Firstpostoperative dose

Bemiparin2.500 IU/day or 3.500 IU/day

during 7 days

Eco-doppler

30 d

ays

Clinical assessment ofthromboembolic events

402 patients

119 patients

208 patients

30 patients

Data taken from Lozano FS et al5

02There were no documented cases of symptomatic thromboembolic episodes in any patient group5

03Distribution of risk groups in accordance with consensus before and after surgical procedure, after knowing the results of the thrombophilia study5

No risk

Risk groupBefore the procedure*(a priori) n=402

Moderate risk

High risk

n=14135,1%

n=22856,7%

n=338,2%

After the procedure**(a posteriori) n=402

n=10325,6%

n=19949,5%

n=10024,9%

Data taken from Lozano FS et al5

* Patients with thrombophilia n=38** Patients with thrombophilia n= 67

Convenience and adherence

01Patients who received BEMIPARIN showed a high degree of compliance and acceptance of the prophylaxis5

02In most cases, the drug was administered by the patient himself or by a family member, therefore, the assistance of a healthcare professional was not required5

BEMIPARIN SODIUM (I.N.N) COMPANY CORE DATA SHEET

1. NAME OF THE MEDICINAL PRODUCT.Bemiparin sodium 3,500 IU anti Xa/0.2 ml solution for injection in pre-filled syringes.Bemiparin sodium 2,500 IU anti Xa/0.2 ml solution for injection in pre-filled syringes.Bemiparin sodium 5,000 IU anti Xa/0.2 ml solution for injection in pre-filled syringes.Bemiparin sodium 7,500 IU anti Xa/0.3 ml solution for injection in pre-filled syringes.Bemiparin sodium 10,000 IU anti Xa/0.4 ml solution for injection in pre-filled syringes.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION.Bemiparin sodium: 3,500 IU (anti Factor Xa*) per 0.2 ml pre-filled syringe (equivalent to 17,500 IU (antiFactor Xa*) per millilitre of solution for injection).Bemiparin sodium: 2,500 IU (anti Factor Xa*) per 0.2 ml pre-filled syringe (equivalent to 12,500 IU (antiFactor Xa*) per millilitre of solution for injection).Bemiparin sodium: 5,000 IU (anti-Factor Xa*) per 0.2 ml pre-filled syringe (equivalent to 25,000 IU (antiFactor Xa*) per millilitre of solution for injection).Bemiparin sodium: 7,500 IU (anti-Factor Xa) per 0.3 ml pre-filled syringe (equivalent to 25,000 IU (antiFactor Xa*) per millilitre of solution for injection).Bemiparin sodium: 10,000 IU (anti-Factor Xa) per 0.4 ml pre-filled syringe (equivalent to 25,000 IU (antiFactor Xa*) per millilitre of solution for injection).*Potency is described in International anti-Factor Xa activity units (IU) of the 1st International Low Molecular Weight Heparin Reference Standard of the WHO.For excipients, see 6.1.

3. PHARMACEUTICAL FORM.Solution for injection in pre-filled syringes. (Colourless, clear or slightly yellowish solution, free from visible particles).

4. CLINICAL PAR TICULARS.4.1. Therapeutic indications.Prevention of thromboembolic disease in patients undergoing general and orthopaedic surgery.

Prevention of thromboemobolic disease in non-surgical patients with high or mild risk.Secondary prevention of venous thromboembolism recurrences in patients with deep vein thrombosis and transient risk factors.Prevention of clotting in the extracorporeal circuit during haemodialysis.The treatment of established deep vein thrombosis, with or without pulmonary embolism.

4.2. P osology and method of administration:WARNING: The different low molecular weight heparins are not necessarily equivalent. Therefore compliance with the dosage regimen and the specific method of usefor each of these medicinal products is required.Adults:General surgery with mild risk of venous thromboembolism:On the day of the surgical procedure, 2,500 IU anti-Xa are to be administered by subcutaneous route, 2 hours before or 6 hours after surgery. On subsequent days, 2,500 IU anti-Xa sc are to be administered every 24 hours.Orthopaedic surgery with high risk of venous thromboembolism:On the day of the surgical procedure, 3,500 IU anti-Xa are to be administered by subcutaneous route, 2 hours before or 6 hours after surgery. On subsequent days, 3,500 IU anti-Xa sc is to be administered every 24 hours.Prophylactic treatment must be followed in accordance with the physician’s opinion during the period of risk or until the patient is mobilised. As a general rule, it is considered necessary to maintain prophylactic treatment for at least 7 – 10 days after the surgical procedure and until the risk of thromboembolic disease has decreased.Prevention of the thromboembolic disease in non-surgical patients:The recommended posology of bemiparin is 2,500 IU/day or 3,500 IU/day by subcutaneous route, according to whether the set of risk factors of the patients defines them as mild or high-risk thromboembolic patients.Prophylactic treatment must be continued, according to the physician’s criteria, during the risk period or until the complete mobilisation of the patient.Secondary prevention of venous thromboembolism recurrence in patients with deep vein thrombosis and transient risk factors:Bemiparin can be administered at a fixed dose of 3,500 IU/day (up to a maximum of 3 months) in patients who have received anticoagulant treatment for deep vein thrombosis with or without pulmonary embolism, as therapeutic alternative to the administration of oral anti-coagulants or whenever they are contra-indicated.Prevention of clotting in the extracorporeal circuit during haemodialysis:For patients undergoing repeated haemodialysis of no longer than 4 hours in duration and with no risk of bleeding, the prevention of clotting in the extracorporeal circuit during haemodialysis is obtained by injecting a single dose in the form of bolus into the arterial line at the beginning of the dialysis session. For patients weighing less than 60 kg, the dose will be 2,500 IU, whereas for patients weighing more than 60 kg, the dose will be 3,500 IU.Treatment of deep vein thrombosis:Bemiparin should be administered by the subcutaneous route at a dose of 115 IU anti-Xa/kg weight, once daily. The recommended duration of treatment is 7 ± 2 days. The daily dose generally corresponds - depending on the body weight range- to the following doses and volumes of the product in prefilled syringes: < 50 kg, 0.2 ml (5,000 IU anti-Xa);50-70 kg, 0.3 ml (7,500 IU anti-Xa), > 70 kg, 0.4 ml (10,000 IU anti-Xa). In patients weighing more than 100 kg body-weight, the dose should be calculated on the basis of 115 IU anti-Xa/kg/day, where the concentration of anti-Xa is 25,000 IU/mL.In the absence of any contra-indication, oral anticoagulation should be commenced 3-5 days after beginning Bemiparin first administration, and the dose adjusted so as to keep the International Normalized Ratio (INR) value between 2-3 times the control value. Bemiparin administration can be stopped as soon as the said INR value is achieved.Oral anticoagulation should be continued for at least 3 months.Children: The safety and efficacy of the use of bemiparin in children has not been established, therefore the usage in children is not recommended.Elderly: No dose adjustment required.Renal and hepatic impairment: There are insufficient data to recommend a dose adjustment of bemiparin in this group of patients.Method of administration. Subcutaneous injection technique:

The pre-filled syringes are ready for immediate use and must not be purged before the subcutaneous injection. When Bemiparin is administered subcutaneously, the injection should be given in the subcutaneous cell tissue of the anterolateral or posterolateral abdominal waist, alternately on the left and right sides. The needle should be fully inserted, perpendicularly and not tangentially, into the thick part of a skin fold held between the thumb and the forefinger; the skin fold should be held throughout the whole injection. Do not rub the injection site.

4.3. Contraindications.Hypersensitivity to bemiparin sodium, heparin or substances derived from pigs.History of confirmed or suspected immunologically mediated heparin induced thrombocytopenia (HIT) (see 4.4: Special warnings and precautions for use).Active haemorrhage or increased risk of bleeding due to impairment of haemostasis.Severe impairment of liver and pancreas function.Injuries to and operations on the central nervous system, eyes and ears.Disseminated Intravascular Coagulation (DIC) attributable to heparin-induced thrombocytopenia.Acute bacterial endocarditis and endocarditis lenta.Organic lesion with high risk of bleeding (e.g. active peptic ulcer, haemorragic stroke, cerebral aneurysm or cerebral neoplasms).In patients receiving heparin for treatment rather than for prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated.

4.4. Special warnings and precautions for use.Do not administer by the intramuscular route.Due to the risk of haematoma during bemiparin administration, the intra-muscular injection of other agents should be avoided.Caution should be exercised in patients with liver or renal failure, uncontrolled arterial hypertension, history of gastro-duodenal ulcer disease, thrombocytopenia, nephrolithiasis and/or urethrolithiasis, choroid and retinal vascular disease, or any other organic lesion with an increased risk of bleeding complications, or in patients undergoing spinal or epidural anaesthesia and/or lumbar puncture.Bemiparin, like other LMWHs, can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with the duration of therapy but is usually reversible. Serum electrolytes should be measured in patients at risk before starting bemiparin therapy and monitored regularly thereafter particularly if treatmentis prolonged beyond about 7 days.Occasionally a mild transient thrombocytopenia (type I) at the beginning of therapy with heparin with platelet counts between 100,000/mm3 and 150,000/mm3 due to temporary platelet activation has been observed (see 4.8: Undesirable effects). As a rule, no complications occur, therefore treatment can be continued.In rare cases antibody-mediated severe thrombocytopenia (type II) with platelet counts clearly below 100,000/mm3 has been observed (see 4.8: Undesirable effects). This effect usually occurs within 5 to 21 days after the beginning of treatment; in patients with a history of heparin-induced thrombocytopenia this may occur sooner.Platelet counts are recommended before administration of bemiparin, on the first day of therapy and then regularly every 3 to 4 days and at the end of therapy with bemiparin.In practice, treatment must be discontinued immediately and an alternative therapy initiated if a significantly reduced platelet count is observed (30 to 50%) ,associated with positive or unknown results of in-vitro tests for anti-platelet antibody in the presence of bemiparin or other LMWHs and /or heparins.As with other heparins, cases of cutaneous necrosis, sometimes preceded by purpura or painful erythematous blotches have been reported with bemiparin (see 4.8:Undesirable effects). In such cases, treatment should be discontinued immediately.In patients undergoing epidural or spinal anaesthesia or lumbar puncture, the prophylactic use of heparin may very rarely be associated with epidural or spinal haematoma, resulting in prolonged or permanent paralysis (see 4.8: Undesirable effects). The risk is increased by the use of an epidural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or anticoagulants (see 4.5: Interaction with other medicinal products and other forms of interaction), and by traumatic or repeated puncture. When reaching a decision as to the interval between the last heparin administration at prophylactic doses and the placement or removal of an epidural or spinal catheter, the product characteristics and the patient profile should be taken into account. At least 12 hours should elapse for LMWH. The subsequent dose of bemiparin should not take place until at least four hours after removal of the catheter. The subsequent dose should be delayed until the surgical procedure is completed.Should a physician decide to administer anticoagulation treatment in the context of epidural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment, such as back pain, sensory and motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction. Nurses should be trained to detect such signs and symptoms. Patients should be instructed to inform a nurse or a clinician immediately if they experience any of these symptoms.If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment including spinal decompression should be initiated.

4.5. Interaction with other medicinal products and other forms of interaction.Bemiparin interactions with other medicinal products have not been investigated and the information given on this section is derived from data available from other LMWH.The concomitant administration of bemiparin and the following medicinal products is not advisable:Vitamin K antagonists and other anticoagulants, acetyl salicylic acid and other salicylates and NSAIDs, ticlopidine, clopidogrel and other platelet inhibitors, systemic glucocorticoids and dextran .All these drugs increase the pharmacological effect of bemiparin by interfering with its action on coagulation and/or platelet function and increasing the risk of bleeding.If the combination cannot be avoided, it should be used with careful clinical and laboratory monitoring.Medicinal products that increase the serum potassium concentration should only be taken concomitantly under especially careful medical supervision.Interaction of heparin with intravenous nitroglycerine (which can result in a decrease in efficacy) cannot be ruled out for bemiparin.

4.6. Pregnancy and lactation.Pregnancy: Animal studies have not shown any evidence of teratogenic effects with the use of bemiparin (see 5.3: Preclinical safety data). For bemiparin, no clinical data on exposed pregnancies are available. Therefore, caution should be exercised when prescribing to pregnant women. It is unknown whether bemiparin crosses placental barrier.Lactation: Insufficient information is available as to whether bemiparin passes into breast milk. Therefore, where it is necessary for lactating mothers to receive Bemiparin, they should be advised to avoid breast-feeding.

4.7. Effects on ability to drive and use machines.Bemiparin has no influence on the ability to drive and use precision or dangerous machinery.

4.8. Undesirable effects.The most commonly reported adverse reaction is haematoma and/or ecchymosis at the injection site, occurring in approximately 15% of patients receiving Bemiparin.Osteoporosis has been associated with long-term heparin treatment.The frequency of AEs reported with bemiparin are similar to those reported with other LMWHs and is as follows:Very common ( >1/10):

• Ecchymosis at injection site Common (>1/100, <1/10):• Haematoma and pain at injection site. Bleeding complications (skin, mucous membranes, wounds, gastro-

intestinal tract, urogenital tract).• Mild and transient elevations of transaminases (ASAT, ALAT) and gamma-GT levels. Uncommon (>1/1000, <1/100):• Cutaneous allergic reactions (urticaria, pruritus).• Mild and transient thrombocytopenia (type I) (see 4.4: Special warnings and precautions for use). Rare (<1/1000):• Anaphylactic reactions (nausea, vomiting, fever, dyspnoea, bronchospasm, glottis oedema, hypotension, urticaria,

pruritus).• Severe thrombocytopenia (type II) (see 4.4: Special warnings and precautions for use).• Cutaneous necrosis at the injection site (see 4.4: Special warnings and precautions for use).• Epidural and spinal haematoma following epidural or spinal anaesthesia and lumbar puncture. These haematomas

have caused various degrees of neurological impairment,including prolonged or permanent paralysis (see 4.4: Special warnings and precautions for use).

4.9. Overdose.Bleeding is the main symptom of overdose. Bemiparin should be discontinued depending on the severity of the haemorrhage and the risk of thrombosis.Minor haemorrhages rarely need specific treatment. In case of major haemorrhages, administration of protamine sulphate may be needed.The neutralisation of bemiparin with protamine sulphate has been studied in-vitro and in-vivo, with the aim of observing the reduction of anti-Xa activity and the effect on the APTT. Protamine sulphate exerts a partial decrease on anti-Xa activity for 2 hours after its intravenous administration, at a dose of 1.4 mg of protamine sulphate each 100 IU anti-Xa administered.

5. P HARMACOLOGICAL PROPERTIES.5.1. Pharmacodynamic properties.

Pharmacotherapeutic group: antithrombotic agent, heparin group. ATC Code: B01AB12.Bemiparin sodium is a LMWH obtained by depolymerization of heparin sodium from porcine intestinal mucosa. Its mean molecular weight (MW) is approximately 3,600 Daltons.The percentage of chains with MW lower than 2,000 Daltons is less than 35%. The percentage of chains with MW from 2,000 to 6,000 Daltons ranges between 50-75%. The percentage of chains with MW higher than 6,000 Daltons is less than 15%.The anti-Xa activity ranges between 80 and 120 anti-Xa IU per mg and the anti-IIa activity ranges between 5 and 20 anti-IIa IU per mg, calculated in relation to dry matter. The anti-Xa/anti-IIa ratio is approximately 8.In animal experiment models, bemiparin has shown antithrombotic activity and moderate haemorrhagic effect.In humans, bemiparin has confirmed its antithrombotic activity and, at the recommended doses, it does not significantly prolong global clotting tests.

5.2. Pharmacokinetic properties.The pharmacokinetic properties of bemiparin have been determined by measuring the plasma anti-Xa activity using the amydolitic method; it is based on reference to the W.H.O.First International Low Molecular Weight Heparin Reference Standard (NIBSC).

The absorption and elimination processes follow a linear kinetic of the 1st order. Absorption: Bemiparin sodium is rapidly absorbed following subcutaneous injection and the bioavailability is estimated to be 96%. The maximum plasma anti-Xa effect at prophylactic doses of 2,500 IU and 3,500 IU occurs 2 to 3 hours after subcutaneous injection of bemiparin, reaching peak activities in the order of 0.34 + 0.08 and 0.45 + 0.07 IU anti-Xa/ml, respectively. Anti-IIa activity was not detected at these doses. The maximum plasma anti-Xa effect at treatment doses of 5,000 IU, 7,500 IU, 10,000 IU and 12,500IU occurs 3 to 4 hours after subcutaneous injection of bemiparin, reaching peak activities in the order of 0.54 + 0.06, 1.22 + 0.27, 1.42 + 0.19 and 2.03 + 0.25 IU anti-Xa/ml, respectively. Anti-IIa activity of 0.01 IU/ ml was detected at doses of 7,500 IU, 10,000 IU and 12,500 IU.Elimination: Bemiparin administered in the dose range of 2,500 IU to 12,500 IU has an approximate half-life of between 5 and 6 hours, and should therefore be administered once daily.There are currently no data available with regards to plasma protein binding, metabolism and excretion of bemiparin in humans.

5.3. Preclinical safety data.Preclinical data for bemiparin reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity and reproduction toxicity.Acute and repeated dose toxicity studies following subcutaneous administration of bemiparin in animals have revealed alterations consisting essentially in reversible, dosedependent haemorragic lesions at the injection site. These were considered to result from exaggerated pharmacological activity.In the studies of reproductive toxicity performed with bemiparin in pregnant rats and rabbits, between days 6 and 18 of the pregnancy, no mortality was recorded among the females treated with bemiparin. The main clinical signs recorded were subcutaneous haematomas that were attributable to a pharmacological effect of the test item. No treatment-related embryotoxic effect neither external, skeletal and/or visceral alterations were recorded in the examination of foetuses.

6. PHARMACEUTICAL PAR TICULARS.6.1. List of excipients.

Water for injections.

6.2. Incompatibilities.Bemiparin should not be mixed with any other injections or infusions.

6.3. Shelf life.24 months. After first opening, Bemiparin should be used immediately .

6.4. Special precautions for storage.Bemiparin sodium 2,500 and 3,500 IU anti Xa: Do not store above 30º C. Do not freeze.Bemiparin sodium 5,000; 7,500 and 10,000 IU anti Xa: Do not store above 25º C. Do not freeze.

6.5. Nature and contents of container.0.2 ml solution in pre-filled syringe (Type I glass) with a plunger rod (polypropylene), rubber plunger stopper (chlorobutyl) and injection needle (stainless steel). Packs of 2,10, 30 and 100 syringes. Not all packs sizes may be marketed.

6.6. Special precautions for disposal.Single-dose container. Discard any unused content. Do not use if the protective package is opened or damaged. Only clear colourless or slightly yellowish solutions, free ofvisible particles, should be used. Any unused product and injection needles should be disposed of in accordance with local requirements.

7. MAR KETING AUTHORISATION HOLDER.Laboratorios Farmacéuticos ROVI S.A. Julian Camarillo, 35.28037 MADRID – SPAIN.

9. DATE OF FIRST AUTHORISATION.16th April, 1998 (Spain).

10. DATE OF REVISION OF THE TEXT.January 2008.

1. Bemiparin company core Data sheet.

2. Rocha E, Imberty D, Paschina E. Low-Molecular Weight Heparins: Before or After Surgery? New Concepts and Evidence. Clin Drug Invest 2007; 27(5); 357-366.

3. Abad Ji, Gómez-Outes A, Martínes-González J, Rocha E. A prospective observationall study on the effectiveness and safety of bemiparin, first does administered 6 h afeter knee or hip replacement surgery. Arch Orthop Trauma Surg 2007; 127:665-70

4. Abad Rico JI, Lozano Sánchez FS, Rocha E. Clinical experience with bemiparin. Drug 2010 Dec 14; 70 Suppl 2:25-33

5. Lozano FS, Sánchez-Fernandéz J, Santos JA, García-Alovio J, Mateos R, Gonzalés- Porras JR et al. Venous thromboembolism risk stratification and thromprophylaxis with low molecular weight heparin in patients undergoing major ambulatory surgery: an observational prospective study. Amb Surg 2010, 16:5-11

6. Navarro-Quilis A, Castellet E, Rocha E, Paz-Jiménez J, Planés A. Efficacy and safety of bemiparin compared with enoxaparin in the prvention of venous thromboembolism afeter total knee arthroplasty: a randomized, double blind clinical trial. J Thromb Haemost 2003; 1; 425-32.

7. Honorato J, Gómez-Outes A, Navarro-Quilis A, Martínez-GonzálezJ, Roche-E, planés A. Pharmacoeconomic analysis of

bemiparin and enoxaparin as prophylaxis for venous thromboembolism in total knee replacement surgery. Pharmaceconomic 2004; 22:885-94.

8. Otero-Fernández R, Gomez-Outes A; Martínes- González J, Rocha E, Fontcuberta J. Evaluation of the effectiveness and safety of bemiparin in a large population of orthopedic patients in a normal clinical practice. Clin Appl Thromb Hemost.2008; 14:75-83.

9. Yngve Falck-Ytter,MD; Charles W. Francis, MD, Norma A. Johanson, MD; Catherine Curley, MD; Ola E. Dahi, MD; Sam Schulman, MD, PhD; Thomas L. Ortel, MD, PhD; Stephen G. Pauker, MD; and Clifford W.Colwell Jr, MD Prevention of VTE in Orthopedic Surgery patients. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141(2)(Suppl):e278s-e325s.

10. Kakkar W, Howes J, Sharma V, Kadziola Z.A comparative double-blind, randomized trial of a new generation LMWH (bemiparin) and UFG in the prevention of post-operative venous thromboembolism. The Bemiparin Assessment group. Thromb Haemost 2000;83;523-9.

11. Planés A, Vochelle N, González De Suso MJ, Claracq JP, Prophylactic antothrombotic therapy after orthopaedic surgery with bemiparin, a second generation low molecular weight heparin. Rev Esp Anestesiol Reanim 2001;48(6);258-63.

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