Bemiparin sodium: 3500 IU (anti Factor Xa*) per 0.2 ml pre-filled syringe (equivalent to 17500 IU (antiFactor Xa*) per millilitre solution for injection)

Potency is described in International anti-Factor Xa activity units (IU) of the 1st International Low Molecular Weight Heparin Reference Standard

For excipients, see 6.1

Solution for injection in pre-filled syringe.

(Colourless or slightly yellowish, clear solution, free of visible particles)

Prevention of thromboembolic disease in patients undergoing orthopaedic surgery.

Prevention of clotting in the extracorporeal circuit during haemodialysis.

Adults:

Orthopaedic surgery with high risk of venous thromboembolism:

On the day of the surgical procedure, 3,500 IU anti-Xa is 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 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.

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 ZIBOR 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.

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).

Do not administer by the intramuscular route.

Due to the risk of haematoma during bemiparin administration the intramuscular 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 treatment is 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 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. 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 medullary decompression should be initiated.

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.

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 ZIBOR, they should be advised to avoid breast-feeding

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

The most commonly reported adverse reaction is haematoma and/or ecchymosis at the injection site, occurring in approximately 15 % of patients receiving ZIBOR.

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).

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.

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.

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 12,500 IU 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.

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, dose-dependent 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 fetuses

Water for injections

ZIBOR should not be mixed with any other injections or infusions.

2 years.

After first opening,ZIBOR should be used immediately

Do not store above 30º C. Do not freeze

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, 6, 10, 30 and 100 syringes.

Note: Not all pack sizes may be marketed

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

ROVI IMAGING S.L.

Rufino González, 50

28037 MADRID – SPAIN

ZIBOR 3,500 IU Registration number: 30417/0002

10 March 2002

June 2007