SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zibor 25,000 IU anti-Xa/ml solution for injection in pre-filled syringes.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Bemiparin sodium: 25,000 IU (anti-Factor Xa*) per millilitre solution for injection.

Equivalent to: 5,000 IU (anti-Factor Xa) per 0.2 ml pre-filled syringe 7,500 IU (anti-Factor Xa) per 0.3 ml pre-filled syringe 10,000 IU (anti-Factor Xa) per 0.4 ml pre-filled syringe

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

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection in pre-filled syringes.

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

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment of established deep vein thrombosis, with or without pulmonary embolism, during the acute phase.

4.2 Posology and method of administration

WARNING: The different low molecular weight heparins are different and are not necessarily equivalent. Therefore it is important to comply with the dosage regimen and the specific method of use specified for each of these medicinal products.

Adults:

Treatment of deep vein thrombosis:

PHIVOR 25,000 IU 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 PHIVOR 25,000 IU 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: PHIVOR is not recommended for use in children due to a lack of data on safety and efficacy.

Elderly: No dose adjustment required.

Renal and hepatic impairment: There are insufficient data to recommend 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 PHIVOR 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 of porcine origin.

History of confirmed or suspected immunologically mediated heparin induced thrombocytopenia (HIT) (see section 4.4).

Active haemorrhage or increased risk of bleeding due to impairment of haemostasis.

Severe impairment of liver or pancreatic function.

Injuries to or operations on the central nervous system, eyes and ears within the last 2 months.

Disseminated Intravascular Coagulation (DIC) attributable to heparin-induced thrombocytopenia.

Acute bacterial endocarditis and endocarditis lenta.

Any organic lesion with high risk of bleeding (e.g.: active peptic ulcer, haemorrhagic 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 intramuscular injection of other agents should be avoided.

Caution should be exercised in patients with liver or renal failure (anti-factor Xa levels should be regularly monitored in patients with severe renal impairment), 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 those taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with the duration of therapy but is usually reversible (see section 4.8). Serum electrolytes should be measured in patients at risk before starting bemiparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond 7 days.

Occasionally a mild transient thrombocytopenia (HIT type I) at the beginning of therapy with heparin with platelet counts between 100,000/mm³ and 150,000/mm due to temporary platelet activation has been observed (see section 4.8). As a general rule, no complications occur, therefore treatment can be continued.

In rare cases antibody-mediated severe thrombocytopenia (HIT type II) with platelet counts clearly below 100,000/mm³ has been observed (see section

4.8) . This effect usually occurs within 5 to 21 days after the beginning of treatment, although 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, 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 section 4.8). 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 haematomas, resulting in prolonged or permanent paralysis (see section

4.8) . 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 section 4.5), 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 the above symptoms.

If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord 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 LMWHs.

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 Fertility, Pregnancy and lactation

Pregnancy: Animal studies have not shown any evidence of teratogenic effects with the use of bemiparin (see section 5.3). 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 PHIVOR, they should be advised to avoid breast-feeding.

4.7 Effects on ability to drive and use machines

PHIVOR has no influence on the ability to drive and use machines.

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 PHIVOR. Osteoporosis has been associated with long-term heparin treatment.

The undesirable effects are listed by system organ class and frequency: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data):

The frequency of adverse events (AEs) reported with bemiparin is similar to those reported with other LMWHs and is as follows:

System organ class and frequency	Adverse reaction
Blood and lymphatic system disorders:	Bleeding complications (skin, mucous membranes, wounds, gastro-intestinal
Common	tract, urogenital tract)
Uncommon	Mild and transient thrombocytopenia (HIT type I) (see section 4.4) Severe thrombocytopenia (type II) (see section 4.4)
Rare
Immune system disorders:	Cutaneous allergic reactions (urticaria,
Uncommon	pruritus)
Rare	Anaphylactic reactions (nausea, vomiting, fever, dyspnea, bronchospasm, glottis oedema, hypotension, urticaria, pruritus)
Metabolism and nutrition disorders:
Not known	Hyperkalemia (see section 4.4)
Hepatobiliary disorders:	Mild and transient elevations of
Common	transaminases (ASAT, ALAT) and gamma-GT levels.
Skin and subcutaneous tissue disorders:	Cutaneous necrosis at the injection site (see section 4.4).
Rare
General disorders and administration site conditions:
Very common	Ecchymosis at injection site. Haematoma and pain at injection site.
Rare	Epidural and spinal haematomas following epidural or spinal anaesthesia and lumbar puncture. These haematomas have caused various degrees of neurological impairment, including prolonged or permanent paralysis (see section 4.4)

4.9 Overdose

Bleeding is the main symptom of overdosage. If bleeding occurs 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 systems, with the aim of observing the reduction of anti-Xa activity and the effect on the Activated Partial Thromboplastin Time (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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic agent, heparin group. ATC code B01AB.

Bemiparin sodium is a LMWH obtained by depolymerization of heparin sodium from porcine intestinal mucosa. Its mean molecular weight (MW) is approximately 3,600 dal tons. 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 (National Institute for Biological Standards and Control, NIBSC).

The absorption and elimination processes follow a linear kinetic of the 1^st 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.

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 and genotoxicity.

Acute and repeated dose toxicity studies following subcutaneous administration of bemiparin in animals have revealed alterations consisting essentially in reversible, dose-dependent haemorrhagic lesions at the injection site. These were considered to result from exaggerated pharmacological activity.

No reproductive toxicity or carcinogenicity studies have been performed with bemiparin. Previously published studies of reproductive toxicity in which other LMWHs were administered to pregnant rats and rabbits, did not detect any direct or indirect adverse effects on fertility, embryo-foetal toxicity or peri and post-natal development.

6 PHARMACEUTICAL PARTICULARS

List of excipients

Water for injections

6.2 Incompatibilities

PHIVOR should not be mixed with any other injections and/or infusions.

6.3 Shelf life

2 years.

After first opening, Zibor should be used immediately.

6.4 Special precautions for storage

Do not store above 25° C. Do not freeze.

6.5 Nature and contents of container

0.2 ml, 0.3 ml and 0.4 ml of 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 pack 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 of visible particles, should be used.

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

FROSST IBERICA, S.A.

Via Complutense 140, Alcala de Henares, 28805 Madrid, Spain

8    MARKETING AUTHORISATION NUMBER(S)

PL 17770/0003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/03/2008

10 DATE OF REVISION OF THE TEXT

22/09/2012