ZIBOR 25.000 IU Solution for injection Ref.[8450] Active ingredients: Bemiparin

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.

The kinetics of bemiparin may be affected in patients with severe renal impairment (creatinine clearance <30 mL/min). Regular monitoring is recommended in this population, especially when therapeutic doses are administered. After a careful assessment of the individual bleeding and thrombotic risks, the dose may be necessary to be adjusted. In mild or moderate renal impairment (creatinine clearance 30-80 ml/min) no dose adjustment is necessary, although caution should be exercised. (See sections: 4.2 Posology and method of administration and 5.2 Pharmacokinetic properties).

Caution should be exercised in patients with liver 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 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/mm³ 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.

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.

Pregnancy

Animal studies have not shown any evidence of teratogenic effects with the use of bemiparin (see section 5.3). For bemiparin, clinical data on exposed pregnancies are limited. However, caution should be exercised when prescribing to pregnant women. It is unknown whether bemiparin crosses placental barrier.

Breastfeeding

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 breastfeeding.

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

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 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:

Blood and lymphatic system disorders

Common: Bleeding complications (skin, mucous membranes, wounds, gastro-intestinal tract, urogenital tract)

Uncommon: Mild and transient thrombocytopenia (HIT type I) (see section 4.4)

Rare: Severe thrombocytopenia (type II) (see section 4.4)

Immune system disorders

Uncommon: Cutaneous allergic reactions (urticaria, pruritus)

Rare: Anaphylactic reactions (nausea, vomiting, fever, dyspnea, bronchospasm, glottis oedema, hypotension, urticaria, pruritus)

Metabolism and nutrition disorders

Not known (cannot be estimated from the available data): Hyperkalemia (see section 4.4)

Hepatobiliary disorders

Common: Mild and transient elevations of transaminases (ASAT, ALAT) and gamma-GT levels.

Skin and subcutaneous tissue disorders

Rare: Cutaneous necrosis at the injection site (see section 4.4).

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)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the HPRA Pharmacovigilance Earlsfort Terrace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@hpra.ie.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.