Cibor 2500

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYBOR 2500 (ZIBOR 2500)

Composition:

Active substance: bemiparin sodium;

1 ml of injection solution contains 12,500 IU anti-factor Xa (activity is stated in international units of anti-factor Xa activity according to the 1st International Standard for low-molecular-weight heparin);

1 pre-filled syringe contains 2,500 IU of bemiparin sodium (anti-factor Xa / 0.2 ml);

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, practically particle-free solution, ranging from colorless to light yellow.

Pharmacotherapeutic group. Antithrombotic agents. Heparin group.

ATC code B01A B12.

Pharmacological Properties

Pharmacodynamics

Bemiparin sodium is a low molecular weight heparin (LMWH) obtained by depolymerization of sodium heparin isolated from the intestinal mucosa of pigs. The average molecular weight (MW) of bemiparin is approximately 3600 daltons. The fraction of molecular chains with MW less than 2000 daltons is less than 35%. The fraction of molecular chains with MW between 2000 and 6000 daltons ranges from 50% to 75%. The fraction of molecular chains with MW above 6000 daltons is less than 15%. The anti-Xa factor activity of bemiparin ranges from 80 to 120 anti-Xa IU per 1 mg of dry substance, and the anti-IIa factor activity ranges from 5 to 20 anti-IIa IU per 1 mg of dry substance. The ratio of anti-Xa to anti-IIa factor activity is approximately 8:1. Experimental studies in animals have demonstrated the antithrombotic activity and moderate hemorrhagic effect of bemiparin. Use of bemiparin in humans confirms its antithrombotic activity and, when the recommended dosage is followed, causes only a minor prolongation of blood coagulation test times.

Pharmacokinetics

The pharmacokinetic properties of bemiparin were studied by measuring anti-Xa factor activity in plasma using an amidolytic method with the 1st International Standard of the WHO for low molecular weight heparin (National Institute for Biological Standards and Control, NIBSC).

The absorption and elimination processes follow linear first-order kinetics.

Absorption. Bemiparin sodium is rapidly absorbed after subcutaneous injection, with a bioavailability estimated at 96%. Maximum anti-Xa factor activity after prophylactic doses of 2500 IU and 3500 IU is reached within 2–3 hours after subcutaneous injection of bemiparin, with peak activity levels of approximately 0.34±(0.08) and 0.45±(0.07) IU anti-Xa/mL, respectively. Anti-IIa factor activity is not detected when these doses are administered. Maximum anti-Xa factor activity after administration of 5000 IU, 7500 IU, 10000 IU, and 12500 IU is reached within 3–4 hours after subcutaneous injection, with peak activity levels of approximately 0.54±(0.06), 1.22±(0.27), 1.42±(0.19), and 2.03±(0.25) IU anti-factor-Xa/mL, respectively. Anti-IIa factor activity of approximately 0.01 IU/mL was detected after administration of doses of 7500 IU, 10000 IU, and 12500 IU.

Elimination. The elimination half-life of bemiparin administered at doses ranging from 2500 IU to 12500 IU is between 5 and 6 hours. Therefore, bemiparin should be administered once daily. Currently, there are no data available regarding the ability of bemiparin to bind to plasma proteins, its metabolism, or its elimination in humans.

Elderly Patients

Results of the pharmacokinetic analysis from a clinical study involving young healthy volunteers and elderly patients (≥65 years) with normal renal function showed no significant differences in the pharmacokinetic profile of bemiparin.

Renal Impairment (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

Pharmacokinetic analysis from a clinical study involving young volunteers, elderly patients, and patients with varying degrees of renal impairment (creatinine clearance < 80 mL/min) demonstrates a relationship between multiple prophylactic dosing (3500 IU/24 h) and single therapeutic dosing (115 IU/kg) of bemiparin and creatinine clearance, as well as most pharmacokinetic parameters of anti-Xa factor activity. Furthermore, it was found that the effect of bemiparin (assessed by the area under the concentration-time curve (AUC) of anti-Xa factor activity) was significantly higher in the group of volunteers with severe renal impairment (creatinine clearance < 30 mL/min) compared to other volunteer groups.

On the other hand, pharmacokinetic modeling was performed to evaluate the profile of bemiparin after administration of ten consecutive daily doses. The average maximum anti-Xa factor activity (Amax), reproduced after administration of ten prophylactic doses (3500 IU/24 h), ranged from 0.35 to 0.60 IU anti-Xa/mL in all groups; however, in the group of volunteers with severe renal impairment (creatinine clearance <30 mL/min), one patient had an Amax value of 0.81 IU anti-Xa/mL after the tenth dose. When modeling a dose reduction to 2500 IU/24 h, the model predicted Amax values below 0.60 IU anti-Xa/mL (mean Amax = 0.42 IU anti-Xa/mL) for all volunteers with severe renal impairment. Additionally, the predicted mean Amax after administration of ten therapeutic doses (115 IU/kg/24 h) ranged from 0.89 to 1.22 IU anti-Xa/mL across all groups; in a volunteer from the severe renal impairment group, the Amax value was 2.09 IU anti-Xa/mL after the last dose. When modeling a dose adjustment to 75% of the therapeutic dose (86.25 IU/kg/24 h), the predicted Amax was 1.60 IU anti-Xa/mL for the aforementioned volunteer, and the mean Amax (0.91 IU anti-Xa/mL) for the severe renal impairment group remained within the range observed in other groups without dose adjustment.

Preclinical Safety Data

Preclinical data based on conventional safety pharmacology studies, repeated-dose toxicity, genotoxicity, and reproductive toxicity indicate no special hazard for humans.

Acute toxicity and repeated-dose toxicity studies in animals following bemiparin administration revealed changes primarily consisting of reversible, dose-dependent hemorrhagic lesions at the injection site. These were considered to be the result of excessive pharmacological activity.

In reproductive toxicity studies of bemiparin conducted in pregnant rats and rabbits between days 6 and 18 of gestation, no lethality was observed. The main clinical signs of reproductive toxicity recorded were subcutaneous hematomas, which are also consistent with the pharmacological effects of the test substance. No embryotoxic effects related to the drug were observed in fetuses, including external structural abnormalities, skeletal damage, or internal organ injury.

Clinical characteristics.

Indications.

Prevention of venous thromboembolism with moderate risk level during surgical procedures.

Prevention of blood coagulation in the extracorporeal circulation system during hemodialysis.

Prevention of venous thromboembolism in non-surgical patients with moderate risk of developing venous thromboembolism.

Contraindications.

• Hypersensitivity to bemiparin or to any of the excipients.
• Hypersensitivity to heparin or its derivatives, including other low molecular weight heparins, or substances of porcine origin.
• History of confirmed immune-mediated heparin-induced thrombocytopenia (HIT) or suspicion thereof.
• Active bleeding or increased risk of bleeding due to coagulation disorders.
• Severe liver or pancreatic dysfunction.
• Injury or surgical procedures involving the central nervous system, visual organs, or auditory organs within the past 2 months.
• Disseminated intravascular coagulation (DIC) syndrome associated with heparin-induced thrombocytopenia.
• Acute bacterial endocarditis and subacute bacterial endocarditis.
• Any organic disorders with high risk of bleeding (e.g., active peptic ulcer, hemorrhagic stroke, cerebral aneurysm, or cerebral neoplasm).

Interaction with other medicinal products and other forms of interaction.

Drug interactions of bemiparin have not been studied, and information in this section is based on data obtained from other low molecular weight heparins.

Concomitant use of bemiparin with the following drugs is not recommended:

vitamin K antagonists and other anticoagulants, acetylsalicylic acid, other salicylates and NSAIDs, ticlopidine, clopidogrel and other platelet inhibitors, systemic glucocorticoids, and dextran.

All the above-mentioned drugs enhance the pharmacological effect of bemiparin due to additive effects on coagulation and/or platelet function, thereby increasing the risk of bleeding.

If concomitant use cannot be avoided, careful clinical and laboratory monitoring is required.

Concomitant administration of medicinal products that increase serum potassium concentration should be performed under particularly close medical supervision.

With regard to bemiparin, interaction between heparin and intravenously administered nitroglycerin cannot be excluded (this may lead to reduced efficacy).

Special precautions.

The packaging contains a single dose of the medicinal product. After administration, any unused contents of the syringe must be discarded according to current regulations. Do not use the medicinal product if the protective film of the packaging is opened or damaged. Use only a clear, colorless or slightly yellowish solution free from particles.

Do not administer by intramuscular injection. Due to the risk of hematoma formation, intramuscular injections of other medicinal products should be avoided during bemiparin therapy.

When administering bemiparin at a dose of 2500 IU in patients with impaired renal function (creatinine clearance <80 mL/min), dose adjustment is not considered necessary; however, caution should be exercised due to limited data. In addition, it should be noted that the pharmacokinetics of bemiparin may be altered in patients with severe renal impairment (creatinine clearance <30 mL/min) (see sections "Dosage and administration" and "Pharmacokinetics"). Regular monitoring is recommended in this patient population.

Caution is advised when prescribing the medicinal product to patients with hepatic insufficiency, uncontrolled arterial hypertension, history of peptic ulcer disease of the stomach or duodenum, thrombocytopenia, nephrolithiasis or urolithiasis, vascular abnormalities of the iris or retina, and in patients with any other organic disorders associated with an increased risk of bleeding, as well as when performing spinal or epidural anesthesia or lumbar puncture.

Like other low-molecular-weight heparin (LMWH) products, bemiparin may suppress aldosterone secretion by the adrenal glands, leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal insufficiency associated with existing metabolic acidosis, elevated plasma potassium levels, or in patients receiving potassium-sparing agents. The risk of hyperkalemia increases proportionally with the duration of therapy, but such hyperkalemia is usually reversible. In patients at risk, plasma electrolyte levels should be measured before initiating bemiparin therapy and monitored regularly during treatment, especially if therapy exceeds 7 days.

Mild transient thrombocytopenia (Type I HIT) (platelet count 100,000/mm³–150,000/mm³), related to transient platelet activation, may occasionally occur at the beginning of heparin therapy. This condition usually does not lead to complications, and treatment may be continued.

Rarely, severe antibody-mediated thrombocytopenia (Type II HIT) may develop, with platelet counts significantly below 100,000/mm³. This reaction usually occurs between the 5th and 21st day of therapy. In patients with a history of heparin-induced thrombocytopenia, this complication may develop more rapidly. Therefore, platelet counts should be monitored before starting bemiparin therapy, regularly every 3–4 days during treatment, and after discontinuation of the drug. In practice, if a significant decrease in platelet count (30–50%) occurs in the presence of bemiparin, other LMWHs, and/or heparins, and is associated with positive or unknown results of in vitro tests for antithrombocytic antibodies, bemiparin therapy must be discontinued immediately and alternative treatment initiated.

As with other heparins, cases of skin necrosis have been reported during bemiparin therapy, sometimes preceded by erythema or painful erythematous lesions. In such cases, treatment must be discontinued immediately.

Prophylactic use of heparin in combination with epidural or spinal anesthesia or lumbar puncture may very rarely lead to the development of epidural or spinal hematoma, which may result in long-term or permanent paralysis. The risk of hematoma formation is increased with the use of epidural or spinal catheters for anesthesia, concomitant use of medicinal products affecting blood coagulation (e.g., nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors, or anticoagulants), and in cases of traumatic or repeated puncture.

When determining the time interval between the last prophylactic dose of heparin and insertion or removal of an epidural or spinal catheter, the characteristics of the medicinal product and the patient's condition must be taken into account. After catheter removal, the next dose of bemiparin may be administered no sooner than 4 hours later. Administration of the next dose of bemiparin should also be delayed until completion of the surgical procedure. When deciding on anticoagulant therapy in the context of epidural or spinal anesthesia, extreme caution is required, and frequent monitoring of the patient for neurological symptoms (e.g., back pain, sensory and motor disturbances [numbness and weakness of the lower limbs], and bowel or bladder dysfunction) is essential. Medical staff must be able to recognize such symptoms. Patients should immediately inform nurses or physicians if any of these symptoms occur. In case of suspected epidural or spinal hematoma, immediate diagnosis and therapeutic interventions, including spinal decompression, are required.

Use during pregnancy or breastfeeding.

Pregnancy.

Animal studies have not shown any teratogenic effects of bemiparin. Clinical data on the use of bemiparin in pregnant women are limited; therefore, the medicinal product should be used with caution during pregnancy. Currently, there is no information on the ability of bemiparin to cross the placental barrier.

Breastfeeding period.

Currently, there is insufficient information on whether bemiparin is excreted in breast milk. Therefore, if Cibor 2500 must be administered to breastfeeding women, breastfeeding should be avoided.

Ability to affect the speed of reactions when driving vehicles or operating machinery.

Cibor 2500 has no effect or has a negligible effect on the ability to drive vehicles or operate machinery.

Administration and dosage.

The medicinal product should be used immediately after opening.

Adults.

Surgical procedures with moderate risk of venous thromboembolism (e.g., general surgery procedures). On the day of surgery, 2500 IU anti-factor-Xa is administered subcutaneously 2 hours before the start of surgery or 6 hours after the procedure; thereafter, 2500 IU anti-factor-Xa is given once daily every 24 hours. Prophylactic treatment should only be administered at the physician’s discretion during the period when the patient remains at risk of thromboembolism or during immobilization. Prophylaxis is generally continued for at least 7–10 days after surgery, until the risk of thromboembolism has decreased.

Prevention of blood coagulation in the extracorporeal circulation system during hemodialysis. In patients undergoing repeated hemodialysis sessions lasting no more than 4 hours and who are not at risk of bleeding, anticoagulation in the extracorporeal circuit during the procedure is achieved by a single bolus injection of the drug into the arterial line at the beginning of the session. For patients with body weight less than 60 kg, the dose is 2500 IU anti-factor-Xa; for patients with body weight over 60 kg, the dose is 3500 IU anti-factor-Xa.

Prophylaxis of venous thromboembolism in non-surgical patients with moderate risk of venous thromboembolism (e.g., patients with acute medical conditions). The recommended dose of bemiparin is 2500 IU anti-factor-Xa per day administered as a subcutaneous injection. Prophylactic treatment should be administered at the physician’s discretion during the period when the patient remains at risk or during immobilization.

Elderly patients. Dose adjustment is not required provided renal function is normal (see sections “Dosage and administration (Renal impairment)”, “Special warnings and precautions for use”, “Pharmacokinetics”).

Patients with renal impairment.

(See sections “Special warnings and precautions for use”, “Pharmacokinetics”.)

When bemiparin is administered at daily doses of 2500 IU to patients with renal impairment (creatinine clearance <80 mL/min), limited data suggest that dose adjustment is not required. Careful monitoring is recommended. In patients with severe renal impairment (creatinine clearance <30 mL/min), peak anti-factor-Xa levels should be measured approximately 4 hours after administration.

Patients with hepatic impairment.

Insufficient data are available to provide dose adjustment recommendations for bemiparin in this patient population.

Route of administration. Technique of subcutaneous injection.

Pre-filled syringes are ready for immediate use and do not require sterilization prior to injection. When Cibor 2500 is administered subcutaneously, the injection should be given into the subcutaneous fatty layer of the anterolateral abdominal wall or the posterolateral area of the lumbar region, alternating between right and left sides. The needle should be inserted perpendicularly, not at an angle, to its full depth into a skin fold created by the thumb and index finger. The skin fold should not be released and should be held until the injection is complete. The injection site must not be massaged. Prior to injection, the plunger should not be pressed to expel air bubbles, to avoid loss of the medicinal product.

Children.

The safety and efficacy of Cibor 2500 in children have not been established; therefore, its use in children is not recommended.

Overdose.

The main manifestation of overdose is bleeding. In the event of bleeding, the decision to discontinue bemiparin therapy should be based on the severity of hemorrhage and the risk of thrombosis. Minor hemorrhages rarely require specific treatment. Major bleeding may require administration of protamine sulfate. Neutralization of bemiparin by protamine sulfate has been studied in vitro and in vivo to monitor reduction in anti-Xa activity and effect on activated partial thromboplastin time (aPTT). Protamine sulfate partially reduces the anti-Xa activity of bemiparin within 2 hours after intravenous administration of 1.4 mg protamine sulfate per 100 IU anti-Xa factor.

Side effects

The most commonly reported side effects were hematoma and/or ecchymosis at the injection site, observed in approximately 15% of patients treated with Cibor 2500. Long-term use of heparin may lead to the development of osteoporosis.

Side effects are classified 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 reactions with bemiparin corresponds to the frequency of side effects observed with other low-molecular-weight heparin agents and is listed in the table below:

Reporting of suspected adverse reactions: it is very important to report suspected adverse reactions after the medicinal product has been authorized. This allows continuous monitoring of the benefit/risk balance of the medicinal product.

Shelf life.

2 years. After first opening, the product Cibor 2500 should be used immediately. Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 30 °C. Do not freeze. Keep out of the reach and sight of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products due to the lack of compatibility studies.

Packaging.

0.2 mL of solution for injection in a pre-filled syringe (glass) with a plunger rod (polypropylene), plunger stopper (chlorobutyl rubber), injection needle (stainless steel), and rigid needle cap (natural rubber and rigid polypropylene layer).

Blister pack covered with a protective film containing 2 pre-filled syringes; 1, 5, or 50 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Rovi Farmaceutici Industriales, S.A.

Manufacturer's address and site of activity.

C/Julian Camarero, 35, Madrid 28037, Madrid, Spain.

Marketing Authorisation Holder.

PROPHARMA International Trading Limited.

Address of the Marketing Authorisation Holder.

Level 1, LM Complex, Brewery Street, Zone 3, Central Business District, Birkirkara, CBD3040, Malta.