Reopro^® (Solution) Instructions for Use

Marketing Authorization Holder

Eli Lilly Vostok, S.A. (Switzerland)

Manufactured By

Centocor, B.V. (Netherlands)

ATC Code

B01AC13 (Abciximab)

Active Substance

Abciximab (Rec.INN registered by WHO)

Dosage Form

Reopro®

Solution for intravenous administration 10 mg/5 ml: fl. 1 pc.

Dosage Form, Packaging, and Composition

5 ml – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Reopro is a Fab fragment of chimeric monoclonal antibodies 7E3 that blocks glycoprotein (GP) IIb/IIIa (α_IIbβ₃) receptors located on the surface of human platelets.

Reopro inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to the GP IIb/IIIa receptor site on activated platelets. Reopro also blocks vitronectin receptors on the surface of platelets and endothelial cells. Vitronectin receptors determine the procoagulant properties of platelets and the proliferative properties of vascular wall endothelial cells and smooth muscle cells.

In humans, a single intravenous bolus injection of Reopro at a dose of 0.15-0.30 mg/kg leads to a rapid dose-dependent inhibition of platelet function (determined by ex vivo platelet aggregation in response to adenosine diphosphate (ADP) or by an increase in bleeding time). Two hours after administration of doses of 0.25 and 0.30 mg/kg, the drug blocks more than 80% of GP IIb/IIIa receptors.

Intravenous bolus administration of a dose of 0.25 mg/kg followed by continuous intravenous infusion at a rate of 10 mcg/min for 12-96 hours causes a sustained pronounced blockade of GPIIb/IIIa receptors (≥ 80%) and inhibition of platelet function (ex vivo platelet aggregation in response to 5-20 µM ADP decreases to less than 20% of baseline, and bleeding time increases to more than 30 minutes) throughout the entire infusion. Low levels of GPIIb/IIIa receptor blockade persist for 10 days after the infusion is stopped, but platelet function returns to normal within 24-48 hours, although Abciximab may circulate in the blood in a platelet-bound state for 15 days or more.

Intravenous bolus administration of Reopro at a dose of 0.25 mg/kg followed by continuous infusion at a rate of 10 mcg/min (or 0.125 mcg/kg/min with a maximum rate of 10 mcg/min) creates a relatively constant level of free drug in the blood plasma throughout the entire infusion period. After the end of the infusion, the concentration of the free drug in the blood plasma decreases within 6 hours, after which the decrease occurs more slowly.

Pharmacokinetics

After intravenous bolus administration of abciximab, the concentration of the free drug in the blood plasma decreases rapidly. The initial T_1/2 is less than 10 minutes, and in the second phase it is about 30 minutes, which is caused by the rapid binding of the drug to GPIIb/IIIa receptors of platelets.

The safety and efficacy of the drug in children have not been established.

The positive effect of the drug may be less in patients with kidney and peripheral vascular disease.

Indications

• Prevention of myocardial ischemia in patients undergoing percutaneous transluminal coronary angioplasty (balloon angioplasty, atherectomy, and stent implantation);
• Short-term (1 month) prevention of myocardial infarction in patients with unstable angina resistant to standard therapy, who are scheduled to undergo percutaneous coronary angioplasty within 24 hours.

ICD codes

Dosage Regimen

Reopro is intended for intravenous administration to adults.

Reopro should be used in combination with acetylsalicylic acid and heparin.

The recommended dose of Reopro is: 0.25 mg/kg bolus, followed by continuous intravenous infusion at a rate of 0.125 mcg/kg/min (maximum 10 mcg/min).

For stabilization of patients with unstable angina, after the bolus dose is administered, a continuous infusion is performed, which should be started no more than 24 hours before the possible percutaneous coronary angioplasty and ended 12 hours after the procedure.

For prevention of cardiac ischemic complications in patients undergoing percutaneous coronary angioplasty and who are not currently receiving Reopro infusion, the bolus injection should be administered 10-60 minutes before the procedure, followed by intravenous infusion of the drug for 12 hours.

Instructions for drug administration

1. Do not use Reopro solution containing visible mechanical inclusions;
2. If symptoms of an allergic reaction or anaphylaxis occur, Reopro administration should be stopped immediately and appropriate anti-allergic or symptomatic therapy should be carried out;
3. Draw the required amount of Reopro for bolus injection into a syringe. Filter the solution for bolus injection through a sterile, pyrogen-free syringe filter with low protein binding capacity and a pore size of 0.2/0.22 µm or 5.0 µm. The bolus injection should be administered within 1 minute;
4. Draw the amount of Reopro required for continuous infusion into a syringe. Transfer the contents of the syringe to an appropriate container containing sterile 0.9% saline or 5% dextrose solution, and start the infusion at a pre-calculated rate using a continuous infusion pump. The solution for continuous infusion should be filtered before mixing through a sterile, pyrogen-free syringe filter with low protein binding capacity and a pore size of 0.2/0.22-µm or 5.0 µm, or use a sterile, pyrogen-free filter with low protein binding capacity and a pore size of 0.2 or 0.22-µm in the system during administration. After the infusion is completed, discard the unused portion of the solution.
5. Although no incompatibility with intravenous infusion fluids or commonly used cardiovascular drugs has been identified, it is recommended to administer Reopro through a separate intravenous system whenever possible and not to mix it with other drugs.

Concomitant treatment with acetylsalicylic acid and heparin Reopro is prescribed as an addition to therapy with acetylsalicylic acid and heparin.

Acetylsalicylic acid. It is prescribed orally in a daily dose of at least 300 mg. Heparin .

1. Percutaneous coronary angioplasty. Bolus administration of heparin before percutaneous coronary angioplasty. If the patient’s activated clotting time (ACT) is less than 200 seconds before the start of percutaneous coronary angioplasty, then when creating arterial access, heparin is initially administered as a bolus according to the following scheme: ACT < 150 sec: administer 70 U/kg ACT = 150-199 sec: administer 50 U/kg

The initial bolus dose of heparin should not exceed 7000 U.

After the bolus administration of heparin, no later than two minutes later, the ACT must be checked. If ACT <200 sec, then additional bolus administrations of heparin in doses of 20 U/kg should be performed. If ACT remains <200 sec, then bolus administrations of heparin at 20 U/kg should be performed until ACT >200 sec is achieved.

In situations where there is a clinical need for higher doses of heparin, despite the increased risk of bleeding, it is recommended to ensure that the achieved ACT does not exceed 300 seconds.

Bolus administration of heparin during percutaneous coronary angioplasty. During percutaneous coronary angioplasty, ACT should be monitored every 30 minutes. If ACT < 200 sec, an additional bolus of heparin at a dose of 20 U/kg can be administered. If ACT remains <200 sec, then bolus administrations of heparin at 20 U/kg should be performed until ACT ≥ 200 sec is achieved. ACT should be checked before each bolus administration of heparin and at least 2 minutes after administration.

An alternative to the additional bolus administrations of heparin described above may be a continuous infusion of heparin at a rate of 7 U/kg/h, initiated when ACT ≥ 200 sec is achieved after the initial heparin bolus and continued during the percutaneous coronary angioplasty procedure. Heparin infusion after percutaneous coronary angioplasty.

It is strongly recommended to stop heparin administration immediately after the completion of percutaneous coronary angioplasty, followed by removal of the arterial catheter within 6 hours. If prolonged heparin therapy or late catheter removal is planned after percutaneous coronary angioplasty, it is recommended to perform a heparin infusion at an initial rate of 7 U/kg/h. In all cases, heparin administration must be stopped at least 2 hours before the catheter is removed from the artery.

2. Stabilization of unstable angina. Anticoagulant therapy should be started with heparin to achieve an activated partial thromboplastin time (aPTT) of 60-85 seconds. During the Reopro infusion, the heparin infusion should be continued. After angioplasty, heparin administration is carried out according to the scheme described in section 1 (percutaneous coronary angioplasty).

Adverse Reactions

From the hematopoietic system bleeding within the first 36 hours (Reopro does not increase the risk of intracranial hemorrhages), thrombocytopenia, anemia, leukocytosis, petechiae.

From the cardiovascular system: decreased blood pressure, pulmonary edema, atrioventricular block, supraventricular tachycardia, ventricular tachyarrhythmias, bradycardia, intermittent claudication, peripheral vascular embolism, pulmonary embolism.

From the digestive system constipation or diarrhea, nausea, vomiting, ileus.

From the nervous system confusion, dizziness, cerebral ischemia, hyperesthesia.

From the urinary system renal failure, urinary retention.

Allergic reactions skin itching, anaphylactic shock.

Other myalgia, phlegmon, fever, pain at the injection site, visual impairment, pleural effusion, pneumonia.

After 2-4 weeks, human anti-chimeric antibodies (HACA) may be detected (usually with low titer).

Contraindications

• Ongoing internal bleeding;
• Cerebrovascular disorders (including within the last 2 years);
• Recent (within 2 months) intracranial or intraspinal surgery or trauma;
• Recent (within 2 months) major surgery;
• Recent (within 6 weeks) clinically significant bleeding from the gastrointestinal or genitourinary tract;
• Intracranial neoplasm, arteriovenous malformation, or aneurysm;
• Established hemorrhagic diathesis;
• Severe uncontrolled arterial hypertension;
• Previous thrombocytopenia;
• Vasculitis;
• Hypertensive or diabetic retinopathy;
• Severe impairment of renal and/or liver function;
• Established sensitivity to abciximab, any component of the drug, or murine monoclonal antibodies;
• Residual effects after cerebrovascular accident with neurological deficit;
• Pregnancy;
• Lactation period;
• Age under 18 years.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation.

Pediatric Use

The safety and efficacy of the drug in children have not been established.

Geriatric Use

In patients with low risk but over 65 years of age, a favorable benefit/risk ratio is not achieved.

Special Precautions

Before starting treatment with Reopro, a thorough benefit/risk assessment should be performed. In patients with low risk but over 65 years of age, a favorable benefit/risk ratio is not achieved.

Reopro should be administered only under the following conditions: the presence of experienced specialists and appropriate equipment for transfusion of blood products, the possibility of appropriate care and appropriate hematological tests.

It is recommended to use Reopro with caution in the following cases

• Taking oral anticoagulants within the previous 7 days with a prothrombin time reduced by 1.2 times or more compared to the baseline level;
• Intravenous administration of dextrans before coronary angioplasty;
• Body weight below 75 kg;
• Age over 65 years;
• Failed or prolonged (more than 70 minutes) percutaneous coronary intervention;
• Coronary angioplasty within 12 hours of the development of acute myocardial infarction.

Precautions related to bleeding

Treatment with Reopro is associated with an increased frequency of bleeding, especially at the site of arterial access for catheter insertion into the femoral artery. Special recommendations for precautions at the access site are provided below. Femoral artery catheterization

• Use only arterial access (avoid inserting the catheter into a vein).
• Puncture only the anterior wall of the vessel.
• The through-and-through approach method for determining the vascular structure is not recommended. While the catheter is in the femoral artery
• Check the catheter insertion site and distal pulse on the corresponding leg (legs) every 15 minutes for the first hour, then every hour for 6 hours.
• The patient should be in bed with the head of the bed elevated at an angle of no more than 30°C (86°F) in a state of complete rest.
• Keep the corresponding leg (legs) in an extended position using sheet rolls or soft immobilization.
• If necessary, relieve back and groin pain with medication.
• Counsel the patient on how to behave after percutaneous coronary intervention.

Removal of the catheter from the femoral artery

• Heparin administration must be stopped at least 2 hours before removal of the arterial catheter.
• Before removing the arterial catheter, check the aPTT or ACT: do not remove the catheter until aPTT < 50 sec or ACT < 175 sec is established.
• After catheter removal, apply firm pressure to the access site for at least 30 minutes.
• After hemostasis is achieved, apply a pressure bandage. After removal of the catheter from the femoral artery
• Check for absence of bleeding/hematoma in the groin and the distal pulse every 15 minutes for the first hour or until stable condition is established. Then – every hour for 6 hours after catheter removal.
• Continue to maintain the patient’s state of complete rest. The patient must continue to be in a state of complete rest in bed with the head of the bed elevated at an angle of no more than 30°C (86°F) and with legs extended for 6-8 hours after removal of the catheter from the femoral artery, 6-8 hours after discontinuation of Reopro administration, or 4 hours after discontinuation of heparin administration, depending on which procedure is completed later.
• Before the patient gets out of bed, the pressure bandage must be removed.

Stopping bleeding with or without hematoma formation at the femoral artery access site

• Lower the head of the bed to 0°.
• Apply manual pressure to the access site or use a pressure device until bleeding stops.
• Any hematoma should be measured and its increase monitored.
• Change the pressure bandage if necessary. ,
• Before prescribing heparin, measure the aPTT and adjust the heparin dose. Maintain venous access if the catheter has been removed.

If, despite the indicated measures, groin bleeding continues or the hematoma increases in size during Reopro infusion, then the Reopro infusion should be stopped immediately and, in accordance with the recommendations above, the arterial catheter should be removed. After catheter removal, venous access should be maintained until bleeding control is restored.

Uncontrolled bleeding

In case of serious profuse bleeding or if emergency surgery is required, Reopro administration should be stopped. In most patients, bleeding time returns to 12 minutes within 12 hours. If bleeding time remains greater than 12 minutes, 10 units of platelet mass can be administered. Reopro can be displaced from endogenous platelet receptors with subsequent binding to transfused platelets. However, a single transfusion may be sufficient to reduce receptor blockade to 60-70%. At this level of blockade, platelet function is restored. Repeated transfusions of platelet mass may be required to maintain bleeding time at 12 minutes or less.

Possible bleeding sites

Attention should be paid to all possible bleeding sites, including venous and arterial puncture sites, catheter insertion sites, venesection sites, and needle puncture sites.

Retroperitoneal bleeding

During Reopro administration, the risk of retroperitoneal bleeding associated with femoral vessel punctures increases. The use of femoral catheters should be minimized, and when establishing vascular access, only the anterior wall of the arteries or veins should be punctured.

Pulmonary bleeding

Reopro administration is an infrequent cause of pulmonary (mainly alveolar) bleeding, which may be accompanied by: hypoxemia, increased alveolar infiltration on chest X-ray, hemoptysis, or unexplained decrease in hemoglobin. If bleeding is confirmed, administration of Reopro, all anticoagulants and antiplatelet agents should be stopped.

Prevention of gastrointestinal bleeding

To prevent gastrointestinal bleeding, it is recommended to pre-prescribe patients histamine H₂-receptor antagonists or antacid solutions. Antiemetic drugs should be prescribed if necessary.

General nursing care

Unnecessary arterial and venous punctures, intramuscular injections, routine urinary bladder catheterization, nasotracheal intubation, insertion of a nasogastric tube, and application of an automatic blood pressure cuff should be avoided. When creating venous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided. Blood draws should be performed from a catheter, for the flushing of which heparin or physiological saline should be used. Puncture sites must be documented and monitored. Special care must be taken when removing dressings.

Dynamic Patient Monitoring

Before administering ReoPro to identify existing coagulation disorders, it is necessary to determine the platelet count, CBC, prothrombin time, and aPTT.

An additional platelet count should be performed 2-4 hours and 24 hours after the bolus administration. Hemoglobin and hematocrit levels must be determined before administering Reopro^®, as well as 12 and 24 hours after the bolus administration. A 12-lead ECG must be performed before the ReoPro bolus administration, when the patient returns to the ward from the catheterization laboratory, and 24 hours after the ReoPro bolus administration. Vital signs (including blood pressure and pulse) should be assessed every hour for the first 4 hours after the ReoPro bolus administration and at 6, 12, 18, and 24 hours after the bolus administration.

Restoration of Platelet Function

In case of serious uncontrolled bleeding or the need for emergency surgery, ReoPro administration must be discontinued. In most patients, bleeding time normalizes within 12 hours. In case of persistent prolonged bleeding time, and/or obvious suppression of platelet function, if rapid hemostasis is necessary, and/or absence of adequate hemostasis recovery, the decision should be based on the recommendation of a hematologist experienced in the diagnosis and management of patients with bleeding. If rapid hemostasis is necessary, platelet concentrate (at least 5.5 x 10⁹ platelets) may be administered. Redistribution of ReoPro from endogenous platelet receptors to transfused platelets may occur. A single transfusion can reduce receptor blockade to 60-70% of the level at which platelet function is restored. Repeated platelet transfusions may be required to maintain hemostasis. Thrombocytopenia

To reduce the likelihood of thrombocytopenia, the platelet count should be monitored before starting treatment, 2-4 hours after the ReoPro bolus administration, and at 24 hours. If an acute drop in platelet count is detected in a patient, an additional platelet count determination must be performed. Blood samples for these tests should be collected in three separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate, and heparin, respectively, to rule out pseudothrombocytopenia due to in vitro anticoagulant interactions. If true thrombocytopenia is confirmed, ReoPro should be discontinued immediately and appropriate monitoring and treatment should be initiated. Daily platelet count determination should be performed until the count returns to normal. If the patient’s platelet count drops to 60,000 cells/µL, heparin and aspirin should be discontinued. If the platelet count drops below 50,000 cells/µL, the issue of platelet transfusion should be considered, especially in case of bleeding and/or an ongoing or planned invasive procedure. If the platelet count drops below 20,000 cells/µL, platelet transfusion should be performed. The decision regarding platelet transfusion should be made individually based on the clinical picture.

Re-administration.

Administration of ReoPro can lead to the formation of human anti-chimeric antibodies (HACA), which can potentially cause hypersensitivity and allergic reactions (including anaphylactic reactions), thrombocytopenia, and reduced beneficial effect upon re-administration. In Phase III studies, HACA usually appeared in low titers in approximately 5-6% of patients after a single administration of ReoPro. Available data indicate that human antibodies to other monoclonal antibodies do not cross-react with ReoPro.

Re-administration of ReoPro to patients undergoing percutaneous coronary interventions was evaluated in a registry that included 1342 administrations in 1284 patients. Most patients had a second administration of ReoPro, and 15% of patients had a third and subsequent administrations. The total number of HACA-positive patients before re-administration was 6% and increased to 27% after re-administration. No serious allergic or anaphylactic reactions were reported. Thrombocytopenia was observed more frequently in re-administration studies than in Phase III single-administration studies, suggesting a possible association between re-administration and an increase in the frequency and severity of thrombocytopenia.

Kidney Diseases

In patients with kidney diseases, the positive effects of ReoPro may be reduced. The decision to use ReoPro in patients with severe renal failure should be made after a careful risk-benefit assessment. Since the potential risk of bleeding in patients with severe renal disease is increased, patients should be more closely monitored for bleeding. In case of serious bleeding, the issue of platelet transfusion should be considered. The use of ReoPro is contraindicated in patients on dialysis.

Transportation and Storage Recommendations

ReoPro does not contain preservatives and is intended for single use only. Unused portions must be discarded. For intravenous infusion, the ReoPro solution must be prepared immediately before administration. During transportation of the drug, special containers with cooling elements (coolers 8 MSZ and 4 MS28) must be used to avoid violation of storage temperature conditions.

Overdose

Symptoms: profuse bleeding, acute allergic reaction, thrombocytopenia, vascular collapse.

Treatment: discontinuation of the drug, platelet transfusion, symptomatic treatment.

Drug Interactions

Anticoagulants (heparin in a dose greater than 70 U/kg), thrombolytics, antiplatelet drugs (ticlopidine, dipyridamole, low molecular weight dextran) – increase the risk of bleeding.

Administration of other monoclonal antibodies increases the risk of allergic reactions.

Storage Conditions

Store at a temperature of 2°C (35.6°F)- 8°C (46.4°F). Do not freeze. Do not shake. Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.