Metalize

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Metalyse® (Metalyse®)

Composition:

Active substance: tenecteplase (TNK-tPA);

One vial contains tenecteplase 50 mg (10,000 IU*);

1 ml of reconstituted solution contains 1000 units (5 mg) of tenecteplase;

Excipients: L-arginine, phosphoric acid concentrated, polysorbate 20;

Solvent: water for injections.

*Tenecteplase activity is expressed in units (IU) according to a standard preparation specific to tenecteplase and is not comparable with the units of activity of other thrombolytic medicinal products.

Tenecteplase is produced using recombinant DNA technology with Chinese hamster ovary cells.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties:

Lyophilisate: white to pale yellow porous solid.

Solvent: clear, colorless liquid.

Pharmacotherapeutic group. Antithrombotic agents. Enzymes.

ATC code B01AD11.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Tenecteplase is a recombinant, fibrin-specific plasminogen activator derived from natural tissue plasminogen activator (t-PA) by modifying the protein structure at three positions. It binds to fibrin components of the thrombus (blood clot) and selectively converts thrombus-bound plasminogen into plasmin, which cleaves the fibrin scaffold of the clot. Compared to native t-PA, tenecteplase has higher fibrin specificity and greater resistance to inactivation by endogenous inhibitor (PAI-1).

Pharmacodynamic effects. Following administration of tenecteplase, dose-dependent consumption of α2-antiplasmin (an inhibitor of fluid-phase plasmin) is observed, followed by an increase in systemic plasmin levels. This observation does not preclude the expected plasminogen activation effect. In comparative studies, reductions in fibrinogen concentration of less than 15% and reductions in plasminogen concentration of less than 25% were observed in patients receiving the maximum dose of tenecteplase (10,000 units, equivalent to 50 mg), whereas alteplase caused approximately 50% reduction in fibrinogen and plasminogen levels. Formation of clinically significant antibodies was not observed within 30 days.

Pharmacokinetics

Absorption and distribution. Tenecteplase is a recombinant protein indicated for intravenous administration to activate plasminogen. After intravenous bolus administration of 30 mg tenecteplase to patients with acute myocardial infarction, the initial expected plasma concentration of tenecteplase was 6.45 ± 3.60 µg/mL (mean ± standard deviation). The distribution phase accounted for 31% ± 22% to 69% ± 15% (mean ± standard deviation) of the total AUC following doses ranging from 5 to 50 mg.

Tissue distribution data were obtained from studies using radiolabeled tenecteplase in rats. The liver was the primary organ accumulating tenecteplase. It is unknown whether, and to what extent, tenecteplase binds to plasma proteins in humans. The mean residence time of the drug in the body is approximately 1 hour, and the mean volume of distribution at steady state (Vss) (± standard deviation) ranges from 6.3 ± 2 L to 15 ± 7 L.

Biological transformation. Tenecteplase is cleared from the circulation by binding to specific receptors in the liver, followed by catabolism into small peptides. Binding to liver receptors is reduced compared to native t-PA, resulting in a prolonged elimination half-life.

Elimination. After a single intravenous bolus administration of tenecteplase to patients with acute myocardial infarction, tenecteplase antigen exhibits biphasic elimination from plasma. Within the therapeutic dose range, tenecteplase clearance is not dose-dependent. The initial dominant elimination half-life is 24 ± 5.5 minutes (mean ± standard deviation), which is 5 times longer than that of natural tissue plasminogen activator (t-PA). The terminal elimination half-life is 129 ± 87 minutes, and plasma clearance is 119 ± 49 mL/min.

Increased body weight leads to a moderate increase in tenecteplase clearance, while advanced age results in a slight decrease. Women generally have lower clearance than men, but this can be explained by overall differences in body weight.

Linearity/Non-linearity.

Analysis of dose linearity based on AUC indicates that tenecteplase exhibits non-linear pharmacokinetic behavior within the studied dose range of 5 to 50 mg.

Renal and hepatic impairment. Tenecteplase is eliminated via the liver; therefore, impaired renal function is not expected to affect the pharmacokinetics of METALIZE. This is also supported by animal data. However, the effects of hepatic or renal impairment on the pharmacokinetics of tenecteplase in humans have not been specifically studied. Accordingly, there are no specific dosage adjustment recommendations for patients with hepatic or severe renal impairment.

Clinical characteristics.

Indications.

Thrombolytic therapy in adults with suspected acute myocardial infarction (AMI) with persistent ST-segment elevation or recent left bundle branch block within 6 hours of onset of symptoms of acute myocardial infarction (AMI).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients, or to gentamicin (which may remain in trace amounts after the manufacturing process). If METALIZE therapy is nevertheless considered necessary, resuscitation equipment should be available in case it is needed.

In addition, thrombolytic therapy is associated with an increased risk of bleeding. METALIZE is contraindicated in the following conditions:

• significant bleeding currently or within the past 6 months;
• effective oral anticoagulant therapy, e.g., warfarin (INR > 1.3) (see section "Adverse reactions", subsection "Bleeding");
• history of any central nervous system disorders (e.g., tumors, aneurysms, intracranial or spinal surgery);
• known hemorrhagic diathesis;
• severe uncontrolled hypertension;
• major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (including any trauma associated with the current acute myocardial infarction);
• recent head trauma, including skull trauma;
• prolonged cardiopulmonary resuscitation (> 2 min) within the past 2 weeks;
• acute pericarditis and/or subacute bacterial endocarditis;
• acute pancreatitis;
• severe hepatic dysfunction, including liver failure, cirrhosis, portal hypertension (esophageal varices), and active hepatitis;
• active peptic ulcer;
• arterial aneurysm and known arterial/venous malformation;
• tumor with increased risk of bleeding;
• hemorrhagic stroke or stroke of unknown origin in history;
• ischemic stroke or transient ischemic attack (TIA) within the past 6 months;
• dementia.

Interaction with other medicinal products and other forms of interaction.

Specific studies on the interaction of tenecteplase with other medicinal products commonly used in the treatment of patients with acute myocardial infarction have not been conducted. However, analysis of data from over 12,000 patients treated during phases 1, 2, and 3 did not reveal any clinically significant interactions between medicinal products commonly prescribed for acute myocardial infarction and concomitant use of tenecteplase.

Medicinal products affecting coagulation/platelet function

Medicinal products affecting coagulation or altering platelet function (e.g., ticlopidine, clopidogrel, low molecular weight heparin) may increase the risk of bleeding before, during, and after METALIZE therapy.

Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

Special precautions for use.

Traceability

To improve traceability of biological medicinal products, the brand name and batch number of the administered product must be clearly recorded in the patient's medical record.

Coronary intervention

If primary percutaneous coronary intervention (PCI) is planned according to current treatment guidelines, tenecteplase (see section "Pharmacodynamics") should not be used.

Patients who cannot undergo primary PCI within one hour as recommended by guidelines and who receive tenecteplase as the primary method of coronary revascularization should be promptly referred to a facility capable of coronary intervention within 6–24 hours, or earlier if clinically indicated, for angiography and timely adjunctive coronary intervention (see section "Pharmacodynamics").

Bleeding.

The most common complication during tenecteplase therapy is bleeding. Concomitant use of heparin may increase the risk of bleeding. Since fibrin is dissolved during tenecteplase therapy, bleeding may occur at the site of recent puncture. Therefore, thrombolytic therapy requires careful monitoring of all potential bleeding sites (including those resulting from catheter insertion, arterial and venous punctures, venesection, and needle punctures). During tenecteplase therapy, the use of rigid catheters, intramuscular injections, and non-essential manipulations should be avoided.

Most commonly observed were bleeding at the injection site and, rarely, genitourinary bleeding and gingival bleeding.

In case of serious bleeding, especially intracranial hemorrhage, concomitant heparin therapy should be immediately discontinued and protamine administration should be considered if heparin was administered within 4 hours prior to bleeding onset. Some patients for whom these conservative measures are ineffective may require blood transfusion. The appropriateness of cryoprecipitate, fresh frozen plasma, and platelet transfusion should be evaluated based on clinical and laboratory parameters after each administration. The expected target fibrinogen level after cryoprecipitate infusion is 1 g/L. The use of antifibrinolytic agents should also be considered as a last resort.

The benefit-risk balance should be carefully evaluated before initiating tenecteplase therapy in the presence of conditions associated with increased bleeding risk, including:

• systolic blood pressure > 160 mm Hg (see section "Contraindications");
• cerebrovascular disease;
• recent gastrointestinal or genitourinary bleeding (within the last 10 days);
• high likelihood of left-sided cardiac thrombosis, e.g., mitral stenosis with atrial fibrillation;
• any known recent (within the last 2 days) intramuscular injection;
• advanced age (i.e., patient age ≥ 75 years);
• low body weight (< 60 kg);
• patients taking oral anticoagulants: METALIZE may be considered if the dosing or time since last anticoagulant intake makes residual activity unlikely, and if appropriate tests of anticoagulant activity show no clinically significant coagulation system activity (e.g., INR ≤ 1.3 for vitamin K antagonists or other appropriate tests for other oral anticoagulants within the upper limit of normal range).

Arrhythmia.

Coronary thrombolysis may cause reperfusion-related arrhythmias. Reperfusion arrhythmias can lead to cardiac arrest, may be life-threatening, and may require conventional antiarrhythmic therapy. When administering tenecteplase, availability of antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmia (pacemaker, defibrillator) is recommended.

Glycoprotein IIb/IIIa antagonists.

Concomitant use of glycoprotein IIb/IIIa antagonists increases the risk of bleeding.

Hypersensitivity/Re-administration.

No formation of antibodies against tenecteplase molecules has been observed after treatment. However, there is no systemic experience with repeated administration of tenecteplase. Caution should be exercised when administering tenecteplase to patients with known hypersensitivity (excluding anaphylactic reactions) to the active substance, to any of the excipients, or to gentamicin (used during manufacturing and possibly present in trace amounts). If an anaphylactoid reaction occurs, administration should be stopped and appropriate treatment initiated. In any case, re-administration of tenecteplase should not be performed without prior assessment of haemostatic factors such as fibrinogen, plasminogen, and α2-antiplasmin.

Paediatric patients

METALIZE is not recommended for use in children (under 18 years of age) due to lack of data on safety and efficacy.

Use during pregnancy or breastfeeding.

Pregnancy. There is limited data on the use of METALIZE for treating pregnant women. In preclinical studies, fatal outcomes in females due to bleeding related to the known pharmacological activity of the active substance were observed. Additionally, during preclinical studies, several cases of pregnancy termination and fetal resorption were observed, but only after repeated dosing.

Tenecteplase is not teratogenic. The benefit-risk ratio of treatment should be evaluated in case of myocardial infarction occurring during pregnancy.

Breastfeeding. It is unknown whether tenecteplase is excreted in human breast milk. Caution should be exercised when administering METALIZE to breastfeeding women, and a decision should be made whether to discontinue breastfeeding for the first 24 hours after METALIZE administration.

Fertility. No clinical or preclinical studies on the effect of tenecteplase (METALIZE) on fertility have been conducted.

Ability to affect reaction speed when driving or operating machinery.

Not studied.

Method of Administration and Dosage.

METALIZE must be prescribed by a physician experienced in the use of thrombolytic therapy and who has the ability to monitor such treatment.

Therapy with METALIZE should be initiated as soon as possible after symptom onset.

METALIZE should be administered according to the patient's body weight, with a maximum dose of 10,000 units (50 mg tenecteplase). The volume required to achieve the effective dose can be calculated using the following table:

Patients of advanced age (≥75 years)

METALISE should be used with caution in elderly patients (≥75 years) due to an increased risk of bleeding (see information on bleeding in sections "Adverse reactions" and "Pharmacodynamics").

Concomitant therapy

Antithrombotic concomitant therapy with platelet inhibitors and anticoagulants should be administered according to current guidelines for the treatment of patients with ST-segment elevation myocardial infarction.

For coronary intervention, see section "Dosage and administration".

Unfractionated heparin and enoxaparin were used as concomitant antithrombotic therapy in clinical trials with METALISE.

Acetylsalicylic acid should be administered as soon as possible after symptom onset and continued lifelong, unless contraindicated.

Method of administration

The diluted solution should be administered intravenously and used immediately. The diluted solution is clear, colorless to pale yellow.

The required dose should be given as a single intravenous bolus injection over approximately 10 seconds.

For instructions on dilution of the medicinal product prior to administration, see section "Dosage and administration".

Dosage and administration

METALISE should be reconstituted by adding the full volume of water for injections from a pre-filled syringe into the vial containing the lyophilisate for injection solution.

1. Ensure that the volume of solution selected corresponds to the patient's body weight according to the table above.
2. Check the integrity of the vial cap.
3. Remove the cap from the vial.
4. Open the upper part of the vial transfer device. Remove the cap from the syringe filled with diluent, then immediately and firmly screw the syringe filled with diluent into the vial transfer device and pierce the vial stopper with the transfer device spike.
5. Add the diluent to the vial using the syringe, pressing the plunger slowly to avoid foaming.
6. Leave the syringe attached to the vial transfer device and dissolve the vial contents by gently swirling.
7. The reconstituted injectable solution should be clear, colorless to pale yellow. Only clear, particle-free solutions should be used.
8. Immediately before administration, invert the vial so that the syringe connected to the vial is positioned below.
9. Withdraw the appropriate volume of reconstituted METALISE solution into the syringe, according to the patient's body weight.
10. Unscrew the syringe from the vial transfer device.
11. The existing intravenous access may be used only for administration of METALISE with 9 mg/mL (0.9%) sodium chloride solution. No other medicinal products should be added to the injectable solution.
12. METALISE should be administered over approximately 10 seconds. Do not use an intravenous infusion system containing glucose, as METALISE is incompatible with glucose solutions.
13. The intravenous infusion system should be flushed after METALISE administration to ensure proper delivery.
14. Any unused portion of the reconstituted solution should be discarded.

As an alternative to reconstitution, a needle may be used instead of the vial transfer device.

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

Children. There is insufficient data on the safety and efficacy of METALISE in children (under 18 years of age); therefore, the use of the medicinal product in this age group is not recommended.

Overdose

Symptoms

In case of overdose, there is an increased risk of bleeding.

Treatment

In case of severe, prolonged bleeding, replacement therapy (plasma, platelets) should be considered; also see section "Dosage and administration".

Adverse Reactions

Brief description of the safety profile

Bleeding is the most common adverse reaction associated with tenecteplase use. The type of bleeding is predominantly superficial at the injection site. Bruising (ecchymosis) was frequently observed, but usually did not require any intervention. Cases of death and permanent disability have been reported among patients who experienced stroke (including intracranial hemorrhage) and other serious bleeding events.

Adverse reactions in tabular form

The adverse reactions listed below are classified by system organ class and frequency. Frequency grouping is defined as follows: 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 available data).

Table 1 shows the frequency of adverse reactions.

As with other thrombolytic agents, the following adverse reactions have been observed as a result of myocardial infarction and/or administration of thrombolytic agents:

• very common: arterial hypotension, disturbances in heart rate and cardiac rhythm, angina pectoris;
• common: recurrent ischemia, heart failure, myocardial infarction, cardiogenic shock, pericarditis, pulmonary edema;
• uncommon: cardiac arrest, mitral valve insufficiency, exudative pericarditis, venous thrombosis, cardiac tamponade, myocardial rupture;
• rare: pulmonary artery embolism.

These cardiovascular disorders may be life-threatening and may lead to fatal outcomes.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Incompatibilities

MEZILYZE is incompatible with glucose infusion solutions.

Shelf life 3 years.

Reconstituted solution

The reconstituted solution may be stored for 24 hours at 2–8 °C and for 8 hours at 30 °C.

From a microbiological standpoint, the diluted solution should be used immediately. If not used immediately, the user is responsible for the duration and storage conditions during use, which generally should not exceed 24 hours at 2–8 °C.

Storage conditions

Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

Storage conditions for the reconstituted medicinal product are specified in the section "Shelf life".

Packaging

Lyophilisate in a type I glass vial closed with a grey silicone-coated rubber stopper and an aluminum flip-off cap; 10 ml of solvent in a plastic syringe;

1 vial of lyophilisate and 1 syringe of solvent with a sterile transfer device for the vial, packed in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.

Address

Birkendorfer Strasse 65, 88397 Biberach/Riss, Germany.