Metalyse^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

Boehringer Ingelheim International, GmbH (Germany)

Packaging and Quality Control Release

BOEHRINGER INGELHEIM INTERNATIONAL, GmbH (Germany)

Or

NPO PETROVAKS PHARM, LLC (Russia)

ATC Code

B01AD11 (Tenecteplase)

Active Substance

Tenecteplase (Rec.INN registered by WHO)

Dosage Forms

	Metalyse®	Lyophilisate for preparation of solution for intravenous administration 40 mg (8 thousand IU): vial 1 pc. in a set with solvent
		Lyophilisate for preparation of solution for intravenous administration 50 mg (10 thousand IU): vial 1 pc. in a set with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous administration as a white or light yellow lyophilized mass; reconstituted solution is clear, colorless or light yellow; solvent (water for injections) – colorless clear liquid.

Excipients : arginine (base) – 417.6 mg, phosphoric acid 85% – 131.2 mg (to pH 7.3), polysorbate 20 – 3.2 mg.

Solvent water for injections – 8 ml (syringe).

Colorless glass type I (1) vials with a yellow-green plastic protective cap, in a set with solvent in a plastic syringe, a disposable needle and an adapter – intermediate packaging (transparent plastic blister, sealed with polyethylene film) – cardboard boxes^x.

^x the presence of first opening control is allowed.

Lyophilisate for preparation of solution for intravenous administration as a white or light yellow lyophilized mass; reconstituted solution is clear, colorless or light yellow; solvent (water for injections) – colorless clear liquid.

Excipients : arginine (base) – 522 mg, phosphoric acid 85% – 164 mg (to pH 7.3), polysorbate 20 – 4 mg.

Solvent water for injections – 10 ml (syringe).

Colorless glass type I (1) vials with a red plastic protective cap, in a set with solvent in a plastic syringe, a disposable needle and an adapter – intermediate packaging (transparent plastic blister, sealed with polyethylene film) – cardboard boxes^x.

^x the presence of first opening control is allowed.

Clinical-Pharmacological Group

Fibrinolytic – recombinant, genetically modified plasminogen activator

Pharmacotherapeutic Group

Fibrinolytic agent

Pharmacological Action

Fibrinolytic drug, recombinant plasminogen activator, genetically modified.

Tenecteplase is a recombinant fibrin-specific plasminogen activator, a derivative of natural tissue plasminogen activator modified in three regions.

Tenecteplase binds to the fibrin component of a thrombus and selectively catalyzes the conversion of thrombus-bound plasminogen into plasmin, which destroys the fibrin framework of the thrombus. Compared to natural tissue plasminogen activator, Tenecteplase has a higher affinity for fibrin and resistance to the inactivating action of the endogenous plasminogen activator inhibitor I.

After tenecteplase administration, a dose-dependent consumption of α₂-antiplasmin (plasmin inhibitor in the liquid phase) is observed with a subsequent increase in systemic plasmin concentration, which corresponds to the expected plasminogen activation effect. In comparative studies in patients receiving maximum doses of tenecteplase (10,000 IU, equivalent to 50 mg), a decrease in fibrinogen concentration of less than 15% and plasminogen concentration of less than 25% was noted, while alteplase use led to a decrease in fibrinogen and plasminogen concentrations of approximately 50%. Thirty days after the start of Metalyse^® use, antibodies to tenecteplase were not detected.

Angiographic data show that a single intravenous administration of tenecteplase promotes recanalization of the artery, the thrombosis of which led to acute myocardial infarction. This effect is dose-dependent.

The use of tenecteplase reduces the mortality rate from myocardial infarction (by 6.2% at 30 days). With tenecteplase use, the frequency of bleeding (excluding intracranial) is 26.4% (lower than with alteplase use – 28.9%, p=0.0003). The reduction in bleeding risk is likely due to the higher specificity of tenecteplase for fibrin, as well as the selection of the therapy regimen depending on patient body weight. Therefore, the need for transfusion therapy with tenecteplase use is significantly lower (4.3% in the tenecteplase group and 5.5% in the alteplase group). The frequency of intracranial hemorrhages was 0.93% in the tenecteplase group and 0.94% in the alteplase group. In cases where treatment was started later than 6 hours after the onset of myocardial infarction symptoms, the use of tenecteplase (compared to alteplase) had advantages in terms of 30-day mortality (4.3% in the tenecteplase group and 9.6% in the alteplase group), stroke frequency (0.4% and 3.3% respectively) and intracranial hemorrhage frequency (0% and 1.7% respectively).

Pharmacokinetics

Metabolism and excretion

Tenecteplase is eliminated from the bloodstream by binding to receptors in the liver and degradation to form small peptides.

After a single injection of tenecteplase in patients with acute myocardial infarction, a biphasic elimination of tenecteplase antigen from plasma was noted. When using the drug in therapeutic doses, no dependence of tenecteplase elimination on the administered dose is observed.

The initial T_1/2 is 24±5.5 min (mean ± standard deviation), which is 5 times greater than the T_1/2 of natural tissue plasminogen activator. The terminal T_1/2 is 129±87 min; plasma clearance – 119±49 ml/min.

Pharmacokinetics in special clinical cases

With increased body weight, a moderate increase in plasma clearance is observed; with increasing age, a decrease in this indicator is noted. In women, plasma clearance rates are usually lower than in men, which may be explained by lower body weight in women.

Tenecteplase is excreted in bile, so it is assumed that no changes in pharmacokinetics are observed in case of renal impairment.

Pharmacokinetic studies in patients with hepatic impairment have not been conducted.

Indications

• Thrombolytic therapy of acute myocardial infarction.

ICD codes

Dosage Regimen

The drug is intended for thrombolytic therapy of acute myocardial infarction. Therapy should be started as early as possible after symptom detection.

The dose of Metalyse^® is calculated depending on body weight, the maximum dose should not exceed 10,000 IU (50 mg of tenecteplase). The volume of solution for administration of the required dose is calculated according to the table

The required dose of the drug is administered by rapid single intravenous injection over 5-10 seconds.

A previously established catheter for intravenous administration of only 0.9% sodium chloride solution can be used for Metalyse^® administration.

After Metalyse^® administration, the catheter must be flushed before further use for administration of other medicines.

The drug Metalyse^® must not be mixed with other medicines (even with heparin) either in the infusion vial or in a common system for intravenous administration.

Adjunctive therapy

Adjunctive antithrombotic therapy is indicated in patients with ST-segment elevation myocardial infarction according to current Russian and international guidelines.

Metalyse^® is not compatible with dextrose solution.

Preparation of solution for intravenous administration

To dissolve Metalyse^®, it is necessary to add the full volume of water for injections contained in the supplied syringe into the vial with the powder.

1. Ensure that the vial has sufficient volume to prepare the drug solution according to the patient’s body weight.
2. Check the integrity of the vial cap.
3. Open the protective cap of the vial.
4. Remove the protective cap from the syringe. Then immediately screw the supplied syringe onto the vial adapter and pierce the vial stopper in the center with the adapter tip.
5. Slowly pressing the syringe plunger, add water for injections into the vial, avoid foam formation.
6. Dissolve the powder by gently rotating the vial.
7. The prepared solution should be clear, colorless or pale yellow. Only a clear solution free of visible particles can be used for administration.
8. Immediately before use, turn the vial with the attached syringe so that the syringe is at the bottom.
9. Draw the required volume of the prepared solution into the syringe, calculated depending on the patient’s body weight.
10. Disconnect the syringe from the vial adapter.
11. Metalyse^® should be administered intravenously over 5-10 seconds. For Metalyse^® administration, a catheter through which dextrose was administered should not be used.
12. Unused solution must be destroyed.
13. Dilution of the drug can also be done using the supplied needle.

Adverse Reactions

The most frequent side effect associated with the use of Metalyse^® is bleeding. Bleeding in any location/cavity of the body can lead to a life-threatening situation, disability or death.

Types of bleeding associated with thrombolytic therapy can be divided into two large groups

• External bleeding (usually from vascular puncture sites);
• Internal bleeding: in any part or cavity of the body.

Immune system disorders: anaphylactoid reactions, including rash, urticaria, bronchospasm, laryngeal edema.

Nervous system disorders intracranial hemorrhage (cerebral hemorrhage, cerebral hematoma, hemorrhagic stroke, hemorrhagic transformation of stroke, intracranial hematoma, subarachnoid hemorrhage). The following neurological syndromes may be associated with intracranial hemorrhages: drowsiness, aphasia, hemiparesis, convulsions.

Eye disorders intraocular hemorrhage.

Cardiac disorders: reperfusion arrhythmias (asystole, idioventricular tachyarrhythmia, arrhythmia, extrasystole, atrial fibrillation, AV-block from first degree to complete block, bradycardia, tachycardia, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia). Reperfusion arrhythmias can lead to cardiac arrest, be life-threatening and require the use of conventional antiarrhythmic therapy; pericardial bleeding.

Vascular disorders: bleeding, embolisms.

Respiratory, thoracic and mediastinal disorders: epistaxis, pulmonary hemorrhage.

Gastrointestinal disorders: gastrointestinal bleeding (gastric bleeding, gastric ulcer bleeding, rectal bleeding, hematemesis, melena, oral bleeding), nausea, vomiting, retroperitoneal bleeding (retroperitoneal hematoma).

Skin and subcutaneous tissue disorders ecchymoses.

Renal and urinary disorders: urogenital bleeding (hematuria, urinary tract bleeding).

General disorders and administration site conditions: external bleeding, usually from puncture sites or from damaged blood vessels.

Investigations: decreased blood pressure, increased body temperature.

Injury, poisoning and procedural complications: fat embolism, which can lead to corresponding consequences from the affected internal organs.

Surgical and medical procedures need for blood transfusion.

Contraindications

• Diseases accompanied by significant bleeding within the last 6 months, hemorrhagic diathesis;
• Concomitant use of oral anticoagulants (INR > 1.3);
• History of CNS diseases (neoplasms, aneurysm, surgical intervention on the brain and spinal cord);
• Severe uncontrolled arterial hypertension;
• Major surgical interventions, biopsy of a parenchymal organ or significant trauma within the last 2 months (including trauma combined with current acute myocardial infarction), recently suffered craniocerebral trauma;
• Prolonged or traumatic cardiopulmonary resuscitation (>2 min) within the last 2 weeks;
• Severe liver dysfunction, including hepatic failure, cirrhosis, portal hypertension (including with esophageal varices) and active hepatitis;
• Peptic ulcer of the stomach or duodenum in the acute phase;
• Arterial aneurysm or presence of arterial/venous vascular malformation;
• Neoplasm with increased risk of bleeding;
• Acute pericarditis and/or subacute bacterial endocarditis;
• Acute pancreatitis;
• Hypersensitivity to tenecteplase, gentamicin (residual traces from the manufacturing process) or to any excipient;
• History of hemorrhagic stroke or stroke of unknown etiology;
• Ischemic stroke or transient ischemic attack (TIA) within the last 6 months.

With caution

In the following cases, when prescribing Metalyse^®, the degree of expected benefit and possible risk of bleeding should be carefully assessed

• Systolic BP >160 mm Hg;
• Recent gastrointestinal or genitourinary tract bleeding (within the last 10 days);
• Recent intramuscular injection (within the last 2 days);
• Elderly age (over 75 years);
• Low body weight (< 60 kg);
• Cerebrovascular diseases.

Use in Pregnancy and Lactation

There is no experience with the use of Metalyse^® during pregnancy. There are no data on the excretion of tenecteplase into breast milk.

If it is necessary to prescribe the drug in case of acute myocardial infarction during pregnancy or lactation (breastfeeding), the expected benefit for the mother and the degree of possible risk to the fetus or child should be correlated.

Use in Hepatic Impairment

The drug is contraindicated in severe liver dysfunction, including hepatic failure, cirrhosis, portal hypertension (including with esophageal varices) and active hepatitis.

Geriatric Use

In elderly age (over 75 years), when prescribing Metalyse^®, the degree of expected benefit and possible risk of bleeding should be carefully assessed.

Special Precautions

Prescription of Metalyse^® should be carried out by a specialist with experience in thrombolytic therapy and the ability to monitor its effectiveness. This does not exclude the possibility of using Metalyse^® at the prehospital stage. Like other thrombolytic agents, administration of Metalyse^® is recommended in conditions where standard resuscitation equipment and medicines are available.

Primary percutaneous coronary intervention (PCI)

If PCI is planned according to current guidelines (treatment standards), Metalyse^® should not be pre-administered in a full dose together with a single bolus of up to 4000 IU of unfractionated heparin, administered in the time interval of 60-180 minutes before primary PCI in patients with extensive myocardial infarction.

Bleeding

The most frequent complication associated with the use of Metalyse^® is bleeding. Concomitant use of heparin may contribute to bleeding occurrence. After fibrin dissolution as a result of Metalyse^® use, bleeding may occur at sites of recent punctures and injections. Therefore, thrombolytic treatment requires careful monitoring of areas of possible bleeding (including the catheter insertion site, arterial and venous puncture sites, incisions and injections). The use of rigid catheters, intramuscular injections and unjustified manipulations during Metalyse^® treatment should be avoided.

In case of serious bleeding, especially intracranial hemorrhage, concomitant heparin administration should be immediately discontinued. Protamine sulfate may be prescribed if heparin was administered within 4 hours before bleeding onset. When conservative therapy is ineffective, transfusion of blood products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma and platelets may be prescribed according to clinical and laboratory parameters determined repeatedly after each administration. Infusion of cryoprecipitate is desirable until a fibrinogen concentration of about 1 g/l is achieved. Antifibrinolytic agents may also be used.

Arrhythmias

Coronary thrombolysis may be accompanied by the occurrence of arrhythmias associated with reperfusion. Reperfusion arrhythmias can lead to cardiac arrest, be life-threatening and require the use of conventional antiarrhythmic therapy.

Glycoprotein IIb/IIIa Antagonists

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

Thromboembolism

The use of Metalyse^® may be associated with an increased risk of thromboembolic complications in patients with left-sided heart thrombosis, including mitral stenosis or atrial fibrillation.

Hypersensitivity

No antibody formation against the tenecteplase molecule was detected after treatment. However, there is no experience with the repeated use of Metalyse^®. Anaphylactoid reactions associated with the use of Metalyse^® have been rarely observed and could be due to hypersensitivity to tenecteplase, gentamicin (trace amounts, used in the manufacturing process), or to any other excipient. If an anaphylactoid reaction occurs, the injection should be discontinued.

Reconstituted Solution

The reconstituted solution remains stable for 24 hours at a temperature of 2-8°C (17.6°F) and for 8 hours at a temperature of 30°C (86°F). From a microbiological point of view, the solution should be used immediately after reconstitution. If the solution has been prepared in advance and not administered, the storage time and conditions prior to use become the responsibility of the prescribing practitioner; the shelf life usually does not exceed 24 hours at 2-8°C (17.6°F) and 8 hours at 30°C (86°F). Any unused solution must be discarded.

Overdose

Symptoms overdose of the drug may increase the risk of bleeding.

Treatment in case of prolonged significant bleeding, a blood transfusion may be required.

Drug Interactions

There are no data on clinically significant interactions of Metalyse^® with other drugs frequently used in patients with acute myocardial infarction.

Drugs that alter coagulation properties, as well as drugs affecting platelet function, may increase the risk of bleeding if used before, concurrently with, or after the administration of Metalyse^®.

Pharmaceutical Incompatibility

The drug is incompatible with dextrose solutions.

The Metalyse^® injection solution should not be mixed with other medicinal products.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life of the lyophilisate is 2 years. The shelf life of the solvent is 3 years.

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.