Metalase - instructions for use, dose, side effects, contraindications

Active substanceTenecteplaseTenecteplase

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Metalize®

lyophilizate in / in

Boehringer Ingelheim Pharma GmbH & Co. KG. KG Germany

Dosage form: & nbsplyophilizate for the preparation of a solution for intravenous administration

Composition:

Composition per 1 bottle:

Active substance:

METALISE 6000 ED - 30 mg of tenecteplase;

METALISE 8000 ED - 40 mg of tenecteplase;

METALISE 10000 ED - 50 mg tenecteplases;

Excipients:

arginine (base) 313.2 mg, 417.6 mg, 522

mg; 85% phosphoric acid 98.4 mg, 131.2

mg, 164 mg (to a pH of about 7.3); polysorbate 20

(Tween 20) 2.4 mg, 3.2 mg, 4.0 mg.

Solvent: water for injection 6 ml, 8 ml, 10 ml.

The activity of tenecteplase is measured in units of action (ED), calculated with using a special standard of tenecteplase activity and incompatible with units of activity of other thrombolytic agents.

Residual footprints: gentamicin (used in the production process).

In 1 ml of diluted solution contains 1000 units (5 mg) of tenecteplase.

Description:

The white or pale yellow mass is almost odorless.

Pharmacotherapeutic group:fibrinolytic agent.

ATX: & nbsp

B.01.A.D.11 Tenecteplase

Pharmacodynamics:

Tenecteplase is a recombinant fibrin-specific activator of plasminogen, a derivative of natural tissue activator plasminogen,

modified in three sections. Tenecteplase binds to the fibrin component of the thrombus and selectively catalyzes the transformation of the thrombus-bound plasminogen into plasmin, which destroys the fibrin base of the thrombus. In comparison with the natural tissue plasminogen activator, tenecteplase has a higher affinity for fibrin and resistance to the inactivating action of the endogenous inhibitor of the plasminogen I activator. After the introduction of tenecteplase, a dose-dependent consumption α2-antiplasmin (plasmin inhibitor in the liquid phase) followed by an increase in the concentration of systemic plasmin, which corresponds to the expected effect of plasminogen activation. In comparative studies in patients receiving the maximum dose of tenecteplase (10,000 units, equivalent to 50 mg), the fibrinogen concentration was reduced by less than 15%, and the plasminogen concentration was less than 25%, and the use of alteplase led to a decrease in fibrinogen concentration and plasminogen approximately by 50%. 30 days after the start of the use of METALISE antibodies to tenecteplase were not detected. Angiographic data show that a single intravenous injection of tenecteplase promotes recanalizationarteries, due to the thrombosis of which developed an acute myocardial infarction. This effect is dose-dependent. The use of tenecteplase reduces the death rate from myocardial infarction (by 6.2% after 30 days). With tenecteplase, the incidence of bleeding (excluding intracranial) is 26.4% (lower than with alteplase - 28.9%, p = 0.0003). Reducing the risk of bleeding is probably due to the higher specificity of tenecteplase for fibrin, as well as the choice of treatment regimen depending on the body weight of patients. Therefore, the need for transfusion therapy with the use of tenecteplase is significantly lower (4.3% in the tenecteplase group and 5.5% in the alteplase group). The incidence of intracranial hemorrhage 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 symptoms of myocardial infarction, the use of tenecteplase (in comparison with alteplase) had advantages in terms of 30-day mortality (4.3% in the tenecteplase group and 9.6% in the alteplase group), frequencies stroke (0.4% and 3.3%, respectively) and the incidence of intracranial hemorrhages (0% and 1.7%, respectively).

Pharmacokinetics:

Tenecteplase is excreted 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 two-phase excretion of tenecteplase antigen from plasma was noted. When using the drug in therapeutic doses, there is no dependence of the character of excretion of tenecteplase from the administered dose. The initial predominant half-life is 24 ± 5.5 minutes. (mean +/- standard deviation), which is 5 times longer than the half-life of the natural tissue plasminogen activator. The final half-life is 129 ± 87 min; the plasma clearance is 119 ± 49 ml / min.

With an increased body weight, there is a moderate increase in plasma clearance, with an increase in age there is a decrease in this indicator. In women, plasma clearance is usually lower than in men, which may be due to lower body weight in women.

Tenecteplase is excreted with bile, so it is assumed that renal dysfunction does not lead to a change in the pharmacokinetics of METALISE.The study of pharmacokinetics in the violation of liver function was not performed.

Indications:Thrombolytic therapy of acute myocardial infarction (AMI).

Contraindications:

- diseases accompanied by significant bleeding during the last 6 months, hemorrhagic diathesis;

- simultaneous administration of oral anticoagulants (international normalized ratio> 1.3);

- diseases of the central nervous system system (CNS) in the anamnesis (neoplasms, aneurysm, surgical intervention on the brain and spinal cord);

- Heavy uncontrollable arterial hypertension;

- major surgical interventions, biopsy of the parenchymatous organ, or significant trauma in the last 2 months (including trauma in combination with AMI now), recent craniocerebral trauma;

- prolonged or traumatic cardiopulmonary resuscitation (> 2 min) in the last 2 weeks;

- Severe dysfunction of the liver, including, hepatic insufficiency, cirrhosis, portal Hypertension (incl., with varicose veins esophageal veins) and active hepatitis;

- Stomach ulcer or duodenum in the stage exacerbations;

- an aneurysm of an artery or presence arterial / venous malformation development of blood vessels;

- neoplasm with increased risk of bleeding;

- acute pericarditis and / or subacute bacterial endocarditis;

acute pancreatitis;

- hypersensitivity to active substance (tenecteplase), gentamicin (residual traces from process of production) or any auxiliary substance;

- hemorrhagic stroke or stroke of unknown etiology in anamnesis;

ischemic stroke or transient ischemic attack (TIA) in the last 6 months.

Carefully:

In the following cases, with the appointment of METALISE, the extent of the intended benefit and the potential risk of bleeding should be carefully assessed:

- systolic arterial pressure> 160 mm Hg;

- recent bleeding from the gastrointestinal or genito-urinary tract (within the last 10 days);

- recently executed intramuscular injection (within the last 2 days);

- elderly age (over 75 years);

- low body weight <60 kg;

- cerebrovascular diseases

Pregnancy and lactation:

Experience in the use of METALISE in pregnant women is absent.

There is no data on excretion of tenecteplase with breast milk.

It is necessary to correlate the degree of possible risk and the intended use when prescribing the drug in the case of development of AMI during pregnancy and lactation.

Dosing and Administration:

A drug is intended for thrombolytic therapy acute myocardial infarction. Therapy should be started as soon as possible after the detection of symptoms.

The dose of METALYSIS is calculated depending on the body weight, the maximum dose should not exceed 10 000 units (50 mg of tenecteplase). Volume of solution for administration necessary doses calculated according to the table:

Body weight patient a (kg)	Tenekt eplase (ED)	Tenekte plaza (mg)	Scope preparing ence solution (ml)
<60	6000	30	6
>=60	-7000	35	7
<70
>=70	-8000	40	8
<80
>=80	-9000	45	9
<90
>=90	10000	50	10

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

The previously established catheter for intravenous administration of only 0.9% sodium chloride solution can be used to administer METALIZE. After the introduction of METALISE, the catheter must be rinsed before further use for the administration of other drugs.

The drug METALIZE should not be mixed with other drugs (even with heparin), neither in the infusion bottle nor in the common system for intravenous administration.

Auxiliary therapy:

Auxiliary antithrombotic

Therapy is indicated in patients with myocardial infarction with segment elevation ST according to the current Russian and international recommendations.

METALISE is not compatible with dextrose solution.

Preparation of a solution for intravenous administration

To dissolve META LIZE, it is necessary to add the full volume of water for injections contained in the attached syringe into a vial of powder.

1. Ensure that the vial has a volume sufficient to prepare the drug solution in accordance with the patient's body weight (see section "Dosage and Administration"),

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 attached syringe onto the adapter for the vial and pierce the tip of the adapter with the tip of the bottle in the center.

5. Slowly pressing the plunger of the syringe, add water to the bottle for injection, avoid the appearance of foam.

6. Dissolve the powder by gently rotating the vial.

7. The prepared solution must be transparent, colorless or pale yellow. For introduction can be used only transparent solution that does not contain visible particles.

8. Immediately before application, flip the connected to it by a syringe way to a syringe was downstairs.

9. Type in the syringe necessary volume of the prepared solution, calculated according to body weight patient.

10. Disconnect the syringe from the adapter vial.

11. METALISE should be introduced intravenously for 5-10 seconds. For The introduction of METALIZE should not use a catheter through which Dextrose was administered.

12. The unused solution must be be destroyed.

13. Dilution of the drug can also be with the help of the attached needles.

Side effects:

The most common side

effect associated with the application of METALISE, is bleeding.

Bleeding anywhere / body cavity can lead to a life-threatening

situation, disability or death.

Types of bleeding associated with thrombolytic therapy, may be

are divided into two large groups:

external bleeding (as from the puncture sites blood vessels);

- internal bleeding: in any part or cavity of the body.

Immune system disorders

- anaphylactoid reactions, including rash, hives, bronchospasm, edema

larynx.

Disturbances from the nervous system

intracranial hemorrhage (cerebral hemorrhage, cerebral hematoma, stroke transformation, intracranial hematoma, subarachnoidal bleeding). With intracranial hemorrhages, the following neurological syndromes can be associated: drowsiness, aphasia, hemiparesis, convulsions. Disturbances on the part of the organ of sight

- intraocular hemorrhage.

Heart Disease

- reperfusion arrhythmias (asystole, idioventricular tachyarrhythmia, arrhythmia, extrasystole, atrial fibrillation, atrioventricular block from I degree to complete block, bradycardia, tachycardia, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia).

Reperfusion arrhythmias can lead to cardiac arrest, endanger life and require the use of conventional antiarrhythmic therapy.

- pericardial hemorrhage.

Vascular disorders

- bleeding, embolism.

Disturbances from the respiratory, thoracic and mediastinal organs

nosebleeds, pulmonary hemorrhage.

Disorders from the gastrointestinal tract gastrointestinal bleeding (gastric bleeding, bleeding from a stomach ulcer, rectal bleeding, bloody vomiting, melena, bleeding from the mouth),

- nausea,

- vomiting.

bleeding to the retroperitoneal space (retroperitoneal hematoma).

Disturbances from the skin and subcutaneous cellulose

- ecchymosis.

Infringements from kidneys and genito-urinary tract

- urogenital bleeding (hematuria, bleeding from the urinary tract).

Violations of a general nature and reaction in site of drug administration

- external bleeding, usually from puncture sites or from damaged blood vessels.

Reactions identified by special studies

- lowering blood pressure,

- fever. Damage, toxic effects and complications due to procedures associated with the use of the drug

- fat embolism, which can lead to the corresponding consequences from the affected internal organs. Surgical and therapeutic procedures

- need for blood transfusion.

Overdose:

When an overdose of the drug may increase the risk of bleeding. In case of prolonged significant bleeding, a blood transfusion may be required.

Interaction:

There is no evidence of the presence of clinically significant METALISE interactions with other drugs that are often used in patients with AMI.

Drugs that alter coagulation properties of blood, as well as drugs that affect platelet function, can increase the risk of bleeding if they are used before, at the same time, or after the appointment of METALISE.

The drug is incompatible with solutions of dextrose.

Injection solution METALISE should not be mixed with other medications.

Special instructions:

The purpose of METALIZATION should be a specialist with experience in thrombolytic therapy and the possibility of control its effectiveness. Is not excludes the possibility of using METALIZE at the prehospital stage. Like other thrombolytic agents, the introduction of META LIZE is recommended in conditions,when standard resuscitation equipment and medicines are available.

Primary Percutaneous Coronary Intervention (PCI)

If PCI is planned in accordance with the current recommendations (treatment standards), do not first apply METALISE in a full dose together with a single bolus in a dose of up to 4000 ME unfractionated heparin administered in the time interval 60-180 minutes to the primary PCI in patients with extensive myocardial infarction.

Bleeding

The most common complication associated with the use of METALIZE is bleeding. Simultaneous using heparin can contribute emergence of bleeding. After the dissolution of fibrin as a result of the use of METALISE, bleeding can occur in places of recently performed punctures and injections. Thrombolytic treatment therefore requires careful monitoring of the zones of possible bleeding (including the site of insertion of the catheter, arterial and venous punctures, incisions and injections). Should avoid the use of rigid catheters, intramuscular injections and unreasonable manipulations during treatment METALIZE.

In case of serious bleeding, at features, intracranial hemorrhages, simultaneous administration of heparin should be immediately discontinued. It is possible to prescribe protamine sulphate if heparin was prescribed within 4 hours before bleeding occurs. When conservative therapy is not effective, administration of transfusion preparations.

Transfusion the introduction of cryoprecipitate, fresh frozen plasma and platelets can be prescribed in accordance with clinical and laboratory indicators determined repeatedly after each administration. Infusion of cryoprecipitate is desirable to be carried out until the concentration of fibrinogen is about 1 g / l. maybe also use of antifibrinolytic agents.

Arrhythmias

Coronary thrombolysis can be accompanied by the occurrence of arrhythmia associated with reperfusion. Reperfusion arrhythmias can lead to cardiac arrest, endanger life and require application conventional antiarrhythmic therapy.

Glycoprotein IIb / IIIa antagonists

The concomitant use of antagonists of the glycoprotein Hb / Cha increases the risk of bleeding.

Thromboembolism

The use of METALISE may be accompanied by an increased risk of thromboembolic complications in patients with thrombosis of the left heart, incl. with mitral stenosis or atrial fibrillation. Hypersensitivity The formation of antibodies to molecule Tenecteplase after treatment has not been identified. However, the experience of re-use of METALIZE absent.

Anaphylactoid reactions associated with the use of METALISE have been observed rarely and could be reason hypersensitivity to tenecteplase, gentamicin (trace amounts, used in the manufacturing process) or to any other auxiliary substance. In case of anaphylactoid reaction, introduction injection should be discontinued. The prepared solution The prepared solution remains stable for 24 hours at a temperature of 2-8 ° C and for 8 hours at a temperature of 30 ° C.

From the microbiological point of view, the solution should be used immediately after preparation. If the solution has been prepared in advance and not entered, the period and conditions of its storage prior to use pass over under the responsibility of a specialist who prescribes the drug; the shelf life usually does not exceed 24 hours at a temperature of 2-8 ° C and 8 hours at a temperature of 30 ° C.

Incompleteness used solution must be destroyed (see "Method of administration and dose")

Effect on the ability to drive transp. cf. and fur:

Form release / dosage:

A bottle of colorless glass type I, containing 30 mg (6000 ED), 40 mg (8000 ED), or 50 mg (10,000 units) of lyophilizate for the preparation of a solution for intravenous administration.

The bottle is sealed with a gray bromobutyl stopper, rolled up with an aluminum cap, and a plastic protective cover (gray for 30 mg, yellow-green for 40 mg and red for 50 mg).

In the kit: a plastic syringe with a solvent of 6 ml, or 8 ml, or 10 ml, a disposable needle, adapter.

A bottle, a syringe, an adapter and a needle with instructions for use are placed in a cardboard box.

Packaging:(1) - vials (1) / complete with a solvent: water for injection (syringes) 10 ml, disposable needle and adapter / - packs cardboard
(1) - vials (1) / complete with solvent: water for injection (syringes) 6 ml, disposable needle and adapter / - packs cardboard
(1) - vials (1) / complete with solvent: water for injection (syringes) 8 ml, disposable needle and adapter / - packs cardboard

Storage conditions:At a temperature not exceeding 30 ° C, in a dark place out of the reach of children.

Shelf life:

Lyophilizate - 2 years.

Solvent - 3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N016055 / 01

Date of registration:16.10.2009

The owner of the registration certificate:Boehringer Ingelheim Pharma GmbH & Co. KG. KGBoehringer Ingelheim Pharma GmbH & Co. KG. KG Germany

Manufacturer: & nbsp

Boehringer Ingelheim Pharma GmbH & Co. KG

Representation: & nbspBehringer Ingelheim, LLCBehringer Ingelheim, LLC

Information update date: & nbsp16.09.2015

Illustrated instructions

Instructions

Metalize® (Metalyse®)