Метализе®

General characteristics. Structure:

Active ingredient: 30 mg, 40 mg or 50 mg of a tenekteplaza.

Excipients: arginine, 85% phosphoric acid, polysorbate 20. Solvent: water for injections.

Pharmacological properties:

Pharmacodynamics. Tenekteplaza - recombinant fibrin - a specific plasminogen activator, is derivative the natural fabric plasminogen activator modified in three sites. Tenekteplaza contacts a fibrinous component of blood clot and selectively catalyzes transformation of the plasminogen connected with blood clot into plasmin which destroys a fibrinous basis of blood clot. In comparison with a natural fabric plasminogen activator, the tenekteplaza has higher affinity to fibrin and resistance to the inactivating effect of endogenous inhibitor of a plasminogen activator of I.

After introduction of a tenekteplaz dozozavisimy consumption of alfa2-anti-plasmin (plasmin inhibitor in a liquid phase) with the subsequent increase in concentration of system plasmin is observed that corresponds to estimated effect of activation of plasminogen. In comparative researches at the patients receiving the maximum doses of a tenekteplaza (10000 PIECES, экв. 50 mg), are noted decrease in concentration of fibrinogen less than for 15%, and concentration of plasminogen less, than for 25%, and use of an alteplaza led to decrease in concentration of fibrinogen and plasminogen approximately by 50%. In 30 days after the beginning of use to Metaliza antibodies to a tenekteplaza were not revealed.

Angiographic data show that single intravenous administration of a tenekteplaza promotes a rekanalization of an artery owing to which thrombosis the acute myocardial infarction developed. This effect is dozozavisimy. Use of a tenekteplaza reduces myocardial infarction mortality rate (by 6,2% in 30 days). At use of a tenekteplaza the frequency of bleedings (excepting intracranial) makes 26,4% (below, than when using an alteplaza - 28,9%). Therefore the need for transfusion therapy when using a tenekteplaza is significantly lower (4,3% in group of a tenekteplaza and 5,5% in group of an alteplaza). Frequency of intracraneal hemorrhages made 0,93% in group of a tenekteplaza and 0,94% in group of an alteplaza. In cases when treatment was begun later, than in the 6th hour after emergence of symptoms of a myocardial infarction, use of a tenekteplaza  (    in comparison with  alteplazy)  had  advantages  on indicators of 30-day mortality (4,3% in group of a tenekteplaza and 9,6% in group of an alteplaza), stroke frequencies (0,4% and 3,3%, respectively) and frequencies of intracraneal hemorrhages (0% and 1,7% respectively).

Pharmacokinetics. Tenekteplaza is brought from a blood-groove by linkng with receptors in a liver and degradation with formation of small peptides. After a single injection of a tenekteplaza at patients with an acute myocardial infarction two-phase removal of antigen of a tenekteplaza from a blood plasma is noted. When using drug in therapeutic doses of dependence of nature of removal of a tenekteplaza on the entered dose it is not observed. The initial stage of semi-removal makes 24 ± 5,5 min. (average value +/-a standard deviation) that in 5 times more an elimination half-life of a natural fabric plasminogen activator. The final elimination half-life makes 129 ± 87 min.; plasma clearance - 119 ± 49 ml/min.

At the increased body weight moderate increase in an indicator of clearance of plasma is observed, with increase in age reduction of this indicator is noted. At women indicators of clearance of plasma are usually lower, than at men that can speak lower body weight at women.

Tenekteplaza is brought with bile therefore it is supposed that the renal failure does not lead to change of pharmacokinetics of METALIZE. The pharmacokinetics research at an abnormal liver function was not conducted.

Indications to use:

Thrombolytic therapy of the acute myocardial infarction (AMI).

Route of administration and doses:

The dose of METALIZE is calculated depending on body weight, the maximum dose should not exceed 10 000 PIECES (50 mg of a tenekteplaza). Solution volume for introduction of a necessary dose is calculated according to the table:

Body weight of the patient (kg)	Tenekteplaza (PIECE)	Tenekteplaza (mg)	The volume of the prepared solution (ml)
<60	6 000	30	6
≥ 60 - <70	7 000	35	7
≥ 70 - <80	8 000	40	8
≥ 80 - <90	9 000	45	9
≥90	10 000	50	10

The necessary dose of drug is entered by a bystry single intravenous injection during 5-10 sec. The catheter established earlier for intravenous administration only of 0,9% of solution of sodium of chloride, can be used for introduction of METALIZE.

After introduction of METALIZE the catheter needs to be washed out before its further use for administration of other medicines.

Efficiency of therapy of METALIZE requires use of acetylsalicylic acid (ASK) and heparin. These drugs should be administered at once after establishment of the diagnosis of OIM for prevention of a thrombogenesis.

Use of ASK needs to be begun right after identification of symptoms of OIM and to continue, at least, to the patient's extract from a hospital. The recommended initial dose for intake makes 150-325 mg/days. If the patient cannot swallow tablets, the initial dose of 150-250 mg of ASK can be entered intravenously. ASK dose in the next days is defined by the attending physician.

Administration of heparin needs to be begun right after confirmation of the diagnosis of OIM and to continue, at least, during the 24th hour. The dose of heparin is calculated depending on body weight. For patients with the body weight of 67 kg and less, the initial single dose of heparin for intravenous jet administration should not exceed 4000 PIECES, with the subsequent infusional administration of heparin with a speed of 800 PIECES/hour. For patients with body weight more than 67 kg the initial single dose of heparin for intravenous jet administration should not exceed 5000 PIECES, with the subsequent infusional administration of heparin with a speed of 1000 PIECES/hour. It is not necessary to appoint an initial dose of heparin for intravenous jet administration to the patients who are already receiving heparin. Speed of infusional administration of heparin has to be adjusted for maintenance of an indicator of the activated partial thrombin time (APTT) at the level of 50-75 sec. (is 1,5-2,5 times higher than control time or the content of heparin in plasma of 0,2-0,5 PIECES/ml).

Preparation of solution for intravenous administration. For dissolution of METALIZE it is necessary to add the full volume of water for injections which is contained in the enclosed syringe to a bottle with powder.
1. Make sure that the bottle has the volume sufficient for drug solution preparation according to the body weight of the patient (see the section "Route of Administration and Doses").
2. Check integrity of a cover of a bottle.
3. Open a protective cover of a bottle.
4. Remove a protective cap from the syringe. Then at once screw the enclosed syringe on the adapter for a bottle and pierce an adapter edge a bottle stopper in the center.
5. Slowly pressing the syringe piston, add to a bottle water for injections, avoid emergence of foam.
6. Dissolve powder, carefully rotating a bottle.
7. The prepared solution has to be transparent, colourless or pale yellow color. For introduction only transparent solution which is not containing visible particles can be used.
8. Just before use turn a bottle with the syringe attached to it so that the syringe was below.
9. Gain the necessary volume of the prepared solution calculated depending on the body weight of the patient in the syringe.
10. Disconnect the syringe from the bottle adapter.
11. METALIZE should be entered intravenously during 5-10 sec. For introduction of METALIZE it is not necessary to use a catheter through which introduction of a dextrose was carried out.
12. Unused solution has to be destroyed.

Cultivation of drug can also be carried out by means of the enclosed needle.

Features of use:

The doctor having experience of performing thrombolytic therapy and a possibility of control of its efficiency has to carry out purpose of METALIZE. It does not exclude a possibility of use of METALIZE at a pre-hospital stage. As well as other thrombolytic means, introduction of METALIZE are recommended to be carried out in conditions when the standard resuscitation equipment and medicines is available.

Bleeding. The most frequent complication connected using METALIZE is bleeding. Simultaneous use of heparin can promote developing of bleeding. After dissolution of fibrin as a result of use of METALIZE, developing of bleeding in places of recently executed punctures and injections is possible. Therefore thrombolytic treatment demands careful observation of zones of possible developing of bleeding (including an injection site of a catheter, arterial and venous punctures, cuts and injections). It is necessary to avoid use of rigid catheters, intramuscular injections and unreasonable manipulations during treatment of METALIZE.

In case of developing of serious bleeding, in particular, of intracraneal hemorrhage, simultaneous administration of heparin has to be immediately stopped. It is necessary to remember a possibility of purpose of protamin if heparin was appointed during the 4th hour before developing of bleeding. In rare instances when the listed measures of conservative treatment are inefficient, reasonable administration of transfusion drugs can be shown. Transfusion administration of cryoprecipitate, the fresh frozen plasma and thrombocytes can be appointed according to the clinical and laboratory indicators defined repeatedly after each introduction. About 1 g/l are desirable to carry out infusion of cryoprecipitate to achievement of concentration of fibrinogen. Perhaps also use of anti-fibrinolitic means.

Arrhythmias. The coronary thrombolysis can be followed by developing of the arrhythmia connected with reperfusion.

Antagonists of a glycoprotein of IIb/IIIa Experience of use of antagonists of a glycoprotein of IIb/IIIa during the first the 24th hour after an initiation of treatment is absent.

Thromboembolism. Use of METALIZE can be followed by increase in risk of tromboembolic episodes at patients with thrombosis of the left departments of heart, including at a mitral stenosis or fibrillation of auricles.

Repeated treatment. Antibody formation to a tenekteplaza molecule after treatment is not revealed. However experience of repeated use of METALIZE is absent.

The prepared solution. Physical and chemical properties of the prepared solution are stable during the 24th hour at a temperature of 2-8 °C and during the 8th hour at a temperature of 30 °C.

From the microbiological point of view, solution should be used right after preparation. If solution was not used at once, the term and conditions of its storage before use pass under responsibility of the doctor appointing drug; the period of storage usually does not exceed the 24th hour at a temperature of 2-8 °C and 8 hour at a temperature of 30 °C.

Side effects:

The most often found side effect connected using METALIZE is bleeding. Types of the bleedings connected with thrombolytic therapy can be divided into two big groups:
- outside bleeding (as a rule from places of punctures of blood vessels);
- internal bleedings: gastrointestinal, pulmonary and bleedings from an urinogenital path, a hemopericardium, hemorrhages in retroperitoneal space and  a brain (with   development of the corresponding neurologic symptoms, such as block, aphasia, spasms). At patients with a stroke and intracranial bleeding cases of death and a resistant invalidism are described.

Disturbances from a nervous system Infrequently (> 1/1000, <1/100): intracraneal hemorrhage.

Disturbances from heart It is very frequent (> 1/10): reperfusion arrhythmias. Seldom (> 1/10 000, <1/1000): hemopericardium.

Vascular disorders Very often (> 1/10): bleeding. Often (> 1/100, <1/10): ecchymomas. Infrequently (> 1/1000, <1/100): thromboembolisms.

Disturbances from a respiratory organs, bodies of a chest cavity and a mediastinum. Often (> 1/100, <1/10): nasal bleeding. Infrequently (> 1/1000, <1/100): pulmonary bleeding.

Disturbances from digestive tract Often (> 1/100, <1/10): gastrointestinal bleeding, nausea, vomiting. Infrequently (> 1/1000, <1/100): bleeding in retroperitoneal space.

Disturbances from outside from an urinogenital path Often (> 1/100, <1/10): bleeding from an urinogenital path.

Disturbances of the general character and reaction in a drug injection site Very often (> 1/10): outside bleedings, usually from places of punctures or from the damaged blood vessels.

The reactions revealed at special researches It is very frequent (> 1/10): lowering of arterial pressure. Often (> 1/100, <1/10): fervescence.

Damages, the toxic phenomena and complications owing to the procedures connected using drug. Infrequently (> 1/1000, <1/100): anaphylactoid reactions (including rash, urticaria, a bronchospasm, throat hypostasis). Very seldom (<1/10 000): embolization by cholesterol crystals.

Surgical and therapeutic procedures. Often (> 1/100, <1/10): need for hemotransfusion.

Interaction with other medicines:

There are no data on existence of clinically significant interactions of METALIZE with other drugs which are often applied at patients with OIM.

The medicines changing coagulative properties of blood, and also the drugs influencing function of thrombocytes can increase risk of development of bleeding if they are used to, at the same time or after purpose of METALIZE.

Drug is incompatible with dextrose solutions. The METALIZE injection solution should not be mixed with other medicines.

Contraindications:

• the diseases which are followed by considerable bleedings within the last 6 months, hemorrhagic diathesis;
• a concomitant use of peroral anticoagulants (the international standardized index> 1,3);
• diseases of the central nervous system (CNS) in the anamnesis (new growths, aneurism, surgical intervention on a head and spinal cord);
• heavy uncontrollable arterial hypertension;
• large operative measures, a biopsy of parenchymatous body or a considerable injury within the last 2 months (including an injury in combination with OIM now), recently postponed craniocereberal injuries;
• long or traumatic cardiopulmonary resuscitation (> 2 min.) within the last 2 weeks;
• a heavy abnormal liver function, including, a liver failure, cirrhosis, portal hypertensia (including, with a gullet varicosity) and active hepatitis;
• diabetic hemorrhagic retinopathy or other hemorrhagic diseases of eyes;
• a peptic ulcer of a stomach or duodenum in an aggravation stage;
• aneurism of an artery or existence of an arterial/venous malformation of vessels;
• a new growth with the increased risk of development of bleeding;
• acute pericardis and/or subacute bacterial endocarditis;
• acute pancreatitis;
• hypersensitivity to active agent (tenekteplaz) or to any other component of drug.

With care. In the following cases, at purpose of METALIZE it is necessary to estimate carefully degree of estimated advantage and possible risk of bleeding:
• systolic arterial pressure> 160 mm of mercury;
• a stroke or passing disturbance of cerebral circulation in the anamnesis;
•  recently postponed bleeding from a gastrointestinal or urinogenital path (during the last 10 days);
• recently executed intramuscular injection (during the last 2 days);
• advanced age (75 years are more senior);
• low body weight <60 kg;
• cerebrovascular diseases

Pregnancy and lactation
Experience of use of METALIZE for pregnant women is absent.
There are no data on removal of a tenekteplaza with breast milk.
It is necessary to correlate degree of possible risk and estimated advantage at
purpose of drug in case of development of OIM during pregnancy and
lactations.

Overdose:

At overdose of drug increase in risk of development of bleeding is possible. In case of long considerable bleeding hemotransfusion can be required.

Storage conditions:

At a temperature not above 30 °C, in the place unavailable to children protected from light. The Lyophilisate period of validity - 2 years. Solvent 3 years. Not to use after expiry date.

Issue conditions:

According to the recipe

Packaging:

Bottle from colourless glass the type I containing 30 mg (6000 PIECES), 40 mg (8000 PIECES), or 50 mg (10000 PIECES) of lyophilisate for preparation of solution for intravenous administration. The bottle is corked by the gray brombutilovy stopper which is rolled up by an aluminum cap, and a plastic protective cover (gray color for 30 mg, flavovirent color for 40 mg and red color for 50 mg). In a set: the syringe plastic with solvent on 6 ml, either 8 ml, or 10 ml, a one-time needle, the adapter. The bottle, the syringe, the adapter and a needle with the application instruction are placed in a cardboard pack.