4.1. Therapeutic indications

Metalyse is indicated in adults for the thrombolytic treatment of suspected myocardial infarction with persistent ST elevation or recent left Bundle Branch Block within 6 hours after the onset of acute myocardial infarction (AMI) symptoms.

4.2. Posology and method of administration

Posology

Metalyse should be prescribed by physicians experienced in the use of thrombolytic treatment and with the facilities to monitor that use.

Treatment with Metalyse should be initiated as early as possible after onset of symptoms.

The appropriate presentation of tenecteplase product should be chosen carefully and in line with the indication. The 40 mg and 50 mg presentations are only intended for use in acute myocardial infarction.

Metalyse should be administered on the basis of body weight, with a maximum dose of 10 000 units (50 mg tenecteplase). The volume required to administer the correct dose can be calculated from the following scheme:

Patients' body weight category

(kg)

Tenecteplase

(U)

Tenecteplase

(mg)

Corresponding volume of reconstituted solution

(mL)

< 60

6 000

30

6

≥ 60 to < 70

7 000

35

7

≥ 70 to < 80

8 000

40

8

≥ 80 to < 90

9 000

45

9

≥ 90

10 000

50

10

For details see section 6.6: Special precautions for disposal and other handling

Elderly (≥ 75 years)

Metalyse should be administered with caution in the elderly (≥ 75 years) due to a higher bleeding risk (see information on bleeding in section 4.4 and on the STREAM study in section 5.1).

Paediatric population

The safety and efficacy of Metalyse in children (below 18 years) have not been established. No data are available.

Adjunctive therapy

Antithrombotic adjunctive therapy with platelet inhibitors and anticoagulants should be administered according to the current relevant treatment guidelines for the management of patients with ST‑elevation myocardial infarction.

For coronary intervention see section 4.4.

Unfractionated heparin and enoxaparin have been used as antithrombotic adjunctive therapy in clinical studies with Metalyse.

Acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with lifelong treatment unless it is contraindicated.

Method of administration

The reconstituted solution should be administered intravenously and is for immediate use. The reconstituted solution is a clear and colourless to slightly yellow solution.

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

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to gentamicin (a trace residue from the manufacturing process). If treatment with Metalyse is nevertheless considered to be necessary, facilities for resuscitation should be immediately available in case of need.

Furthermore, Metalyse is contraindicated in the following situations because thrombolytic therapy is associated with a higher risk of bleeding:

- Significant bleeding disorder either at present or within the past 6 months

- Patients receiving effective oral anticoagulant treatment, (e.g. vitamin K antagonists with INR > 1.3) (see section 4.4, subsection “Bleeding”)

- Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)

- Known haemorrhagic diathesis

- Severe uncontrolled hypertension (see section 4.4)

- Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with the current AMI)

- Recent trauma to the head or cranium

- Bacterial endocarditis, pericarditis

- Acute pancreatitis

- Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis

- Active ulcerative gastro-intestinal disease

- Known arterial aneurysm and/or arterial/venous malformation

- Neoplasm with increased bleeding risk

- Any known history of haemorrhagic stroke or stroke of unknown origin

- Known history of ischaemic stroke or transient ischaemic attack in the preceding 6 months

- Dementia

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded.

Coronary intervention

If primary percutaneous coronary intervention (PCI) is scheduled according to the current relevant treatment guidelines, tenecteplase (see section 5.1 ASSENT-4 study) should not be given.

Patients who cannot undergo primary PCI within one hour as recommended by guidelines and receive tenecteplase as primary coronary recanalization treatment should be transferred without delay to a coronary intervention capable facility for angiography and timely adjunctive coronary intervention within 6‑24 hours or earlier if medically indicated (see section 5.1 STREAM study).

Bleeding

The most common complication encountered during tenecteplase therapy is bleeding. The concomitant use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during tenecteplase therapy, bleeding from recent puncture site may occur. Therefore, thrombolytic therapy requires careful attention to all possible bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites and needle puncture sites). The use of rigid catheters as well as intramuscular injections and non-essential handling of the patient should be avoided during treatment with tenecteplase.

Most frequently haemorrhage at the injection site, and occasionally genitourinary and gingival bleeding were observed.

Should serious bleeding occur, in particular cerebral haemorrhage, concomitant heparin administration should be terminated immediately. Administration of protamine should be considered if heparin has been administered within 4 hours before the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/L is desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative. In the following conditions, the risk of tenecteplase therapy may be increased and should be weighed against the anticipated benefits:

- Systolic blood pressure > 160 mm Hg, see section 4.3

- Recent gastrointestinal or genitourinary bleeding (within the past 10 days)

- Recent intramuscular injection or small recent traumas, puncture of major vessels

- Advanced age, i.e. patients 75 years or older

- Body weight < 50 kg

- Patients receiving oral anticoagulants: The use of Metalyse may be considered when dosing or time since the last intake of anticoagulant treatment makes residual efficacy unlikely and if appropriate test(s) of anticoagulant activity for the product(s) concerned show no clinically relevant activity on the coagulation system (e.g. INR ≤ 1.3 for vitamin K antagonists or other relevant test(s) for other oral anticoagulants are within the respective upper limit of normal)

- Prolonged (> 2 minutes) or traumatic cardiopulmonary resuscitation or cardiac massage.

Arrhythmias

Coronary thrombolysis may result in arrhythmias associated with reperfusion. Reperfusion arrhythmias may lead to cardiac arrest, can be life threatening and may require the use of conventional antiarrhythmic therapies. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (pacemaker, defibrillator) is available when tenecteplase is administered.

GPIIb/IIIa antagonists

Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.

Thrombo-embolism

The use of Metalyse can increase the risk of thrombo-embolic events in patients with existing thrombi, e.g. left heart thrombus (mitral stenosis or atrial fibrillation, etc).

Hypersensitivity/Re-administration

No sustained antibody formation to the tenecteplase molecule has been observed after treatment. However there is no systematic experience with re-administration of tenecteplase. Caution is needed when administering tenecteplase to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients, or to gentamicin (a residue from the manufacturing process). If an anaphylactoid reaction occurs, the injection should be discontinued immediately and appropriate therapy should be initiated. In any case, tenecteplase should not be re-administered before assessment of haemostatic factors like fibrinogen, plasminogen and alpha2-antiplasmin.

Paediatric population

Metalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and efficacy.

Metalyse contains polysorbate 20

This medicine contains 4.0 mg of polysorbate 20 in each 50 mg vial. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No formal interaction studies with tenecteplase and medicinal products commonly administered in patients with AMI have been performed. However, the analysis of data from more than 12 000 patients treated during phase I, II and III did not reveal any clinically relevant interactions with medicinal products commonly used in patients with AMI and concomitantly used with tenecteplase.

Drugs affecting coagulation/platelet function

Medicinal products that affect coagulation or those that alter platelet function (e.g. ticlopidine, clopidogrel, LMWH) may increase the risk of bleeding prior to, during or after tenecteplase therapy.

Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data from the use of Metalyse in pregnant women. Nonclinical data performed with tenecteplase have shown bleeding with secondary mortality of dams due to the known pharmacological activity of the active substance and in a few cases abortion and resorption of the foetus occurred (effects only have been observed with repeated dose administration). Tenecteplase is not considered to be teratogenic (please see section 5.3).

The benefit of treatment must be evaluated against the potential risks in case of myocardial infarction during pregnancy.

Breast-feeding

It is unknown whether tenecteplase is excreted in human milk.

Caution should be exercised when Metalyse is administered to a nursing woman and a decision must be made whether breast-feeding should be discontinued within the first 24 hours after administration of Metalyse.

Fertility

Clinical data as well as nonclinical studies on fertility are not available for tenecteplase (Metalyse).

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Summary of the safety profile

Haemorrhage is a very common undesirable effect associated with the use of tenecteplase. The type of haemorrhage is predominantly superficial at the injection site. Ecchymoses are observed commonly but usually do not require any specific action. Death and permanent disability are reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.

Tabulated list of adverse reactions

Adverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are defined according to the following convention: 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), not known (cannot be estimated from the available data).

Table 1 displays the frequency of adverse reactions.

System organ class

Adverse reaction

Immune system disorders

Rare

Anaphylactoid reaction (including rash, urticaria, bronchospasm, laryngeal oedema)

Nervous system disorders

Uncommon

Intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation stroke, intracranial haematoma, subarachnoid haemorrhage) including associated symptoms as somnolence, aphasia, hemiparesis, convulsion

Eye disorders

Uncommon

Eye haemorrhage

Cardiac disorders

Uncommon

Reperfusion arrhythmias (such as asystole, accelerated idioventricular arrhythmia, arrhythmia, extrasystoles, atrial fibrillation, atrioventricular first degree to atrioventricular block complete, bradycardia, tachycardia, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia) occur in close temporal relationship to treatment with tenecteplase.

Rare

Pericardial haemorrhage

Vascular disorders

Very common

Haemorrhage

Rare

Embolism (thrombotic embolisation)

Respiratory, thoracic and mediastinal disorders

Common

Epistaxis

Rare

Pulmonary haemorrhage

Gastrointestinal disorders

Common

Gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, rectal haemorrhage, haematemesis, melaena, mouth haemorrhage)

Uncommon

Retroperitoneal haemorrhage (such as retroperitoneal haematoma)

Not known

Nausea, vomiting

Skin and subcutaneous tissue disorders

Common

Ecchymosis

Renal and urinary disorders

Common

Urogenital haemorrhage (such as haematuria, haemorrhage urinary tract)

General disorders and administration site conditions

Common

Injection site haemorrhage, puncture site haemorrhage

Investigations

Rare

Blood pressure decreased

Not known

Body temperature increased

Injury, poisoning and procedural complications

Not known

Fat embolism, which may lead to corresponding consequences in the organs concerned

As with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction and/or thrombolytic administration:

- very common: hypotension, heart rate and rhythm disorders, angina pectoris

- common: recurrent ischaemia, cardiac failure, myocardial infarction, cardiogenic shock, pericarditis, pulmonary oedema

- uncommon: cardiac arrest, mitral valve incompetence, pericardial effusion, venous thrombosis, cardiac tamponade, myocardial rupture

- rare: pulmonary embolism

These cardiovascular events can be life-threatening and may lead to death.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Symptoms

In the event of overdose there may be an increased risk of bleeding.

Therapy

In case of severe prolonged bleeding substitution therapy may be considered (plasma, platelets), see also section 4.4.