METALYSE Powder and solvent for solution for injection Ref.[9393] Active ingredients: Tenecteplase

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
• Cerebrovascular disease
• Recent gastrointestinal or genitourinary bleeding (within the past 10 days)
• High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
• Any known recent (within the past 2 days) intramuscular injection
• Advanced age, i.e. over 75 years
• Low body weight <60 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).

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.

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.

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.

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).

Not relevant.

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.

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 the national reporting system listed in Appendix V.

Metalyse is incompatible with glucose infusion solutions.