Tenecteplase

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.

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 mmHg
• 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 tenecteplase 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).

There is a limited amount of data from the use of tenecteplase 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.

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

It is not known if tenecteplase is excreted in human milk. Breast-feeding should be discarded within the first 24 hours after thrombolytic therapy.

Fertility

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

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.

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).

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. Reperfusion arrhythmias may lead to cardiac arrest, can be life threatening and may require the use of conventional antiarrhythmic therapies.

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.