Metalyse · 4.4 Special warnings and precautions for use · 2

HOS-084232 · has-adverse-reaction-information · PDF-Seite 6

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 (frequency cannot be estimated from the available data). 6 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 disord

Auszug; vollständigen Abschnitt im Original lesen.

HOS-084238 · has-adverse-reaction-information · PDF-Seite 20

Summary of the safety profile Haemorrhage is the most common undesirable effect associated with the use of tenecteplase. The type of haemorrhage can be superficial at the injection site or internal at any site or body cavity. Death and permanent disability are reported in patients who have experienced 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 (frequency cannot be estimated from the available data). Except for the occurrence of ADR reperfusion arrhythmias in the indication acute myocardial infarction and the frequency of ADR intracranial haemorrhage in the indication acute ischaemic stroke, there is no medical reason to assume that the safety profile of Metalyse in the indication acute ischaemic stroke is different from the profile in the indication acute myocardial infarction. 20 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 Very common 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 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 Gastroi

Auszug; vollständigen Abschnitt im Original lesen.

HOS-084234 · has-contraindication-information · PDF-Seite 16

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). 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 anticoagulation (e.g. vitamin K antagonists with INR > 1.7) (see section 4.4, subsection “Bleeding”) - Known history of or suspected intracranial haemorrhage - Symptoms suggestive of subarachnoid haemorrhage, even if CT-scan is normal - Severe stroke as assessed clinically (e.g. NIHSS > 25) and/or by appropriate imaging techniques 16 - Acute ischaemic stroke without disabling neurological deficit, or symptoms rapidly improving before start of injection - Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery) - Known haemorrhagic diathesis - Severe uncontrolled arterial hypertension (see section 4.4) - Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months - 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 - Administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory - Patients with any history of prior stroke and concomitant diabetes - Prior stroke within the last 3 months - Platelet count of below 100 000/mm3 - Systolic blood pressure > 185 mmHg or diastolic BP > 110 mmHg, or when BP cannot be reduced below these limits by careful management - Blood glucose < 50 mg/dL (see section 4.4) or > 400 mg/dL (< 2.8 mM or > 22.2 mM)

HOS-084228 · has-contraindication-information · PDF-Seite 3

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. 3 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

HOS-084227 · has-indication-information · PDF-Seite 2

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.

HOS-084233 · has-indication-information · PDF-Seite 15

Metalyse is indicated in adults for the thrombolytic treatment of acute ischaemic stroke (AIS) within 4.5 hours from last known well and after exclusion of intracranial haemorrhage.

HOS-084236 · has-interaction-information · PDF-Seite 19

No formal interaction studies with Metalyse and medicinal products commonly administered in patients with acute ischaemic stroke have been performed. Drugs affecting coagulation/platelet function Medicinal products that affect coagulation or those that alter platelet function may increase the risk of bleeding (when administered prior to, during or after tenecteplase therapy). These products should be avoided in the first 24 hours after Metalyse treatment for acute ischaemic stroke. With regard to pre- treatment with these substances, see sections 4.2, 4.3 and 4.4. ACE Inhibitors Concomitant treatment with ACE inhibitors may enhance the risk of experiencing a hypersensitivity reaction, see section 4.4. Published academic randomised trials involving more than 2 000 patients treated with tenecteplase did not show any clinically relevant interactions with other medicinal products commonly used in patients with AIS.

HOS-084230 · has-interaction-information · PDF-Seite 6

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.

HOS-084237 · has-pregnancy-information · PDF-Seite 19

Pregnancy There is a limited amount of data from the use of Metalyse in pregnant women. 19 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 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).

HOS-084231 · has-pregnancy-information · PDF-Seite 6

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 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).

HOS-084235 · has-warning-information · PDF-Seite 17

Thrombolytic treatment requires adequate monitoring. Treatment must be performed under the responsibility and follow-up of physicians trained and experienced in neurovascular care and the use of thrombolytic treatments, with the facilities to monitor that use. For the indication verification remote diagnostic measures may be considered as appropriate, see sections 4.1 and 4.2. 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. Bleeding The most common complication encountered during tenecteplase therapy is bleeding. The concomitant use of other active substances affecting coagulation or platelet function (e.g. heparin) may contribute to bleeding, see sections 4.2 and 4.3. 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. 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. 17 In the following conditions, the risk of tenecteplase therapy may be increased and should be weighed against the anticipated benefits: - Recent intramuscular injection or small recent traumas, puncture of major vessels - Patients receiving oral anticoagulants: The use of Metalyse may be considered when appropriate test(s) show no clinically relevant activity on the coagulation system (e.g. INR ≤ 1.7 for vitamin K antagonists or other relevant test(s) for oth

Auszug; vollständigen Abschnitt im Original lesen.

HOS-084229 · has-warning-information · PDF-Seite 4

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 4 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

Auszug; vollständigen Abschnitt im Original lesen.