METALYSE 8000U 5mg / ml (1000U / ml) powder + solvent for injection medication leaflet

Metalyse 8 000 units (40 mg) powder and solvent for solution for injection

Metalyse 10 000 units (50 mg) powder and solvent for solution for injection

Metalyse 8 000 units (40 mg) powder and solvent for solution for injection

Each vial contains 8 000 units (40 mg) tenecteplase.

Each pre-filled syringe contains 8 mL solvent.

Metalyse 10 000 units (50 mg) powder and solvent for solution for injection

Each vial contains 10 000 units (50 mg) tenecteplase.

Each pre-filled syringe contains 10 mL solvent.

The reconstituted solution contains 1 000 units (5 mg) tenecteplase per mL.

Potency of tenecteplase is expressed in units (U) by using a reference standard which is specific fortenecteplase and is not comparable with units used for other thrombolytic agents.

Tenecteplase is a fibrin-specific plasminogen activator produced in a Chinese hamster ovary cell lineby recombinant DNA technology.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

The powder is white to off-white.

The solvent is clear and colourless.

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

Metalyse should be prescribed by physicians experienced in the use of thrombolytic treatment andwith 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 theindication. The 40 mg and 50 mg presentations are only intended for use in acute myocardialinfarction.

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 thefollowing scheme:

Patients’ body weight Tenecteplase Tenecteplase Corresponding volumecategory (U) (mg) of reconstituted solution(kg) (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).

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

Adjunctive therapy

Antithrombotic adjunctive therapy with platelet inhibitors and anticoagulants should be administeredaccording 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 clinicalstudies with Metalyse.

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

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

The required dose should be administered as a single intravenous bolus over approximately10 seconds.

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

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

Furthermore, Metalyse is contraindicated in the following situations because thrombolytic therapy isassociated 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. warfarin sodium (INR > 1.3) (seesection 4.4, subsection “Bleeding”)

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

- Known haemorrhagic diathesis

- Severe uncontrolled hypertension

- 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

- Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks

- Acute pericarditis and/or subacute bacterial endocarditis

- Acute pancreatitis

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

- Active peptic ulceration

- Arterial aneurysm and known 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

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

Coronary intervention

If primary percutaneous coronary intervention (PCI) is scheduled according to the current relevanttreatment 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 receivetenecteplase as primary coronary recanalization treatment should be transferred without delay to acoronary intervention capable facility for angiography and timely adjunctive coronary interventionwithin 6-24 hours or earlier if medically indicated (see section 5.1 STREAM study).

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

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

Should serious bleeding occur, in particular cerebral haemorrhage, concomitant heparin administrationshould be terminated immediately. Administration of protamine should be considered if heparin hasbeen administered within 4 hours before the onset of bleeding. In the few patients who fail to respondto these conservative measures, judicious use of transfusion products may be indicated. Transfusion ofcryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratoryreassessment after each administration. A target fibrinogen level of 1 g/L is desirable withcryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative. In the followingconditions, the risk of tenecteplase therapy may be increased and should be weighed against theanticipated 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. patients over 75 years

- Low body weight < 60 kg

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

Arrhythmias

Coronary thrombolysis may result in arrhythmias associated with reperfusion. Reperfusionarrhythmias may lead to cardiac arrest, can be life threatening and may require the use of conventionalantiarrhythmic therapies. It is recommended that antiarrhythmic therapy for bradycardia and/orventricular 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 neededwhen administering tenecteplase to persons with a known hypersensitivity (other than anaphylacticreaction) to the active substance, to any of the excipients, or to gentamicin (a residue from themanufacturing process). If an anaphylactoid reaction occurs, the injection should be discontinuedimmediately and appropriate therapy should be initiated. In any case, tenecteplase should not be re-administered before assessment of haemostatic factors like fibrinogen, plasminogen andalpha2-antiplasmin.

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

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

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 damsdue to the known pharmacological activity of the active substance and in a few cases abortion andresorption 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 infarctionduring pregnancy.

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 mustbe made whether breast-feeding should be discontinued within the first 24 hours after administrationof Metalyse.

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

Not relevant.

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

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), veryrare (< 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

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

Uncommon Intracranial haemorrhage (such as cerebral haemorrhage,cerebral haematoma, haemorrhagic stroke, haemorrhagictransformation stroke, intracranial haematoma, subarachnoidhaemorrhage) including associated symptoms as somnolence,aphasia, hemiparesis, convulsion

Uncommon Eye haemorrhage

Uncommon Reperfusion arrhythmias (such as asystole, acceleratedidioventricular arrhythmia, arrhythmia, extrasystoles, atrialfibrillation, atrioventricular first degree to atrioventricularblock complete, bradycardia, tachycardia, ventriculararrhythmia, ventricular fibrillation, ventricular tachycardia)occur in close temporal relationship to treatment withtenecteplase.

Rare Pericardial haemorrhage

Very common Haemorrhage

Rare Embolism (thrombotic embolisation)

Common Epistaxis

Rare Pulmonary haemorrhage

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

Uncommon Retroperitoneal haemorrhage (such as retroperitonealhaematoma)

Not known Nausea, vomiting

Common Ecchymosis

Common Urogenital haemorrhage (such as haematuria, haemorrhageurinary tract)

Common Injection site haemorrhage, puncture site haemorrhage

Rare Blood pressure decreased

Not known Body temperature increased

Not known Fat embolism, which may lead to corresponding consequencesin the organs concerned

As with other thrombolytic agents, the following events have been reported as sequelae of myocardialinfarction 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Pharmacotherapeutic group: Antithrombotic agents, enzymes; ATC code: B01A D11

Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PAby modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus(blood clot) and selectively converts thrombus-bound plasminogen to plasmin, which degrades thefibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance toinactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.

After administration of tenecteplase dose dependent consumption of 2-antiplasmin (the fluid-phaseinhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have beenobserved. This observation is consistent with the intended effect of plasminogen activation. Incomparative studies a less than 15% reduction in fibrinogen and a less than 25% reduction inplasminogen were observed in subjects treated with the maximum dose of tenecteplase (10 000 U,corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen andplasminogen levels. No clinically relevant antibody formation was detected at 30 days.

Patency data from the phase I and II angiographic studies suggest that tenecteplase, administered as asingle intravenous bolus, is effective in dissolving blood clots in the infarct-related artery of subjectsexperiencing an AMI on a dose related basis.

ASSENT-2

A large scale mortality trial (ASSENT-2) in approx. 17 000 patients showed that tenecteplase istherapeutically equivalent to alteplase in reducing mortality (6.2% for both treatments, at 30 days,upper limit of the 95% CI for the relative risk ratio 1.124) and that the use of tenecteplase is associatedwith a significantly lower incidence of non-intracranial bleedings (26.4% vs. 28.9%, p = 0.0003). Thistranslates into a significantly lower need of transfusions (4.3% vs. 5.5%, p = 0.0002). Intracranialhaemorrhage occurred at a rate of 0.93% vs. 0.94% for tenecteplase and alteplase, respectively.

Coronary patency and limited clinical outcome data showed that AMI patients have been successfullytreated later than 6 hours after symptom onset.

ASSENT-4

The ASSENT-4 PCI study was designed to show if in 4 000 patients with large myocardial infarctionspre-treatment with full dose tenecteplase and concomitant single bolus of up to 4 000 IUunfractionated heparin administered prior to primary PCI to be performed within 60 to 180 minutesleads to better outcomes than primary PCI alone. The trial was prematurely terminated with 1 667randomised patients due to a numerically higher mortality in the facilitated PCI group receivingtenecteplase. The occurrence of the primary endpoint, a composite of death or cardiogenic shock orcongestive heart failure within 90 days, was significantly higher in the group receiving the exploratoryregimen of tenecteplase followed by routine immediate PCI: 18.6% (151/810) compared to 13.4%(110/819) in the PCI only group, p = 0.0045. This significant difference between the groups for theprimary endpoint at 90 days was already present in-hospital and at 30 days.

Numerically all of the components of the clinical composite endpoint were in favour of the PCI onlyregimen: death: 6.7% vs. 4.9% p = 0.14; cardiogenic shock: 6.3% vs. 4.8% p = 0.19; congestive heartfailure: 12.0% vs. 9.2% p = 0.06 respectively. The secondary endpoints re-infarction and repeat targetvessel revascularisation were significantly increased in the group pre-treated with tenecteplase:re-infarction: 6.1% vs. 3.7% p = 0.0279; repeat target vessel revascularisation: 6.6% vs. 3.4%p = 0.0041.

The following adverse events occurred more frequently with tenecteplase prior to PCI: intracranialhaemorrhage: 1% vs. 0% p = 0.0037; stroke: 1.8% vs. 0% p < 0.0001; major bleeds: 5.6% vs. 4.4%p = 0.3118; minor bleeds: 25.3% vs. 19.0% p = 0.0021; blood transfusions: 6.2% vs. 4.2% p = 0.0873;abrupt vessel closure: 1.9% vs. 0.1% p = 0.0001.

STREAM study

The STREAM study was designed to evaluate the efficacy and safety of a pharmaco-invasive strategyversus a strategy of standard primary PCI in patients presenting with ST elevation acute myocardialinfarction within 3 hours of onset of symptoms not able to undergo primary PCI within one hour offirst medical contact. The pharmaco-invasive strategy consisted of early fibrinolytic treatment withbolus tenecteplase and additional antiplatelet and anticoagulant therapy followed by angiographywithin 6-24 hours or rescue coronary intervention.

The study population consisted of 1 892 patients randomised by means of an interactive voiceresponse system. The primary endpoint, a composite of death or cardiogenic shock or congestive heartfailure or re-infarction within 30 days, was observed in 12.4% (116/939) of the pharmaco-invasivearm versus 14.3% (135/943) in the primary PCI arm (relative risk 0.86 (0.68-1.09)).

Single components of the primary composite endpoint for the pharmaco-invasive strategy versusprimary PCI respectively were observed with the following frequencies:

Pharmaco-invasive Primary PCI p(n = 944) (n = 948)

Composite death, shock, congestiveheart failure, re-infarction 116/939 (12.4%) 135/943 (14.3%) 0.21

All-cause mortality 43/939 (4.6%) 42/946 (4.4%) 0.88

Cardiogenic shock 41/939 (4.4%) 56/944 (5.9%) 0.13

Congestive heart failure 57/939 (6.1%) 72/943 (7.6%) 0.18

Re-infarction 23/938 (2.5%) 21/944 (2.2%) 0.74

Cardiac mortality 31/939 (3.3%) 32/946 (3.4%) 0.92

The observed incidence of major and of minor non-ICH bleeds were similar in both groups:

Pharmaco-invasive Primary PCI p(n = 944) (n = 948)

Major non-ICH bleed 61/939 (6.5%) 45/944 (4.8%) 0.11

Minor non-ICH bleed 205/939 (21.8%) 191/944 (20.2%) 0.40

Incidence of total strokes and intracranial haemorrhage

Pharmaco-invasive Primary PCI p(n = 944) (n = 948)

Total stroke (all types) 15/939 (1.6%) 5/946 (0.5%) 0.03*

Intracranial haemorrhage 9/939 (0.96%) 2/946 (0.21%) 0.04**

Intracranial haemorrhage after protocolamendment to half dose in patients≥ 75 years: 4/747 (0.5%) 2/758 (0.3%) 0.45

* the incidences in both groups are those expected in STEMI patients treated by fibrinolytics orprimary PCI (as observed in previous studies).

** the incidence in the pharmaco-invasive group is as expected for fibrinolysis with tenecteplase (asobserved in previous studies).

After the dose reduction of tenecteplase by half in patients ≥ 75 years there was no further intracranialhemorrhage (0 of 97 patients) (95% CI: 0.0-3.7) versus 8.1% (3 of 37 patients) (95% CI: 1.7-21.9)prior to dose reduction. The bounds of the confidence interval of the observed incidences prior andafter dose reduction are overlapping.

In patients ≥ 75 years the observed incidence of the primary efficacy composite end point for thepharmaco-invasive strategy and primary PCI were as follows: before dose reduction 11/37 (29.7%)(95% CI: 15.9-47.0) versus 10/32 (31.3%) (95% CI: 16.1-50.0), after dose reduction: 25/97 (25.8%)(95% CI: 17.4-35.7) versus 25/88 (24.8%) (95% CI: 19.3-39.0). In both groups the bounds of theconfidence interval of the observed incidences prior and post dose reduction are overlapping.

Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen.

Following intravenous bolus administration of 30 mg tenecteplase in patients with acute myocardialinfarction, the initially estimated tenecteplase plasma concentration was 6.45 ± 3.60 µg/mL (mean± SD). The distribution phase represents 31% ± 22% to 69% ± 15% (mean ± SD) of the total AUCfollowing the administration of doses ranges from 5 to 50 mg.

Data on tissue distribution were obtained in studies with radioactively labelled tenecteplase in rats.

The main organ to which tenecteplase distributed was the liver. It is not known whether and to whichextent tenecteplase binds to plasma proteins in humans. The mean residence time (MRT) in the bodyis approximately 1 h and the mean (± SD) volume of distribution at the steady-state (Vss) ranged from6.3 ± 2 L to 15 ± 7 L.

Tenecteplase is cleared from circulation by binding to specific receptors in the liver followed bycatabolism to small peptides. Binding to hepatic receptors is, however, reduced compared to nativet-PA, resulting in a prolonged half-life.

After single intravenous bolus injection of tenecteplase in patients with acute myocardial infarction,tenecteplase antigen exhibits biphasic elimination from plasma. There is no dose dependence oftenecteplase clearance in the therapeutic dose range. The initial, dominant half-life is 24 ± 5.5 (mean± SD) min, which is 5 times longer than native t-PA. The terminal half-life is 129 ± 87 min, andplasma clearance is 119 ± 49 mL/min.

Increasing body weight resulted in a moderate increase of tenecteplase clearance, and increasing ageresulted in a slight decrease of clearance. Women exhibit in general lower clearance than men, but thiscan be explained by the generally lower body weight of women.

Linearity/Non-Linearity

The dose linearity analysis based on AUC suggested that tenecteplase exhibits non-linearpharmacokinetics in the dose range studied, i.e. 5 to 50 mg.

Because elimination of tenecteplase is through the liver, it is not expected that renal dysfunction willaffect its the pharmacokinetics. This is also supported by animal data. However, the effect of renal andhepatic dysfunction on pharmacokinetics of tenecteplase in humans has not been specificallyinvestigated. Accordingly, there is no guidance for the adjustment to tenecteplase dose in patients withhepatic and severe renal insufficiency.

Intravenous single dose administration in rats, rabbits and dogs resulted only in dose-dependent andreversible alterations of the coagulation parameters with local haemorrhage at the injection site, whichwas regarded as a consequence of the pharmacodynamic effect of tenecteplase. Multiple-dose toxicitystudies in rats and dogs confirmed these above-mentioned observations, but the study duration waslimited to two weeks by antibody formation to the human protein tenecteplase, which resulted inanaphylaxis.

Safety pharmacology data in cynomolgus monkeys revealed reduction of blood pressure followed bychanges of ECG, but these occurred at exposures that were considerably higher than the clinicalexposure.

With regard to the indication and the single dose administration in humans, reproductive toxicitytesting was limited to an embryotoxicity study in rabbits, as a sensitive species. Tenecteplase inducedtotal litter deaths during the mid-embryonal period. When tenecteplase was given during the mid- orlate-embryonal period maternal animals showed vaginal bleeding on the day after the first dose.

Secondary mortality was observed 1-2 days later. Data on the foetal period are not available.

Mutagenicity and carcinogenicity are not expected for this class of recombinant proteins andgenotoxicity and carcinogenicity testing were not necessary.

No local irritation of the blood vessel was observed after intravenous, intra-arterial or paravenousadministration of the final formulation of tenecteplase.

Arginine

Concentrated phosphoric acid

Polysorbate 20

Trace residue from manufacturing process: Gentamicin

Water for injections

Metalyse is incompatible with glucose infusion solutions.

Shelf life as packaged for sale3 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8 °C and 8 hours at30 °C.

From a microbiological point of view, the reconstituted solution should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2-8 °C.

Do not store above 30 °C. Keep the container in the outer carton in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

Metalyse 8 000 units (40 mg) powder and solvent for solution for injection20 mL glass vial type I, with a coated (B2-42) grey rubber stopper and a flip-off cap filled withpowder for solution for injection. Each vial contains 40 mg tenecteplase.10 mL plastic pre-filled syringe with 8 mL of solvent.

Sterile vial adapter.

Metalyse 10 000 units (50 mg) powder and solvent for solution for injection20 mL glass vial type I, with a coated (B2-42) grey rubber stopper and a flip-off cap filled withpowder for solution for injection. Each vial contains 50 mg tenecteplase.10 mL plastic pre-filled syringe with 10 mL of solvent.

Sterile vial adapter.

Metalyse should be reconstituted by adding the complete volume of solvent from the pre-filled syringeto the vial containing the powder for solution for injection.

1. Ensure that the appropriate vial size is chosen according to the body weight of the patient.

Patients’ body weight Volume of Tenecteplase Tenecteplasecategory reconstituted solution (U) (mg)(kg) (mL)< 60 6 6 000 30≥ 60 to < 70 7 7 000 35≥ 70 to < 80 8 8 000 40≥ 80 to < 90 9 9 000 45≥ 90 10 10 000 502. Check that the cap of the vial is still intact.3. Remove the flip-off cap from the vial.4. Open the top of the vial adapter. Remove the tip-cap from the pre-filled syringe with thesolvent. Then immediately screw the pre-filled syringe on the vial adapter tightly and penetratethe vial stopper in the middle with the spike of the vial adapter.

5. Add the solvent into the vial by pushing the syringe plunger down slowly to avoid foaming.6. Keep the syringe attached to the vial adapter and reconstitute by swirling gently.7. The reconstituted solution for injection results in a colourless to pale yellow, clear solution.

Only clear solution without particles should be used.8. Directly before the solution will be administered, invert the vial with the syringe still attached,so that the syringe is below the vial.9. Transfer the appropriate volume of Metalyse reconstituted solution into the syringe, based onthe patient’s weight.10. Unscrew the syringe from the vial adapter.11. A pre-existing intravenous line may be used for administration of Metalyse in sodium chloride9 mg/mL (0.9%) solution only. No other medicinal product should be added to the injectionsolution.

12. Metalyse is to be administered to the patient, intravenously in about 10 seconds. It should not beadministered in a line containing glucose as Metalyse is incompatible with glucose solution.

13. The line should be flushed after Metalyse injection for a proper delivery.14. Any unused reconstituted solution should be discarded.

Alternatively, the reconstitution can be performed with a needle instead of the included vial adapter.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Boehringer Ingelheim International GmbH

Binger Strasse 17355216 Ingelheim am Rhein

Germany

Metalyse 8 000 units (40 mg) powder and solvent for solution for injection

EU/1/00/169/005

Metalyse 10 000 units (50 mg) powder and solvent for solution for injection

EU/1/00/169/006

Date of first authorisation: 23 February 2001

Date of last renewal: 23 February 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu