METALYSE 5000U 5mg / ml (1000U / ml) powder for injection medication leaflet

Metalyse 5 000 units (25 mg) powder for solution for injection

Metalyse 5 000 units (25 mg) powder for solution for injection

Each vial contains 5 000 units (25 mg) tenecteplase.

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 for solution for injection.

The powder is white to off-white.

Metalyse is indicated in adults for the thrombolytic treatment of acute ischaemic stroke (AIS) within4.5 hours from last known well and after exclusion of intracranial haemorrhage.

Metalyse must be prescribed by physicians experienced in neurovascular care and the use ofthrombolytic treatment, with the facilities to monitor that use, see section 4.4.

Treatment with Metalyse must be initiated as early as possible and no later than 4.5 hours after lastknown well and after exclusion of intracranial haemorrhage by appropriate imaging techniques, seesection 4.4. The treatment effect is time-dependent; therefore, earlier treatment increases theprobability of a favourable outcome.

The appropriate presentation of tenecteplase product should be chosen carefully and in line with theindication. The 25 mg presentation of tenecteplase is only intended for use in acute ischaemic stroke.

Metalyse should be administered on the basis of body weight, with a maximum single dose of5 000 units (25 mg tenecteplase) for the indication acute ischaemic stroke.

Benefit-risk of tenecteplase treatment should be carefully evaluated in patients weighing 50 kg or lessdue to limited availability of data.

The volume required to administer the correct total dose can be calculated from the following scheme:

Patients’ body weight Tenecteplase Tenecteplase Corresponding volumecategory (U) (mg) of reconstituted solution(kg) (mL)< 60 3 000 15.0 3.0≥ 60 to < 70 3 500 17.5 3.5≥ 70 to < 80 4 000 20.0 4.0≥ 80 to < 90 4 500 22.5 4.5≥ 90 5 000 25.0 5.0

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

Elderly (> 80 years)

Metalyse should be administered with caution in the elderly (> 80 years) due to a higher bleeding risk(see information on bleeding in section 4.4).

The safety and efficacy of Metalyse in children below 18 years of age have not been established. Nodata are available.

Adjunctive therapy

The safety and efficacy of this regimen with concomitant administration of heparin or plateletaggregation inhibitors such as acetylsalicylic acid during the first 24 hours after treatment with

Metalyse have not been sufficiently investigated. Therefore, administration of intravenous heparin orplatelet aggregation inhibitors such as acetylsalicylic acid should be avoided in the first 24 hours aftertreatment with Metalyse due to an increased haemorrhagic risk.

If heparin is required for other indications the dose should not exceed 10 000 IU per day, administeredsubcutaneously.

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 approximately 5 to10 seconds.

40 mg and 50 mg vials of tenecteplase are not intended for use in acute ischaemic stroke. Forinstructions 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).

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 with effective anticoagulation (e.g. INR > 1.3) (please 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

- Acute ischaemic stroke without disabling neurological deficit, or symptoms rapidly improvingbefore start of injection

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

- Known haemorrhagic diathesis

- Severe uncontrolled arterial hypertension

- Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months

- 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

- Symptoms of ischaemic attack beginning more than 4.5 hours prior to injection or symptoms forwhich the onset time is unknown and could potentially be more than 4.5 hours ago

- Seizure at onset of stroke

- Administration of heparin within the previous 48 hours and a thromboplastin time exceeding theupper 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 aggressive management(intravenous pharmacotherapy) necessary to reduce BP to these limits

- Blood glucose < 50 mg/dL or > 400 mg/dL (< 2.8 mM or > 22.2 mM)

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

Thrombolytic treatment requires adequate monitoring. Metalyse should only be used with theinvolvement and follow-up of physicians trained and experienced in neurovascular care and the use ofthrombolytic treatments, with the facilities to monitor that use. For the verification of treatmentindication remote diagnostic measures may be considered as appropriate, see sections 4.1 and 4.2.

The most common complication encountered during tenecteplase therapy is bleeding. The concomitantuse of other active substances affecting coagulation or platelet function (e.g. heparin) may contributeto bleeding, see sections 4.2 and 4.3. As fibrin is lysed during tenecteplase therapy, bleeding fromrecent puncture site may occur. Therefore, thrombolytic therapy requires careful attention to allpossible bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdownsites 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 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 following conditions, the risk of tenecteplase therapy may be increased and should be weighedagainst the anticipated benefits:

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

- Conditions with an increased risk of haemorrhage which are not mentioned in section 4.3

- Low body weight < 60 kg

- Patients receiving oral anticoagulants: The use of Metalyse may be considered when appropriatetest(s) show no clinically relevant activity on the coagulation system (e.g. INR ≤ 1.3 forvitamin K antagonists or other relevant test(s) for other oral anticoagulants are within therespective upper limit of normal), see section 4.3.

Intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemicstroke (up to 19 % of patients without any increase of overall morbidity or mortality).

Risk of intracranial haemorrhage in patients with acute ischaemic stroke may be increased with the useof Metalyse.

This applies in particular in the following cases:

- all situations involving a high risk of haemorrhage including those listed in section 4.3

- late time to treatment from last known well. Therefore, the administration of Metalyse shouldnot be delayed

- patients pre-treated with acetylsalicylic acid (ASA) may have a greater risk of intracerebralhaemorrhage, particularly if Metalyse treatment is delayed

- Compared to younger patients, patients of advanced age (over 80 years) may have a somewhatpoorer outcome independent of treatment and may have an increased risk of intracerebralhaemorrhage when thrombolysed. In general, the benefit-risk of thrombolysis in patients ofadvanced age remains positive. Thrombolysis in AIS patients should be evaluated on individualbenefit-risk basis.

Treatment must not be initiated later than 4.5 hours after last known well because of unfavourablebenefit/risk ratio mainly based on the following:

- positive treatment effects decrease over time

- particularly in patients with prior ASA treatment the mortality rate increases

- increased risk of symptomatic haemorrhage.

Blood pressure monitoring

BP monitoring up to 24 hours after tenecteplase treatment is necessary; intravenous antihypertensivetherapy is recommended if systolic BP > 180 mmHg or diastolic BP > 105 mmHg.

Special groups at reduced benefit/risk

The benefit/risk ratio is considered less favourable in patients that had a prior stroke or in those withknown uncontrolled diabetes, but still positive in these patients.

In stroke patients the likelihood of a favourable outcome decreases with longer time from onset ofsymptoms to thrombolytic treatment, increasing age, increasing stroke severity and increased levels ofblood glucose on admission while the likelihood of severe disability and death or symptomaticintracranial bleeding increases, independently of treatment.

Cerebral oedema

Reperfusion of the ischaemic area may induce cerebral oedema in the infarcted zone.

Hypersensitivity/Re-administration

Immune-mediated hypersensitivity reactions associated with the administration of Metalyse can becaused by the active substance tenecteplase, gentamicin (a trace residue from the manufacturingprocess) or any of the excipients, see sections 4.3 and 6.1.

No sustained antibody formation to the tenecteplase molecule has been observed after treatment.

However there is no systematic experience with re-administration of tenecteplase.

There is also a risk of hypersensitivity reactions mediated through a non-immunological mechanism.

Angio-oedema represents the most common hypersensitivity reaction reported with Metalyse. Thisrisk may be enhanced in the indication acute ischaemic stroke and/or by concomitant treatment with

ACE inhibitors. Patients treated with Metalyse should be monitored for angio-oedema during and forup to 24 h after administration.

If a severe hypersensitivity reaction (e.g. angio-oedema) occurs, appropriate treatment should bepromptly initiated. This may include intubation.

Safety and efficacy data in children below 18 years of age are not available for Metalyse. Therefore,

Metalyse is not recommended for use in children below 18 years of age.

No formal interaction studies with Metalyse and medicinal products commonly administered inpatients 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 ofbleeding prior to, during or after tenecteplase therapy and should be avoided in the first 24 hours aftertreatment for acute ischaemic stroke, see section 4.3.

ACE Inhibitors

Concomitant treatment with ACE inhibitors may enhance the risk of suffering a hypersensitivityreaction, see section 4.4.

Published academic randomised trials involving more than 2 000 patients treated with tenecteplase didnot show any clinically relevant interactions with other medicinal products commonly used in patientswith AIS.

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 during 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 the most common undesirable effect associated with the use of tenecteplase. The typeof 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.

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).

Except for the occurrence of ADR reperfusion arrhythmias in the indication acute myocardialinfarction and the frequency of ADR intracranial haemorrhage in the indication acute ischaemicstroke, there is no medical reason to assume that the safety profile of Metalyse in the indication acuteischaemic stroke is different from the profile in the indication acute myocardial infarction.

Table 1 displays the frequency of adverse reactions.

System organ class Adverse reaction

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

Very common Intracranial haemorrhage (such as cerebral haemorrhage,cerebral haematoma, haemorrhagic stroke, haemorrhagictransformation stroke, intracranial haematoma,subarachnoid haemorrhage) including associated symptomsas somnolence, aphasia, hemiparesis, convulsion

Uncommon Eye haemorrhage

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 correspondingconsequences in the organs concerned

Surgical and medical procedures

Not known Transfusion

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.

AcT study

The Alteplase Compared to Tenecteplase (AcT) trial, was designed as a pragmatic, registry based,prospective, randomized, controlled, open label trial with blinded endpoint assessment of intravenoustenecteplase vs. intravenous alteplase to provide evidence that tenecteplase is non-inferior to alteplasein patients with acute ischemic stroke within 4.5 h from last known well otherwise eligible forintravenous thrombolysis as per current guidelines. The trial achieved its primary outcomedemonstrating non inferiority with tenecteplase 0.25 mg/kg (max. 25 mg) vs alteplase 0.9 mg/kg (max.90 mg): 296 (36.9%) of 802 patients in the tenecteplase group and 266 (34.8%) of 765 in the alteplasegroup had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2.1% [95% CI - 2.6 to 6.9].

Results in the mITT and mPP populations were similar.

Key safety outcomes were symptomatic intracerebral haemorrhage, orolingual angio-oedema, andextracranial bleeding requiring blood transfusion, all occurring within 24 h of thrombolyticadministration, and 90-day all-cause mortality.

There were no meaningful differences in the rate of 24 h symptomatic intracerebral haemorrhage.

Rates of imaging-defined intracranial haemorrhage (assessed blinded to symptom status and treatmentallocation) showed no differences between the two groups, and the imaging-defined rates of type 2parenchymal haematoma (i.e., haematoma occupying ≥ 30% of infarct with obvious mass effect) weresimilar to the observed rates of symptomatic intracerebral haemorrhage in the trial. There were nomeaningful differences in the rate of 90-day mortality 90 days from treatment. Orolingual angio-oedema and peripheral bleeding requiring blood transfusion were rare and similar in both groups (see

Table 2).

Table 2. Incidence of key safety outcomes in tenecteplase and alteplase group.

Tenecteplase group Alteplase group Risk difference(95% CI)24 h symptomatic intracerebral 27/800 (3.4%) 24/763 (3.2%) 0.2 (-1.5 to 2.0)haemorrhage

Imaging-identified intracranial 154/800 (19.3%) 157/763 (20.6%) -1.3 (-5.3 to 2.6)haemorrhage

Extracranial bleeding requiring 6/800 (0.8%) 6/763 (0.8%) 0.0 (-0.9 to 0.8)blood transfusions

Death within 90 days of 122/796 (15.3%) 117/758 (15.4%) -0.1 (-3.7 to 3.5)randomisation (n = 1 554)

Orolingual angio-oedema 9/800 (1.1%) 9/763 (1.2%) -0.1 (-1.1 to 1.0)

Parenchymal haematoma type 2 21/800 (2.6%) 18/763 (2.4%) 0.3 (-1.3 to 1.8)(haematoma occupying ≥ 30% ofinfarct with obvious mass effect)

EXTEND-IA TNK study

EXTEND-IA TNK was designed to assess whether tenecteplase is non-inferior to alteplase inachieving reperfusion at initial angiogram when administered within 4.5 h of ischaemic stroke onset inpatients planned to undergo endovascular therapy.

Patients with ischaemic stroke who had occlusion of the internal carotid, basilar, or middle cerebralartery and who were eligible to undergo thrombectomy were randomised to receive tenecteplase0.25 mg/kg or alteplase 0.9 mg/kg within 4.5 h after symptom onset. There were 101 patients in eachtreatment group. The primary outcome was reperfusion of greater than 50% of the involved ischaemicterritory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Non-inferiority of tenecteplase was tested, followed by superiority.

The primary outcome occurred in 22% of the patients treated with tenecteplase vs 10% of those treatedwith alteplase (incidence difference, 12%; 95% CI 2, 21; incidence ratio, 2.2; 95% CI 1.1, pct. 4.4).

Secondary outcomes included the mRS score at 90 days. The proportion of mRS 0-1 at 90 days was 51%for the tenecteplase group and 43% for the alteplase group (adjusted incidence ratio1.2;95% CI 0.9 to 1.6).

The sICH occurred in 1% of the patients in each group. There were 10 deaths (10%) in thetenecteplase group and 18 (18%) in the alteplase group, which was not significant in the pre-specifiedlogistic-regression analysis. Most of the deaths were related to progression of major stroke (9 intenecteplase group and 14 in alteplase group). Tenecteplase 0.25 mg/kg showed a similar safety profilecompared to alteplase 0.9 mg/kg.

Several non-interventional studies compared tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) in

AIS with or without large vessel occlusion (LVO) within 4.5 hours after symptom onset. Theseobservational studies reported adjusted (or propensity score matched) estimates, included in total> 2 900 AIS patients (from studies with over 100 patients treated with tenecteplase), and reported aconsistent similar safety and effectiveness profile of tenecteplase in comparison with alteplase.

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

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 5 000 units (25 mg) powder for solution for injection10 mL clear glass vial, with a coated (B2-44) grey rubber stopper and a crimp cap filled with powderfor solution for injection. Each vial contains 25 mg tenecteplase.

Metalyse should be reconstituted by adding 5 mL of sterile water for injections to the vial containingthe powder for solution for injection using a needle and a syringe (not provided in the package).

1. Remove the crimp cap from the vial.2. Fill a syringe with 5 mL of sterile water for injection and penetrate the vial stopper in themiddle with the needle.3. Add all the sterile water for injection into the vial by pushing the syringe plunger down slowlyto avoid foaming.4. Keep the syringe attached to the vial and reconstitute by swirling gently.5. The reconstituted solution for injection results in a colourless to pale yellow, clear solution.

Only clear solution without particles should be used.6. Directly before the solution is administered, invert the vial with the syringe still attached, so thatthe syringe is below the vial.7. Transfer the appropriate volume of Metalyse reconstituted solution into the syringe, based onthe patient’s weight.

Patients’ body weight Volume of Tenecteplase Tenecteplasecategory reconstituted solution (U) (mg)(kg) (mL)< 60 3.0 3 000 15.0≥ 60 to < 70 3.5 3 500 17.5≥ 70 to < 80 4.0 4 000 20.0≥ 80 to < 90 4.5 4 500 22.5≥ 90 5.0 5 000 25.08. 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.

9. Metalyse is to be administered to the patient, intravenously in about 5 to 10 seconds. It shouldnot be administered in a line containing glucose as Metalyse is incompatible with glucosesolution.

10. The line should be flushed after Metalyse injection for a proper delivery.11. Any unused reconstituted solution should be discarded.

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

EU/1/00/169/007

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