Metalyse 8,000 units

Powder and solvent for solution for injection

Metalyse 10,000 units

Powder and solvent for solution for injection

Metalyse 8,000 units

1 vial contains 8,000 units (40 mg) tenecteplase.

1 prefilled syringe contains 8 ml water for injections.

Metalyse 10,000 units

1 vial contains 10,000 units (50 mg) tenecteplase.

1 prefilled syringe contains 10 ml water for injections.

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 for tenecteplase 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 line by 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 reconstituted preparation is a clear and colourless to slightly yellow solution

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.

Metalyse should be prescribed by physicians experienced in the use of thrombolytic treatment and with the facilities to monitor that use.

Treatment with Metalyse should be initiated as soon as possible after onset of symptoms.

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 the following scheme:

The required dose should be administered as a single intravenous bolus over approximately 10 seconds.

A pre-existing intravenous line may be used for administration of Metalyse in 0.9% sodium chloride solution only. Metalyse is incompatible with dextrose solution.

No other medicinal product should be added to the injection solution.

Paediatric population

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

Adjunctive therapy

Antithrombotic adjunctive therapy with platelet inhibitors and anticoagulants should be administered according to the current relevant treatment guidelines for the management of patients with ST-elevation myocardial infarction.

Unfractionated heparin and enoxaparin have been used as antithrombotic adjunctive therapy in clinical studies with Metalyse.

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

Metalyse must not be administered to patients with a history of an anaphylactic (i.e. life-threatening) reaction to any of the constituents (i.e. tenecteplase or any excipient) or 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.

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 with current concomitant oral anticoagulant therapy (INR > 1.3)
- Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
- 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

Bleeding

The most common complication encountered during Metalyse therapy is bleeding. The concomitant use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during Metalyse 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 Metalyse.

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 Metalyse therapy may be increased and should be weighed against the anticipated benefits:

- Systolic blood pressure > 160 mm Hg
- 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

Arrhythmias

Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (pacemaker, defibrillator) be available when Metalyse 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 Metalyse. Caution is needed when administering Metalyse 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.

Primary Percutaneous Coronary Intervention (PCI)

If primary PCI is scheduled according to the current relevant treatment guidelines, Metalyse as administered in the ASSENT-4 PCI study (see section 5.1) should not be given.

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 Metalyse 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 Metalyse.

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 Metalyse therapy.

Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.

Pregnancy

No experience in pregnant women is available for tenecteplase. Because animal studies (see also section 5.3) have shown a high risk of vaginal bleeding presumably from the placenta and of pregnancy loss, the benefit of treatment has to be evaluated against the potential risks which may aggravate an acute life-threatening situation.

Lactation

It is not known if tenecteplase is excreted into breast milk. Breast milk should be discarded within the first 24 hours after thrombolytic therapy.

Fertility

No preclinical fertility studies were performed for tenecteplase. In the preclinical repeat-dose toxicity studies conducted with tenecteplase, histopathology did not reveal any findings regarding the male reproductive organs.

Not relevant.

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.

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 (>1/10): hypotension, heart rate and rhythm disorders, angina pectoris
- common (>1/100, <1/10): recurrent ischaemia, cardiac failure, myocardial infarction, cardiogenic shock, pericarditis, pulmonary oedema
- uncommon (>1/1,000, <1/100): cardiac arrest, mitral valve incompetence, pericardial effusion, venous thrombosis, cardiac tamponade, myocardial rupture
- rare (>1/10,000, <1/1,000): pulmonary embolism

These cardiovascular events can be life-threatening and may lead to death.

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), see also section 4.4.

Pharmacotherapeutic group

Antithrombotic agents, ATC code: B01A D11

Mechanism of action

Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA by 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 the fibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.

Pharmacodynamic effects

After administration of tenecteplase dose dependent consumption of α2-antiplasmin (the fluid-phase inhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have been observed. This observation is consistent with the intended effect of plasminogen activation. In comparative studies a less than 15% reduction in fibrinogen and a less than 25% reduction in plasminogen 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 and plasminogen levels. No clinically relevant antibody formation was detected at 30 days.

Clinical effects

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

A large scale mortality trial (ASSENT II) in approx. 17,000 patients showed that tenecteplase is therapeutically 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 associated with a significantly lower incidence of non-intracranial bleedings (26.4% vs. 28.9%, p=0.0003). This translates into a significantly lower need of transfusions (4.3% vs. 5.5%, p=0.0002). Intracranial haemorrhage 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 successfully treated later than 6 hours after symptom onset.

The ASSENT-4 PCI study was designed to show if in 4000 patients with large myocardial infarctions pre-treatment with full dose tenecteplase and concomitant single bolus of up to 4,000 IU unfractionated heparin administered prior to primary Percutaneous Coronary Intervention (PCI) to be performed within 60 to 180 minutes leads to better outcomes than primary PCI alone. The trial was prematurely terminated with 1667 randomised patients due to a numerically higher mortality in the facilitated PCI group receiving tenecteplase. The occurrence of the primary endpoint, a composite of death or cardiogenic shock or congestive heart failure within 90 days, was significantly higher in the group receiving the exploratory regimen 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 the primary 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 only regimen: death: 6.7% vs. 4.9% p=0.14; cardiogenic shock: 6.3% vs. 4.8% p=0.19; congestive heart failure: 12.0% vs. 9.2% p=0.06 respectively. The secondary endpoints re-infarction and repeat target vessel 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: intracranial haemorrhage: 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.

Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen. Tenecteplase is cleared from circulation by binding to specific receptors in the liver followed by catabolism to small peptides. Binding to hepatic receptors is, however, reduced compared to native t-PA, resulting in a prolonged half-life. Data on tissue distribution and elimination 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 what extent tenecteplase binds to plasma proteins in humans.

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 of tenecteplase 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, and plasma clearance is 119 ± 49 ml/min.

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

The effect of renal and hepatic dysfunction on pharmacokinetics of tenecteplase in humans is not known. There is no specific experience to guide the adjustment to tenecteplase dose in patients with hepatic and severe renal insufficiency. However, based on animal data it is not expected that renal dysfunction will affect the pharmacokinetics.

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

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

With regard to the indication and the single dose administration in humans, reproductive toxicity testing was limited to an embryotoxicity study in rabbits, as a sensitive species. Tenecteplase induced total litter deaths during the mid-embryonal period. When tenecteplase was given during the mid- or late-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 and genotoxicity and carcinogenicity testing were not necessary.

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

Powder:

L-arginine

Phosphoric acid

Polysorbate 20.

Solvent:

Water for injections.

Metalyse is incompatible with dextrose infusion solutions.

Shelf life as packaged for sale

2 years

Reconstituted solution

Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C and 8 hours at 30°C.

From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and 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.

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

20 ml glass vial type I, with a coated (B2-42) grey rubber stopper and a flip-off cap filled with powder for solution for injection.

10 ml plastic syringe pre-filled with 8 ml or 10 ml of water for injections for reconstitution.

Sterile vial adapter.

Sterile needle for single use.

Metalyse should be reconstituted by adding the complete volume of water for injections from the pre-filled syringe to the vial containing the powder for injection.

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

2. Check that the cap of the vial is still intact.
3. Remove the flip-off cap from the vial.
4. Remove the tip-cap from the syringe. Then immediately screw the pre-filled syringe on the vial adapter and penetrate the vial stopper in the middle with the spike of the vial adapter.
5. Add the water for injections into the vial by pushing the syringe plunger down slowly to avoid foaming.
6. Reconstitute by swirling gently.
7. The reconstituted preparation 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 reconstituted solution of Metalyse into the syringe, based on the patient's weight.
10. Disconnect the syringe from the vial adapter.
11. Metalyse is to be administered to the patient, intravenously in about 10 seconds. It should not be administered in a line containing dextrose.
12. Any unused solution should be discarded.

Alternatively the reconstitution can be performed with the included needle.

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim am Rhein

Germany

EU/1/00/169/005 (8,000 units)

EU/1/00/169/006 (10,000 units)

Date of first authorisation: 23 February 2001

Date of last renewal: 23 February 2006

04 June 2010