RAPILYSIN 10U powder + solvent for injection medication leaflet

Rapilysin 10 U powder and solvent for solution for injection.

1 vial contains 10 U* reteplase ** in 0.56 g powder1 prefilled syringe contains 10 ml water for injections.

The reconstituted solution contains 1 U reteplase per ml.

For the full list of excipients, see section 6.1.

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

** Recombinant plasminogen activator produced in Escherichia coli by recombinant DNA technology.

Powder and solvent for solution for injection.

White powder and clear colourless liquid (water for injections).

Rapilysin is indicated for the thrombolytic treatment of suspected myocardial infarction with persistent

ST elevation or recent left Bundle Branch Block within 12 hours after the onset of acute myocardialinfarction AMI symptoms.

Treatment with reteplase should be initiated as soon as possible after the onset of AMI symptoms.

Rapilysin should be prescribed by physicians experienced in the use of thrombolytic treatment andwith the facilities to monitor its use.

Dosage of Rapilysin

Rapilysin is administered as a 10 U bolus dose followed by a second 10 U bolus dose 30 minutes later(double bolus).

Each bolus is administered as a slow intravenous injection within 2 minutes. Ensure that the injectionis not mistakenly given paravenously.

Heparin and acetylsalicylic acid should be administered before and following the administration of

Rapilysin to reduce the risk of re-thrombosis.

Dosage of Heparin

The recommended dose of heparin is 5000 I.U. given as a bolus injection prior to reteplase therapyfollowed by an infusion of 1000 I.U. per hour starting after the second reteplase bolus. Heparin shouldbe administered for at least 24 hours, preferably for 48 - 72 hours, aiming to keep aPTT values 1.5 to2 times normal.

Dosage of Acetylsalicylic Acid

The initial dose of acetylsalicylic acid prior to thrombolysis should be at least 250 mg (250 - 350 mg)followed by 75 - 150 mg/day at least until discharge.

No data are available.

Reteplase is supplied as a freeze-dried substance in vials. The lyophilisate is reconstituted with thecontents of the accompanying syringe. For instructions on reconstitution of the medicinal productbefore administration, see section 6.6.

Rapilysin should be injected preferably through an intravenous line whose sole purpose is the injectionof Rapilysin. No other medicines should be injected through the line reserved for Rapilysin, neither atthe same time, nor prior to, nor following Rapilysin injection. This applies to all products includingheparin, and acetylsalicylic acid, which should be administered before and following theadministration of reteplase to reduce the risk of re-thrombosis.

In those patients where the same line has to be used, this line (including Y-line) must be flushedthoroughly with 0.9 % sodium chloride or 5 % glucose solution prior to and following the Rapilysininjection.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Because thrombolytic therapy increases the risk of bleeding, reteplase is contra-indicated in thefollowing situations:

- known haemorrhagic diathesis

- patients with current concomitant therapy with oral anticoagulants (e.g. warfarin sodium)

- intracranial neoplasm, arteriovenous malformation or aneurysm

- neoplasm with increased bleeding risk

- history of cerebrovascular accident

- recent (< 10 days) prolonged and vigorous external heart massage

- severe uncontrolled hypertension

- active peptic ulceration

- portal hypertension (oesophageal varices)

- severe liver or renal dysfunction

- acute pancreatitis, pericarditis, bacterial endocarditis

- within 3 months of severe bleeding, major trauma or major surgery (e.g. coronary artery bypassgraft, intracranial or intraspinal surgery or trauma), obstetrical delivery, organ biopsy, previouspuncture of non-compressible vessels.

Each patient being considered for therapy with reteplase should be carefully evaluated.

For information on product incompatibilities see section 6.2.

The most common complication encountered during reteplase therapy is bleeding. In the followingconditions the risks of reteplase therapy may be increased and should be weighed against theanticipated benefits:

- cerebrovascular disease

- systolic blood pressure at entry > 160 mmHg

- recent gastrointestinal or genitourinary bleeding (within 10 days)

- high likelihood of left heart thrombus, e.g. mitral stenosis with atrial fibrillation

- septic thrombophlebitis or occluded arteriovenous cannula at seriously infected site

- age over 75 years

- any other condition in which bleeding constitutes a significant hazard or would be particularlydifficult because of its location

The concomitant use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed duringreteplase therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapyrequires careful attention to all possible bleeding sites (including catheter insertion sites, arterial andvenous puncture sites, cut down sites and needle puncture sites). The use of rigid catheter as well asintramuscular injections and nonessential handling of the patient should be avoided during treatmentwith reteplase.

Caution should be employed when used with other medicinal products affecting haemostasis such asheparin, low-molecular-weight heparins, heparinoids, oral anticoagulants and antiplatelet agents otherthan acetylsalicylic acid, such as dipyridamole, ticlopidine, clopidogrel or glycoprotein IIb/IIIareceptor antagonists.

Should serious bleeding, in particular cerebral haemorrhage, occur any concomitant heparin should beterminated immediately. In addition, the second bolus of reteplase should not be given if the seriousbleeding occurs before it is administered. In general, however, it is not necessary to replace thecoagulation factors because of the relatively short half-life of reteplase. Most patients who havebleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volumereplacement and manual pressure applied to an incompetent vessel. Protamine should be considered ifheparin has been administered within 4 hours of the onset of bleeding. In the patients who fail torespond to these conservative measures, judicious use of transfusion products may be indicated.

Transfusions of cryoprecipitate, fibrinogen, fresh frozen plasma and platelets should be consideredwith clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/l isdesirable with cryoprecipitate or fibrinogen infusion.

At present, insufficient data in patients with a diastolic blood pressure > 100 mmHg prior tothrombolytic therapy are available for reteplase.

Arrhythmias

Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is stronglyrecommended that antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (e.g.ventricular tachycardia or fibrillation) be available when reteplase is administered.

Since at present there is no experience with readministration of reteplase, the readministration is notrecommended. However, no antibody formation to the reteplase molecule has been observed.

If an anaphylactoid reaction occurs, the injection should be discontinued immediately and appropriatetherapy should be initiated.

No interaction studies have been performed. Retrospective analyses of clinical studies did not revealany clinically relevant interactions with medicinal product used concomitantly with reteplase inpatients with acute myocardial infarction. Heparin, vitamin K antagonists and medicinal product thatalter platelet function (such as acetylsalicylic acid, dipyridamole and abciximab) may increase the riskof bleeding if administered prior to, during or after reteplase therapy.

Attention should be paid to this effect especially during periods of low plasma fibrinogen (up to about2 days after fibrinolytic therapy of AMI).

For information on product incompatibilities see section 4.2.

There are no adequate data on the use of reteplase in pregnant women. The only relevant availableanimal data refer to studies performed in rabbits, which showed vaginal bleedings associated withabortions (see section 5.3). The potential risk for humans is unknown.

Except in life-threatening situations, Rapilysin should not be used in pregnant women.

It is not known whether reteplase is excreted into breast milk. Breast milk should be discarded withinthe first 24 hours after thrombolytic therapy.

Not relevant.

The most commonly reported adverse drug reaction associated with reteplase treatment ishaemorrhage, predominantly at the injection site. Local reactions at injection site can also occur.

As with other thrombolytic agents, recurrent ischaemia/angina, hypotension and heartfailure/pulmonary oedema have been reported frequently as sequelae of myocardial infarction and/orthrombolytic administration.

The most frequent adverse drug reaction associated with reteplase treatment is haemorrhage.

Reports of intracranial bleeding, many of which are fatal, are of particular concern.

Systolic blood pressure over 160 mmHg before thrombolysis with reteplase was associated withgreater risk for cerebral bleeding. The risk of intracranial bleeding and fatal intracranial bleedingincreases with increasing age. Blood transfusions were rarely required. Death and permanent disabilityare not uncommonly reported in patients who have experienced stroke (including intracranialbleeding) and other serious bleeding episodes.

The frequency of adverse reactions reported is listed in the following table. Frequencies are defined asvery 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) and not known (cannot be estimated from the availabledata).

System Organ Class Frequency Adverse reactions seen with reteplase

Immune system Uncommon Hypersensitivity reactions (e.g. allergicdisorders reactions)1

Very rare Serious anaphylaxis/anaphylactoidreactions1

Nervous system Uncommon Cerebral haemorrhage2disorders

Very rare Events related to the nervous system(e.g. epileptic seizure, convulsion,aphasia, speech disorder, delirium,acute brain syndrome, agitation,confusion, depression, psychosis)

Cardiac disorders3 Very common Recurrent ischaemia/angina,hypotension and heartfailure/pulmonary oedema

Common Arrhythmias (e.g. AV block, atrialfibrillation/flutter, ventriculartachycardia/fibrillation,electromechanical dissociation (EMD)),cardiac arrest, cardiogenic shock andreinfarction

Uncommon Mitral regurgitation, pulmonaryembolism, other systemicembolism/cerebral embolism andventricular septal defect

Vascular disorders Common Gastrointestinal haemorrhage(haematemesis, melena), gingival orgenitourinary bleeding

Uncommon Haemopericardium, retroperitonealbleeding, cerebral haemorrhage,epistaxis, haemoptysis, eyehaemorrhage and ecchymosis

General disorders and Very common Haemorrhage at the injection site (e.g.administration site haematoma), a local reaction atconditions injection site, for example a burningsensation

Injury, poisoning and Not known Fat embolism, which may lead toprocedural corresponding consequences in thecomplications organs concerned41. Available evidence on reteplase does not indicate an antibody-mediated origin of thesehypersensitivity reactions.2. Ischaemic or haemorrhagic cerebrovascular events may be contributing or underlying conditions.3. As with other thrombolytic agents these cardiovascular events have been reported as sequelae ofmyocardial infarction and/or thrombolytic administration. These events can be life-threatening andmay lead to death.4. This event has been reported for the therapeutic class of thrombolytic agents.

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 overdosage one might expect depletion of fibrinogen and other blood coagulationcomponents (e.g. coagulation factor V) with a consequent risk of bleeding.

For further information see section 4.4, section bleeding.

Pharmacotherapeutic group: antithrombotic agent, ATC Code: B01AD07

Reteplase is a recombinant plasminogen activator that catalyzes the cleavage of endogenousplasminogen to generate plasmin. This plasminogenolysis occurs preferentially in the presence offibrin. Plasmin in turn degrades fibrin, which is the main component of the matrix of thrombi, therebyexerting its thrombolytic action.

Reteplase (10+10 U) dose-dependently reduces plasma fibrinogen levels by about 60 to 80 %. Thefibrinogen level normalises within 2 days. As with other plasminogen activators a reboundphenomenon then occurs during which fibrinogen levels reach a maximum within 9 days and remainelevated for up to 18 days.

Reductions of plasma levels of plasminogen and α2-antiplasmin normalise within 1 to 3 days.

Coagulation factor V, clotting factor VIII, α2-macroglobulin, and C1-esterase inhibitor are onlyslightly reduced and normalise within 1 to 2 days. Plasminogen activator inhibitor 1 (PAI-1) activitycan be reduced to around zero, but rapidly normalises within two hours showing a reboundphenomenon. Prothrombin activation fragment 1 levels and thrombin-antithrombin III-complexesincrease during thrombolysis indicating thrombin production of which the clinical relevance isunknown.

A large comparative mortality trial (INJECT) in approx. 6000 patients showed that reteplase reducedthe incidence of heart failure (secondary efficacy criterion) in a significant manner and was at leastequally effective in terms of reducing mortality (primary efficacy criterion) when compared tostreptokinase. In two clinical trials aiming primarily at coronary artery patency (RAPID I and II)reteplase was associated with higher early patency rates (primary efficacy criterion), as well as with alower incidence of heart failure (secondary efficacy criterion) than alteplase (3 hour and 'accelerated'dosage regimens). A clinical trial in approximately 15 000 patients comparing reteplase with theaccelerated dose regimen of alteplase (GUSTO III) (2:1 randomisation reteplase: alteplase) did notshow statistically different results for the primary endpoint of 30-day mortality (reteplase: 7.47 %,alteplase 7.23 %, p = 0.61) or for the combined endpoint of 30-day mortality and non-fatal disablingstroke (reteplase: 7.89 %, alteplase 7.88 %, p = 0.99). Overall stroke rates were 1.64 % in the reteplaseand 1.79 % in the alteplase group. In the reteplase group, 49.4 % of these strokes were fatal and27.1 % were disabling. In the alteplase group 33.0 % were fatal and 39.8 % were disabling.

Following intravenous bolus injection of 10 + 10 U in patients with acute myocardial infarctionreteplase antigen is distributed in plasma with a dominant half-life (t1/2α) of 18±5 min and eliminatedwith a terminal half-life (t1/2ß) of 5.5 hours±12.5 min at a clearance rate of 121±25 ml/min. Reteplaseactivity is cleared from the plasma at a rate of 283±101 ml/min, resulting in a dominant half-life(t1/2α) of 14.6±6.7 min and a terminal half-life (t1/2ß) of 1.6 hours±39 min. Only minor amounts ofreteplase were immunologically detected in the urine. Exact data on the main elimination routes forreteplase in humans are not available and the consequences of hepatic or renal insufficiency are notknown. Experiments in rats indicate that the liver and the kidneys are the main organs of active uptakeand lysosomal degradation.

Additional studies in human plasma samples in vitro suggest that complexation with C1-inactivator,α2-antiplasmin and α2-antitrypsin contributes to the inactivation of reteplase in plasma. The relativecontribution of the inhibitors to inactivation of reteplase decreases as follows: C1-inactivator > α2-antiplasmin > α2-antitrypsin.

The half-life of reteplase was increased in patients with AMI as compared to healthy volunteers. Anadditional increase of half-life of activity in patients with myocardial infarction and severely impairedliver and renal function cannot be excluded, but no clinical data of pharmacokinetics of reteplase inthese patients are available. Animal data show that in case of severely impaired renal function with apronounced increase in serum creatinine and serum urea an increase in half-life of reteplase has to beexpected. Mild impairment of renal function did not significantly affect the pharmacokineticproperties of reteplase.

Acute toxicity studies were performed in rats, rabbits and monkeys Subacute toxicity studies wereperformed in rats, dogs and monkeys. The predominant acute symptom after single high doses ofreteplase in rats and rabbits was transient apathy shortly after injection. In cynomolgus monkeys, thesedative effect ranged from slight apathy to unconsciousness, caused by a reversible dose-related dropin blood pressure. There was increased local haemorrhage at the injection site.

Subacute toxicity studies did not reveal any unexpected adverse events. In dogs repeated dosing of thehuman peptide reteplase led to immunologic-allergic reactions. Genotoxicity of reteplase wasexcluded by a complete battery of tests at different genetic end points in vitro and in vivo.

Reproductive toxicity studies were performed in rats (fertility and embryo-foetotoxicity studyincluding a littering phase) and in rabbits (embryo-foetotoxicity study, dose-range finding only). Inrats, a species insensitive to the pharmacological effects of reteplase, there were no adverse effects onfertility, embryo-foetal development and offspring. In rabbits, vaginal bleedings and abortionspossibly associated to prolonged haemostasis, but no foetal abnormalities were noted. A pre- andpostnatal toxicity study was not performed with reteplase.

Tranexamic aciddi potassium-hydrogen phosphatephosphoric acidsucrose

Polysorbate 80

Water for injections

This medicinal product should not be mixed with Heparin and/or acetylsalicylic acid.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Heparin and Rapilysin are incompatible when combined in solution. Other incompatibilities may alsoexist. No other medicines should be added to the injection solution.

Shelf-life as package for sale:3 years.

Reconstituted product:

Chemical and physical in-use stability has been demonstrated for 8 hours between 2° and 30 °C afterdissolving with water for injection.

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

Do not store above 25 °C.

Keep the vial in the outer carton in order to protect from light.

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

Each pack contains:

2 colourless glass vials (type I) with a rubber (butyl) closure and an aluminium flip-off cap, containing0.56 mg of powder.2 pre-filled glass syringes (borosilicate, type I) for single use, with a bromobutyl plunger stopper and abromobutyl rubber tip cap, containing 10 ml of solvent.2 reconstitution spikes2 needles 19 G1

Incompatibility of some prefilled glass syringes (including Rapilysin) with certain needle freeconnectors has been reported. Therefore, the compatibility of the glass syringe and intravenous accessshould be ensured before use. In case of incompatibility an adaptor can be used and removed togetherwith the glass syringe immediately after administration

Use aseptic technique throughout.

1. Remove the protective flip-cap from the vial of Rapilysin 10 U and clean the rubber closurewith an alcohol wipe.

2. Open the package containing the reconstitution spike, remove both protective caps from thereconstitution spike.

3. Insert the spike through the rubber closure into the vial of Rapilysin 10 U.

4. Take the 10 ml syringe out of the package. Remove the tip cap from the syringe. Connect thesyringe to the reconstitution spike and transfer the 10 ml of solvent into the vial of Rapilysin10 U.

5. With the reconstitution spike and syringe still attached to the vial, swirl the vial gently todissolve the Rapilysin 10 U powder. DO NOT SHAKE.

6. The reconstituted preparation results in a clear, colourless solution. If the solution is not clearand colourless it should be discarded.

7. Withdraw 10 ml of Rapilysin 10 U solution back into the syringe. A small amount of solutionmay remain in the vial due to overfill.

8. Disconnect the syringe from the reconstitution spike. The dose is now ready for intravenousadministration9. The reconstituted solution must be used immediately. Visual inspection of the solution isnecessary after reconstitution. Only clear, colourless solutions should be injected. If the solutionis not clear and colourless it should be discarded.

10. No other medicines should be injected through the line reserved for Rapilysin either at the sametime, or prior to, or following Rapilysin injection. This applies to all products including heparinand acetylsalicylic acid, which should be administered before and following the administrationof reteplase to reduce the risk of re-thrombosis11. In those patients where the same line has to be used, this line (including Y-line) must be flushedthoroughly with a 0.9 % sodium chloride or 5 % glucose solution prior to and following the

Rapilysin injection (see section 4.2 Posology and method of administration).

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

Actavis Group PTC ehf

Reykjavíkurvegi 76-78220 Hafnarfjordur

Iceland.

EU/1/96/018/001

Date of first authorisation: 29 August 1996

Date of last renewal: 29 August 2006

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

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