Rapilysin

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Rapilysin 10 U powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 vial contains 10 U* reteplase ** in 0.56 g powder 
1 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 for 
reteplase and is not comparable with units used for other thrombolytic agents. 
 
** Recombinant plasminogen activator produced in Escherichia coli by recombinant DNA technology. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
White powder and clear colourless liquid (water for injections).  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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 myocardial 
infarction AMI symptoms.  
 
4.2 Posology and method of administration 
 
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 and 
with the facilities to monitor its use. 
 
Posology 
 
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 injection 
is 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 therapy 
followed by an infusion of 1000 I.U. per hour starting after the second reteplase bolus. Heparin should 



3 

be administered for at least 24 hours, preferably for 48 – 72 hours, aiming to keep aPTT values 1.5 to 
2 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. 
 
Paediatric population 
 
No data are available. 
 
Method of administration 
 
Reteplase is supplied as a freeze-dried substance in vials. The lyophilisate is reconstituted with the 
contents of the accompanying syringe. For instructions on reconstitution of the medicinal product 
before administration, see section 6.6. 
 
Rapilysin should be injected preferably through an intravenous line whose sole purpose is the injection 
of Rapilysin. No other medicines should be injected through the line reserved for Rapilysin, neither at 
the same time, nor prior to, nor following Rapilysin injection. This applies to all products including 
heparin, and acetylsalicylic acid, which should be administered before and following the 
administration 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 flushed 
thoroughly with 0.9 % sodium chloride or 5 % glucose solution prior to and following the Rapilysin 
injection. 
 
4.3 Contraindications 
 
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 the 
following 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 
 



4 

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

 
4.4 Special warnings and precautions for use 
 
Each patient being considered for therapy with reteplase should be carefully evaluated. 
For information on product incompatibilities see section 6.2. 
 
Bleeding 
 
The most common complication encountered during reteplase therapy is bleeding. In the following 
conditions the risks of reteplase therapy may be increased and should be weighed against the 
anticipated 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  particularly 

difficult because of its location 
 
The concomitant use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during 
reteplase therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy 
requires careful attention to all possible bleeding sites (including catheter insertion sites, arterial and 
venous puncture sites, cut down sites and needle puncture sites). The use of rigid catheter as well as 
intramuscular injections and nonessential handling of the patient should be avoided during treatment 
with reteplase. 
 
Caution should be employed when used with other medicinal products affecting haemostasis such as 
heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants and antiplatelet agents other 
than acetylsalicylic acid, such as dipyridamole, ticlopidine, clopidogrel or glycoprotein IIb/IIIa 
receptor antagonists. 
 
Should serious bleeding, in particular cerebral haemorrhage, occur any concomitant heparin should be 
terminated immediately. In addition, the second bolus of reteplase should not be given if the serious 
bleeding occurs before it is administered. In general, however, it is not necessary to replace the 
coagulation factors because of the relatively short half-life of reteplase. Most patients who have 
bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume 
replacement and manual pressure applied to an incompetent vessel. Protamine should be considered if 
heparin has been administered within 4 hours of the onset of bleeding. In the patients who fail to 
respond to these conservative measures, judicious use of transfusion products may be indicated. 
Transfusions of cryoprecipitate, fibrinogen, 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 or fibrinogen infusion. 
 
At present, insufficient data in patients with a diastolic blood pressure > 100 mmHg prior to 
thrombolytic therapy are available for reteplase. 
 



5 

Arrhythmias 
 
Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is strongly 
recommended that antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (e.g. 
ventricular tachycardia or fibrillation) be available when reteplase is administered. 
 
Readministration 
 
Since at present there is no experience with readministration of reteplase, the readministration is not 
recommended. However, no antibody formation to the reteplase molecule has been observed. 
If an anaphylactoid reaction occurs, the injection should be discontinued immediately and appropriate 
therapy should be initiated. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. Retrospective analyses of clinical studies did not reveal 
any clinically relevant interactions with medicinal product used concomitantly with reteplase in 
patients with acute myocardial infarction. Heparin, vitamin K antagonists and medicinal product that 
alter platelet function (such as acetylsalicylic acid, dipyridamole and abciximab) may increase the risk 
of 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 about 
2 days after fibrinolytic therapy of AMI). 
 
For information on product incompatibilities see section 4.2. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no adequate data on the use of reteplase in pregnant women. The only relevant available 
animal data refer to studies performed in rabbits, which showed vaginal bleedings associated with 
abortions (see section 5.3). The potential risk for humans is unknown. 
Except in life-threatening situations, Rapilysin should not be used in pregnant women. 
 
Breast-feeding 
It is not known whether reteplase is excreted into breast milk. Breast milk should be discarded within 
the first 24 hours after thrombolytic therapy. 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most commonly reported adverse drug reaction associated with reteplase treatment is 
haemorrhage, predominantly at the injection site. Local reactions at injection site can also occur. 
 
As with other thrombolytic agents, recurrent ischaemia/angina, hypotension and heart 
failure/pulmonary oedema have been reported frequently as sequelae of myocardial infarction and/or 
thrombolytic administration. 
 
Haemorrhage 
 
The most frequent adverse drug reaction associated with reteplase treatment is haemorrhage. 
 



6 

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 with 
greater risk for cerebral bleeding. The risk of intracranial bleeding and fatal intracranial bleeding 
increases with increasing age. Blood transfusions were rarely required. Death and permanent disability 
are not uncommonly reported in patients who have experienced stroke (including intracranial 
bleeding) and other serious bleeding episodes. 
 
Tabulated list of adverse reactions 
 
The frequency of adverse reactions reported is listed in the following table. Frequencies are defined as 
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) and not known (cannot be estimated from the available 
data). 
 
System Organ Class Frequency Adverse reactions seen with reteplase 
Immune system 
disorders 

Uncommon 
 
 

Very rare 

Hypersensitivity reactions (e.g. allergic 
reactions)1 
 
Serious anaphylaxis/anaphylactoid 
reactions1 

Nervous system 
disorders 

Uncommon 
 

Very rare 

Cerebral haemorrhage2 
 
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 
 
 
 

Common 
 
 
 
 
 
 

Uncommon 

Recurrent ischaemia/angina, 
hypotension and heart 
failure/pulmonary oedema 
 
Arrhythmias (e.g. AV block, atrial 
fibrillation/flutter, ventricular 
tachycardia/fibrillation, 
electromechanical dissociation (EMD)), 
cardiac arrest, cardiogenic shock and 
reinfarction 
 
Mitral regurgitation, pulmonary 
embolism, other systemic 
embolism/cerebral embolism and 
ventricular septal defect 

Vascular disorders Common 
 
 
 

Uncommon 

Gastrointestinal haemorrhage 
(haematemesis, melena), gingival or 
genitourinary bleeding 
 
Haemopericardium, retroperitoneal 
bleeding, cerebral haemorrhage, 
epistaxis, haemoptysis, eye 
haemorrhage and ecchymosis 

General disorders and 
administration site 
conditions 

Very common Haemorrhage at the injection site (e.g. 
haematoma), a local reaction at 
injection site, for example a burning 
sensation 

Injury, poisoning and 
procedural 

Not known Fat embolism, which may lead to 
corresponding consequences in the 



7 

complications organs concerned4 
1. Available evidence on reteplase does not indicate an antibody-mediated origin of these 
hypersensitivity 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 of 
myocardial infarction and/or thrombolytic administration. These events can be life-threatening and 
may lead to death. 
4. This event has been reported for the therapeutic class of thrombolytic agents. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In the event of overdosage one might expect depletion of fibrinogen and other blood coagulation 
components (e.g. coagulation factor V) with a consequent risk of bleeding. 
 
For further information see section 4.4, section bleeding. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antithrombotic agent, ATC Code: B01AD07 
 
Mechanism of action 
Reteplase is a recombinant plasminogen activator that catalyzes the cleavage of endogenous 
plasminogen to generate plasmin. This plasminogenolysis occurs preferentially in the presence of 
fibrin. Plasmin in turn degrades fibrin, which is the main component of the matrix of thrombi, thereby 
exerting its thrombolytic action. 
 
Reteplase (10+10 U) dose-dependently reduces plasma fibrinogen levels by about 60 to 80 %. The 
fibrinogen level normalises within 2 days. As with other plasminogen activators a rebound 
phenomenon then occurs during which fibrinogen levels reach a maximum within 9 days and remain 
elevated 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 only 
slightly reduced and normalise within 1 to 2 days. Plasminogen activator inhibitor 1 (PAI-1) activity 
can be reduced to around zero, but rapidly normalises within two hours showing a rebound 
phenomenon. Prothrombin activation fragment 1 levels and thrombin-antithrombin III-complexes 
increase during thrombolysis indicating thrombin production of which the clinical relevance is 
unknown. 
 
Clinical efficacy and safety 
A large comparative mortality trial (INJECT) in approx. 6000 patients showed that reteplase reduced 
the incidence of heart failure (secondary efficacy criterion) in a significant manner and was at least 
equally effective in terms of reducing mortality (primary efficacy criterion) when compared to 
streptokinase. 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 a 
lower 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 the 



8 

accelerated dose regimen of alteplase (GUSTO III) (2:1 randomisation reteplase: alteplase) did not 
show 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 disabling 
stroke (reteplase: 7.89 %, alteplase 7.88 %, p = 0.99). Overall stroke rates were 1.64 % in the reteplase 
and 1.79 % in the alteplase group. In the reteplase group, 49.4 % of these strokes were fatal and 
27.1 % were disabling. In the alteplase group 33.0 % were fatal and 39.8 % were disabling. 
 
5.2 Pharmacokinetic properties 
 
Elimination 
Following intravenous bolus injection of 10 + 10 U in patients with acute myocardial infarction 
reteplase antigen is distributed in plasma with a dominant half-life (t1/2α) of 18±5 min and eliminated 
with a terminal half-life (t1/2ß) of 5.5 hours±12.5 min at a clearance rate of 121±25 ml/min. Reteplase 
activity 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 of 
reteplase were immunologically detected in the urine. Exact data on the main elimination routes for 
reteplase in humans are not available and the consequences of hepatic or renal insufficiency are not 
known. Experiments in rats indicate that the liver and the kidneys are the main organs of active uptake 
and 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 relative 
contribution 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. An 
additional increase of half-life of activity in patients with myocardial infarction and severely impaired 
liver and renal function cannot be excluded, but no clinical data of pharmacokinetics of reteplase in 
these patients are available. Animal data show that in case of severely impaired renal function with a 
pronounced increase in serum creatinine and serum urea an increase in half-life of reteplase has to be 
expected. Mild impairment of renal function did not significantly affect the pharmacokinetic 
properties of reteplase. 
 
5.3 Preclinical safety data 
 
Acute toxicity studies were performed in rats, rabbits and monkeys Subacute toxicity studies were 
performed in rats, dogs and monkeys. The predominant acute symptom after single high doses of 
reteplase in rats and rabbits was transient apathy shortly after injection. In cynomolgus monkeys, the 
sedative effect ranged from slight apathy to unconsciousness, caused by a reversible dose-related drop 
in 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 the 
human peptide reteplase led to immunologic-allergic reactions. Genotoxicity of reteplase was 
excluded 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 study 
including a littering phase) and in rabbits (embryo-foetotoxicity study, dose-range finding only). In 
rats, a species insensitive to the pharmacological effects of reteplase, there were no adverse effects on 
fertility, embryo-foetal development and offspring. In rabbits, vaginal bleedings and abortions 
possibly associated to prolonged haemostasis, but no foetal abnormalities were noted. A pre- and 
postnatal toxicity study was not performed with reteplase. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder: 



9 

Tranexamic acid 
di potassium-hydrogen phosphate 
phosphoric acid 
sucrose 
Polysorbate 80 
 
Solvent: 
Water for injections 
 
6.2 Incompatibilities 
 
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 medicinal 
products. 
 
Heparin and Rapilysin are incompatible when combined in solution. Other incompatibilities may also 
exist. No other medicines should be added to the injection solution. 
 
6.3 Shelf life 
 
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 after 
dissolving with water for injection. 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user. 
 
6.4 Special precautions for storage 
 
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. 
 
6.5 Nature and contents of container 
 
Each pack contains: 
 
2 colourless glass vials (type I) with a rubber (butyl) closure and an aluminium flip-off cap, containing 
0.56 mg of powder. 
2 pre-filled glass syringes (borosilicate, type I) for single use, with a bromobutyl plunger stopper and a 
bromobutyl rubber tip cap, containing 10 ml of solvent. 
2 reconstitution spikes 
2 needles 19 G1 
 
6.6 Special precautions for disposal and other handling 
 
Incompatibility of some prefilled glass syringes (including Rapilysin) with certain needle free 
connectors has been reported. Therefore, the compatibility of the glass syringe and intravenous access 
should be ensured before use. In case of incompatibility an adaptor can be used and removed together 
with 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 closure 

with an alcohol wipe. 



10 

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

reconstitution 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 the 

syringe to the reconstitution spike and transfer the 10 ml of solvent into the vial of Rapilysin 
10 U. 

 
5. With the reconstitution spike and syringe still attached to the vial, swirl the vial gently to 

dissolve the Rapilysin 10 U powder. DO NOT SHAKE. 
 
6. The reconstituted preparation results in a clear, colourless solution. If the solution is not clear 

and colourless it should be discarded. 
 
7. Withdraw 10 ml of Rapilysin 10 U solution back into the syringe. A small amount of solution 

may remain in the vial due to overfill. 
 
8. Disconnect the syringe from the reconstitution spike. The dose is now ready for intravenous 

administration 
 
9. The reconstituted solution must be used immediately. Visual inspection of the solution is 

necessary after reconstitution. Only clear, colourless solutions should be injected. If the solution 
is not clear and colourless it should be discarded. 

 
10. No other medicines should be injected through the line reserved for Rapilysin either at the same 

time, or prior to, or following Rapilysin injection. This applies to all products including heparin 
and acetylsalicylic acid, which should be administered before and following the administration 
of reteplase to reduce the risk of re-thrombosis 

 
11. In those patients where the same line has to be used, this line (including Y-line) must be flushed 

thoroughly 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 local 

requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf 
Reykjavíkurvegi 76-78 
220 Hafnarfjordur 
Iceland. 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/96/018/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 August 1996 
Date of last renewal: 29 August 2006 
 



11 

 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



12 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



13 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturers of the biological active substance 
 
Wacker Biotech GmbH 
Heinrich-Damerow-Str. 4 
06120 Halle 
Germany 
 
Name and address of the manufacturers responsible for batch release 
 
Actavis Italy S.p.A.  
Nerviano Plant 
Via Pasteur 10 
20014 Nerviano (Milan) 
Italy  
 
Cenexi 
52, Rue Marcel et Jacques Gaucher 
94120 Fontenay-Sous-Bois 
France 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent published on the European medicines web-portal. 
 
 
 
Not applicable 
 
  



14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

  



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
  



16 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapilysin 10 U powder and solvent for solution for injection  
Water for injections for Rapilysin 10 U solution for intravenous use 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Reteplase 10 U (recombinant plasminogen activator, thrombolytic agent) 
 
 
3. LIST OF EXCIPIENTS 
 
Powder: 
Tranexamic acid 
di potassium-hydrogen phosphate 
phosphoric acid 
sucrose 
Polysorbate 80 
 
Solvent:  
Water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for injection (contains 2x [0.56 g of powder in a vial and 10 ml solvent in a pre-
filled syringe with reconstitution spike and needle]) 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Use the solution immediately after reconstitution 
 
 
8. EXPIRY DATE 
 
EXP 



17 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 °C 
Keep the vial in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf 
Reykjavíkurvegi 76-78 
220 Hafnarfjordur 
Iceland. 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/018/001  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
  



18 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
LABEL OF THE VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rapilysin 10 U powder and solvent for solution for injection 
Reteplase Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Use the solution immediately after reconstitution 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 U reteplase 
 
 
6. OTHER 
 
  



19 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
LABEL OF THE SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Water for injections  
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 ml  
 
 
6. OTHER 
 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



21 

Package leaflet: Information for the user 
 

Rapilysin 10 U powder and solvent for solution for injection 
reteplase 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or your pharmacist. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Rapilysin is and what it is used for 
2. What you need to know before Rapilysin is given to you 
3. How to use Rapilysin 
4. Possible side effects 
5. How to store Rapilysin 
6. Contents of the pack and other information 
 
 
1. What Rapilysin is and what it is used for 
 
Rapilysin contains the active substance reteplase(a recombinant plasminogen activator). It is a 
thrombolytic medicine used to dissolve blood clots that have formed in certain blood vessels and to 
restore the blood flow in these blocked vessels (=thrombolysis). 
 
Rapilysin is used after an acute myocardial infarction (heart attack) in order to dissolve the blood clot 
causing the heart attack. It is given within 12 hours after the onset of symptoms. 
 
 
2. What you need to know before Rapilysin is given to you 
 
The doctor will ask you questions before giving you Rapilysin, to find out if you have an increased 
risk of bleeding. 
 
Do not use Rapilysin 
• if you are allergic to reteplase or any of the other ingredients of this medicine (listed in section 

6). 
• if you have a bleeding disorder. 
• if you are taking medicine to thin your blood (oral anticoagulants, e.g. warfarin). 
• if you have a brain tumour or a malformed blood vessel or a vessel wall dilatation (aneurysm) in 

the brain. 
• if you have other tumours associated with an increased risk of bleeding. 
• if you have had a stroke. 
• if you have had external heart massage within the past 10 days. 
• if you have severe uncontrolled high blood pressure (hypertension). 
• if you have an ulcer in the stomach or small intestine. 
• if you have enlarged blood vessels in the gullet (oesophagus) (frequently caused by liver 

disease). 
• if you have severe liver or kidney disease. 
• if you have acute inflammation of the pancreas or pericardium (the sac surrounding the heart), 

or an infection of the heart muscle (bacterial endocarditis). 
• if you have in the past 3 months had severe bleeding, a major injury or major surgery (e.g. 

coronary artery bypass graft, or surgery or injury to the head or spine), given birth, or had an 
organ biopsy or other medical / surgical procedure. 



22 

 
Warnings and precautions 
 
Bleeding 
The most common side effect of Rapilysin is bleeding. Therefore Rapilysin must be given only in the 
presence and under the instructions of an emergency doctor. 
 
Pay careful attention to all possible bleeding sites (e.g. injection sites). Heparin, which is given 
together with Rapilysin, may also increase bleeding. 
 
The risks of Rapilysin treatment may be increased if you have any of the following conditions: 
• diseases of the blood vessels in the brain 
• systolic blood pressure higher than 160 mmHg 
• bleeding in the gastrointestinal, urinary or genital tract within the past 10 days 
• high likelihood of a blood clot in the heart (e.g. as a result of narrowing of a heart valve or atrial 

fibrillation) 
• septic inflammation of a vein with blood clotting (septic thrombophlebitis) or blocked blood 

vessels at an infected site 
• age over 75 years 
• any other condition in which bleeding might be especially dangerous or might occur at a site 

where it would be difficult to control 
At present, little data are available on the use of Rapilysin in patients with diastolic blood pressure 
higher than 100 mmHg. 
 
Abnormal heart beats (arrhythmias) 
Thrombolytic treatment may cause the heart to beat irregularly. Therefore tell the medical staff 
immediately if you 
 
• feel palpitations or an irregular heart beat 
 
Repeated use 
At present there is no experience with repeated use of Rapilysin. Therefore, repeated use is not 
recommended. Antibody formation to the reteplase molecule has not been seen. 
 
Children 
Safety and effectiveness of Rapilysin in children have not been established. Treatment of children with 
Rapilysin is not recommended. 
 
Other medicines and Rapilysin: 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Heparin and other medicines that thin the blood (anticoagulants) and acetylsalicylic acid (a substance 
used in many medicines used to relieve pain and lower fever) may increase the risk of bleeding. 
 
For information on medicines that should not be physically mixed with Rapilysin solution for 
injection, see section 3. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
 
Pregnancy 
There is no experience with Rapilysin in pregnant women. Therefore it should not be used except in 
life-threatening situations. You must tell your doctor if you are pregnant or think you are pregnant. 
Your doctor can tell you the risks and benefits of using Rapilysin during pregnancy. 
 



23 

Breast-feeding 
You should not breast-feed your baby during treatment with Rapilysin as it is not known whether 
Rapilysin is excreted into mother’s milk. Mother’s milk should be thrown away during the first 24 
hours after thrombolytic treatment. Discuss with your doctor when you can take up breast-feeding 
again. 
 
 
3. How to use Rapilysin  
 
Rapilysin is usually given in a hospital. The medicine is supplied in vials as a powder for injection. 
Before use, the powder for injection must be dissolved in the water for injection supplied in the 
prefilled syringe that is in the package. Do not add any other medicines. The resulting solution must be 
used immediately. The solution must be examined to ensure that only clear, colourless solution is 
injected. If the solution is not clear and colourless it should be thrown away. 
 
Treatment with Rapilysin 10 U should be started as soon as possible after the symptoms of heart attack 
begin. 
 
Heparin and Rapilysin cannot be mixed in the same solution. Other medicines may also not mix well 
with Rapilysin. No other medicines should be added to the injection solution (see below). Rapilysin 
should be injected preferably through an intravenous line that is used only for the injection of 
Rapilysin. No other medicines should be injected through the line reserved for Rapilysin, either at the 
same time, or before or after Rapilysin injection. This applies to all medicines including heparin and 
acetylsalicylic acid, which are given before and after Rapilysin to reduce the risk of new blood clots 
forming. 
If the same line has to be used, this line (including Y-line) must be flushed thoroughly with a 0.9 % 
sodium chloride or 5 % glucose solution before and after the Rapilysin injection.  
 
Dosage of Rapilysin 
Rapilysin is given as a 10 U injection followed by a second 10 U injection 30 minutes later (double 
bolus).  
 
Each injection should be given slowly within 2 minutes. The injection must not be given mistakenly 
outside the vein. Therefore, be sure to tell the medical staff if you experience pain during the injection. 
 
Heparin and acetylsalicylic acid are given before and after Rapilysin to reduce the risk of new blood 
clots forming. 
 
Dosage of Heparin 
The recommended dose of heparin is 5000 I.U. given as a single injection before Rapilysin, followed 
by an infusion of 1000 I.U. per hour starting after the second Rapilysin injection. Heparin should be 
given for at least 24 hours, preferably for 48-72 hours, in order to keep aPTT values 1.5 to 2 times 
normal. 
 
Dosage of Acetylsalicylic Acid  
The dose of acetylsalicylic acid given before Rapilysin should be at least 250 mg-350 mg and should 
be followed by 75-150 mg/day, at least until discharge from hospital. 
 
If more Rapilysin is used than recommended 
In the event of overdosage there may be an increased risk of bleeding. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Very common side effects (may affect more than 1 in 10 people) 



24 

• Bleeding at the injection site, e.g. blood blister (haematoma) 
• Chest Pain / angina, low blood pressure and heart failure /shortness of breath may reappear 
• Burning sensation when Rapilysin is injected 
 
Common side effects (may affect up to 1 in 10 people) 
• Bleeding in the digestive tract (e.g. bloody or black vomit, or stools) in the gums or in the 

urinary or genital tract  
• Abnormal heart beats (arrhythmias), cardiac arrest, circulatory collapse or another heart attack 

may occur 
 
Uncommon side effects (may affect up to 1 in 100 people) 
• Bleeding around the heart, in the abdomen, the brain or the eyes, under the skin, from the nose 

or as coughed up blood 
• Damage to the heart or heart valves, or a blood clot in the lung, brain or other part of body 

mayoccur 
• hypersensitivity (e.g. allergic reactions) 
 
Very rare side effects (may affect up to 1 in 10,000 people) 
• Events related to the nervous system (e.g. epileptic seizure, convulsion, speech disorder, 

delirium, agitation, confusion, depression, psychosis)  
• severe allergic reaction, causing shock or collapse 
 
Side effects of frequency not known (cannot be estimated from the available data) 
• Blockage of blood vessels due to cholesterol (fat) 
 
Cardiovascular events can be life-threatening or cause death.  
 
Patients with systolic blood pressure over 160 mmHg have a greater risk of bleeding in the brain. The 
risk of intracranial bleeding and fatal intracranial bleeding increases with increasing age. Blood 
transfusions were rarely required. Death or permanent disability are not uncommon in patients who 
have a stroke (including bleeding in the brain) or other serious bleeding problem. 
 
Be sure to tell hospital staff immediately if any of these symptoms appear.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Rapilysin 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the label of the vial 
after EXP. The expiry date refers to the last day of that month. 
 
Do not store above 25 °C.  
 
Keep the vial in the outer carton in order to protect from light. 
 
After reconstitution (“when dissolved”), the solution must be used immediately. 



25 

 
 
6. Contents of the pack and other information 
 
What Rapilysin contains 
- The active substance is reteplase 10U/10 ml after reconstitution.  
- The other ingredients are: 

 
Powder: 
Tranexamic acid 
di-potassium-hydrogen phosphate 
phosphoric acid 
sucrose 
polysorbate 80 
 
Solvent: 
10 ml Water for injection (prefilled syringe)  

 
What Rapilysin looks like and contents of the pack 
Rapilysin is presented as a powder and a solvent for injection (0.56 g powder in a vial and 10 ml 
solvent in a pre-filled syringe with a reconstitution spike and a needle-pack of 2) 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf 
Reykjavíkurvegi 76-78 
220 Hafnarfjordur 
Iceland. 
 
Manufacturer 
Actavis Italy S.p.A.  
Nerviano Plant 
Via Pasteur 10 
20014 Nerviano (Milan) 
Italy  
 
Cenexi 
52, Rue Marcel et Jacques Gaucher 
94120 Fontenay-Sous-Bois 
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Actavis Group PTC ehf. 
IJsland / Islande / Island 
 

Lietuva 
UAB "Sicor Biotech" 
Tel: +370 5 266 0203 
 

България 
Актавис ЕАД 
Teл.: +359 2 489 95 85 
 

Luxembourg/Luxemburg 
Actavis Group PTC ehf. 
Islande / Island 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251 007 111 
 

Magyarország 
Teva Gyógyszergyár Zrt  
Tel.: +36 1 288 6400 



26 

Danmark 
Teva Denmark A/S 
Tlf: +45 44985511 
 

Malta 
Actavis Ltd. 
Tel: +35621693533 
 

Deutschland 
PUREN Pharma GmbH & Co. KG 
Tel: +49 (0)89 558909 0 
 

Nederland 
Actavis Group PTC ehf. 
IJsland 
 

Eesti 
UAB "Sicor Biotech" Eesti filiaal 
Tel: +372 661 0801  
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 
 

Ελλάδα 
Specifar ABEE 
Τηλ: +30 2105401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43(0)1 97007 0 
 

España 
Actavis Group PTC ehf. 
Islandia 
 

Polska 
Teva Pharmaceuticals Polska Sp. Z o.o. 
Tel. +48 22 345 93 00 
 

France 
Actavis Group PTC ehf. 
Islande 
 

Portugal 
Generis Farmacêutica, S.A. 
Tel: + 351 214967120 
 
 

Hrvatska 
Pliva Hrvatska d.o.o.  
Tel: +385 1 37 20 000  
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +40 21 230 65 24 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 51 321740 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 
 

Ísland  
Actavis Group PTC ehf. 
Sími: +354 550 3300  
 

Slovenská republika  
TEVA Pharmaceuticals Slovakia s.r.o 
Tel: +421 2 57 26 79 11 
 

Italia 
Actavis Group PTC ehf. 
Islanda 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 (0) 20 180 5900 
 

Kύπρος  
Specifar ABEE  
Τηλ: +30 2105401500 
Ελλάδα 
 

Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 
 

Latvija 
UAB "Sicor Biotech" filiāle Latvijā  
Tel: +371 673 23 666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271 385257 
 

 
This leaflet was last revised in <{MM/YYYY}> 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
--------------------------------------------------------------------------------------------------------------------------- 



27 

 
The following information is intended for healthcare professionals only: 
 
Instructions for use/handling 
Incompatibility of some prefilled glass syringes (including Rapilysin) with certain needle free 
connectors has been reported. Therefore, the compatibility of the glass syringe and intravenous access 
should be ensured before use. In case of incompatibility an adaptor can be used and removed together 
with 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 closure 

with an alcohol wipe. 
 
2. Open the package containing the reconstitution spike, remove both protective caps from the 

reconstitution 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 the 

syringe to the reconstitution spike and transfer the 10 ml of solvent into the vial of Rapilysin 
10 U. 

 
5. With the reconstitution spike and syringe still attached to the vial, swirl the vial gently to 

dissolve the Rapilysin 10 U powder. DO NOT SHAKE.  
 
6. The reconstituted preparation results in a clear, colourless solution. If the solution is not clear 

and colourless it should be discarded. 
 
7. Withdraw 10 ml of Rapilysin 10 U solution back into the syringe. A small amount of solution 

may remain in the vial due to overfill. 
 
8. Disconnect the syringe from the reconstitution spike. The dose is now ready for intravenous 

administration. 
 
9. No other medicines should be injected through the line reserved for Rapilysin either at the same 

time, or prior to, or following Rapilysin injection. This applies to all products including heparin 
and acetylsalicylic acid, which should be administered before and following the administration 
of reteplase to reduce the risk of re-thrombosis. 

 
10. In those patients where the same line has to be used, this line (including Y-line) must be flushed 

thoroughly with a 0.9 % sodium chloride or 5 % glucose solution prior to and following the 
Rapilysin injection. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET