Annex I

List of the invented names, pharmaceutical forms, strengths of the medicinal products, route of administration, marketing authorisation holders in the member states

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Tranexamic acid containing medicinal products with Marketing Authorisation in the European Union Member State (EU/EEA)

Marketing Authorisation Holder

Invented name Strength Pharmaceutical form

Route of administration

AT - Austria Pfizer Corporation Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Wien Austria

Cyklokapron - Ampullen

0,5 g/5 ml Solution for injection intravenous use

BE - Belgium PFIZER S.A.N.V. Bld de la Plaine 17 1050 Brussels Belgium

Cyklokapron 100 mg/5 ml Solution for injection intravenous use

BE - Belgium Eumedica S.A. Winston Churchilllaan 67 1180 Brussels Belgium

Exacyl 500 500 mg/5 ml Solution for injection intravenous use

CY - Cyprus MEDOCHEMIE LTD, 1-10 CONSTANTINOUPOLEOS STREET, P.O.BOX 51409, 3505 LEMESOS, CYPRUS

AZEPTIL INJECTION 500MG/5ML

500MG/5ML INJECTION intravenous use

CY - Cyprus MEDOCHEMIE LTD, 1-10 CONSTANTINOUPOLEOS STREET, P.O.BOX 51409, 3505 LEMESOS, CYPRUS

AZEPTIL INJECTION 250MG/5ML

250MG/5ML INJECTION intravenous use

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CZ - Czech Republic Sanofi-Aventis, s.r.o., Evropská 846/176a, 160 00 Praha 6, Czech Republic

Exacyl 100 mg/ml Solution for injection intravenous use

DE - Germany Pharmacia GmbH Linkstr. 10 D-10785 Berlin

Cyklokapron-Injektionslösung

500mg /5ml Solution for injection intravenous use

DK - Denmark Pfizer ApS, Lautrupvang 8, DK-2750 Ballerup, Denmark

Tranexamsyre "Pfizer"

100 mg/ml Solution for injection intravenous use

EL - Greece A. NIKOLAKOPOULOS A.E. GALATSIOU AVENUE 115, Athens 11146

TRANSAMIN 500MG/5ML Solution for Injection or infusion

intravenous use

ES - Spain ROTTAPHARM S.L. Avda. Diagonal 67-69 08019 Barcelona España

AMCHAFIBRIN 500 mg SOLUCIÓN INYECTABLE

500mg/5 ml solution for injection intravenous use

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ET - Estonia Pfizer Enterprises SARL Round-Point du Kirchberg 51, Avenue J.F. Kennedy L-1855 Luxembourg

CYKLOKAPRON 100mg/ml solution for injection intravenous use

FI - Finland Oy Leiras Finland Ab Paciuksenkatu 21 PL 1406 00101 Helsinki Finland

CAPRILON 100 mg/ml Solution for injection intravenous use

FR - France Sanofi Aventis France 1-13, bd Romain Rolland 75014 Paris France

Exacyl 0,5 g/5 ml I.V., solution injectable

0,5 g/5 ml solution for injection intravenous use

HU - Hungary sanofi-aventis Zrt. Tó u. 1-5. 1045 Budapest, Hungary

Exacyl 0,5g/5ml solution for injection intravenous use

IE - Ireland Pharmacia Ireland Ltd, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 Ireland

Cyklokapron 500mg/5ml solution for injection or infusion

100mg/ml Solution for injection intravenous use

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IS - Iceland Pfizer ApS, Lautrupvang 8, DK-2750 Ballerup, Denmark

Tranexamsyre "Pfizer"

100 mg/ml Solution for injection intravenous use

IT - Italy Rottapharm S.p.A. Via Valosa di Sopra, 9 20052 Monza - Italy

UGUROL 500 mg/5 ml solution for injection intravenous use

IT - Italy Istituto Farmacobiologico Malesci S.p.A. Via Lungo l'Ema 7 50015 Bagno a Ripoli (Firenze) Italy

TRANEX 500 mg/5 ml solution for injection intravenous use

IT - Italy Bioindutria Laboratorio Italiano Medicinali spa Via De Ambrosiis, 2 15067 Novi Ligure Alessandria Italy

ACIDO TRANEXAMICO BIOINDUTRIA L.I.M.

500 mg/5 ml solution for injection intravenous use

LU - Luxembourg Eumedica SA 67, Avenue Winston Churchill B- 1180 Bruxelles

EXACYL 500mg/5ml solution for injection intravenous use

LU - Luxembourg PFIZER S.A.N.V. Bld de la Plaine 17 1050 Brussels Belgium

Cyklokapron 100 mg/ml Solution for injection Intravenous use

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NL - Netherlands Pfizer B.V. Rivium Westlaan 142 2909 LD, Capelle a/d Ijssel

Cyklokapron, oplossing voor injectie 100 mg/ml

100 mg/ml solution for injection intravenous use

NO - Norway Pfizer AS Postboks 3 1324 Lysaker Norway

CYKLOKAPRON 100mg/ml injection for solution intravenous use

PL - Poland Warszawskie Zakłady Farmaceutyczne POLFA S.A. 22/24 karolkowa st. 01-207 Warsaw, Poland

Exacyl 100 mg/ml solution for infusion intravenous use

PL - Poland Sanofi-Aventis France Boulevard Romain Rolland 1-13, F-75014 Paris, France

Exacyl 100 mg/ml solution for infusion intravenous use

SE - Sweden Pfizer AB 191 90 Sollentuna Sweden

Cyklokapron 100mg/ml Solution for injection intravenous use

UK - United Kingdom Pharmacia Limited Walton Oaks, Dorking Road, Tadworth Surrey KT20 7NS United Kingdom

CYKLOKAPRON INJECTION 500MG/ML

500mg/ml Solution for Injection intravenous use

Annex II

Scientific conclusions and grounds for variation to the terms of the marketing authorisations for tranexamic acid containing medicinal products presented by the EMA

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Scientific conclusions Overall summary of the scientific evaluation of referral on antifibrinolytics Tranexamic acid containing medicinal products (see Annex I)

Antifibrinolytics (e.g. aprotinin, aminocaproic acid and tranexamic acid), are a class of haemostatic agents used to prevent excessive blood loss. Aprotinin, a naturally occurring polypeptide, is an inhibitor of proteolytic enzymes. It has a broad action on proteolytic enzymes such as plasmin, trypsin, and kallikrein. The lysine analogues epsilon aminocaproic acid (EACA, also referred as aminocaproic acid) and tranexamic acid (TXA) inhibit more specifically the conversion of plasminogen to plasmin. In March 2010 Germany triggered an article 31 referral to assess the benefits and risks of the antifibrinolytic drugs aprotinin, EACA and TXA in all their approved indications. The marketing authorisations for aprotinin were suspended when concerns over its safety were raised in a previous review in 2007. The preliminary results of a randomised controlled clinical trial, the ‘Blood conservation using antifibrinolytics: a randomised trial in a cardiac surgery population’ (BART) study, had shown that although the use of aprotinin was associated with less serious bleeding than either of the comparator drugs, an increase in 30 day all-cause mortality had been observed among patients receiving aprotinin compared to patients taking other medicines. These concerns echoed those of a few published observational studies. The marketing authorisations of EACA and TXA were not affected by the initial 2007 review. Several data sources informed the opinion of the Committee, including available data from clinical studies, published literature, spontaneous reports and other data submitted by marketing authorisation holders (MAHs) of medicinal products containing aprotinin, EACA or TXA. A CHMP scientific advisory group (SAG) meeting was held in October 2011 and its views were considered by the CHMP in the framework of this review. Separate opinions and conclusions were issued by the CHMP for the three antifibrinolytics (aprotinin, EACA and TXA). This document presents the conclusions on tranexamic acid. Tranexamic acid The safety profile of TXA has evolved since its authorisation, and safety data has accumulated over the years. Thromboembolic events, including interaction with oestrogens have been reported. Acute venous or arterial thrombosis should constitute a contraindication. The same is applicable for fibrinolytic conditions following consumption coagulopathy except in those with predominant activation of the fibrinolytic system with acute severe bleeding. Haematuria and the risk for urethral obstruction should also be included as warnings. In addition, information on convulsions and visual disturbances including impaired colour vision are adverse events which can be serious and have been reported, but these risks had not been considered in the current authorised product information. Tranexamic acid has also been associated with gastrointestinal adverse events, such as nausea, diarrhoea and vomiting. Dermatitis allergic, vascular disorders, such as malaise with hypotension, with or without loss of consciousness and arterial or venous thrombosis, and hypersensitivity reactions including anaphylaxis have been reported. The results of the BART trial did not have a negative impact on the benefit risk profile of TXA. Tranexamic acid had not previously been associated with an increased risk of mortality and this has remained unchanged post-publication of the BART study. The CHMP identified that information on disseminated intravascular coagulation, visual disturbances including impaired colour vision, thromboembolism, haematuria and convulsions should be appropriately reflected through warnings and recommendations in the product information. Tranexamic acid is a lysine analogue authorised for several indication since 1969. Data available from randomised clinical trials and observational studies, including meta-analysis were considered. In addition to cardiac surgery, the CHMP considered that sufficient evidence is available on the safety and efficacy of TXA in other indications, including in patients undergoing dental or surgical procedures or at risk of complications from bleeding. For some conditions modifications to the wording were proposed, in order to bring them in line with current scientific knowledge on the use of TXA. In view of the identified serious limitations of the efficacy data, the available new evidence and/or current medical knowledge on the use of TXA, and considering the adverse reactions profile (some of which serious) associated with the use of TXA, the CHMP considered that some of these indications should be removed. A list of indications for which the CHMP considered that the benefit risk balance remains positive is presented below.

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The product information was modified to ensure that the information to healthcare professionals and patients is up to date. In particular the therapeutic indications were updated to reflect current scientific knowledge on the use of TXA; other changes to the product information were inclusion information on disseminated intravascular coagulation, visual disturbances including impaired colour vision, thromboembolism, haematuria and convulsions as warnings and recommendations. The latest quality review of documents templates were taken into account during this review. Taking into account all the available information on safety and efficacy, the Committee agreed on the variation of the marketing authorisation with the balance of the risks and benefits considered positive in the following revised indications for TXA: Prevention and treatment of haemorrhages due to general or local fibrinolysis in adults and children from one year. Specific indications include: - Haemorrhage caused by general or local fibrinolysis such as: - Menorrhagia and metrorrhagia, - Gastrointestinal bleeding, - Haemorrhagic urinary disorders, further to prostate surgery or surgical procedures affecting the urinary tract, - Ear Nose Throat surgery (adenoidectomy, tonsillectomy, dental extractions), - Gynaecological surgery or disorders of obstetric origin, - Thoracic and abdominal surgery and other major surgical intervention such as cardiovascular surgery, - Management of haemorrhage due to the administration of a fibrinolytic agent. Detailed grounds for re-examination submitted by the marketing authorisation holder One MAH for tranexamic acid containing medicinal products expressed its disagreement with the CHMP Opinion, focusing its grounds for re-examination on the following points: • The MAH was not convinced that the fulfilment of a condition such as performing a pharmacokinetic study in children was an essential condition for the safe and effective use of tranexamic acid IV in adults. This PK study had been requested by the CHMP in the article 31 referral on antifibrinolytics containing aprotinin, aminocaproic acid and tranexamic acid. • The MAH informed that for children, some recent pharmacokinetic studies conducted with tranexamic acid in the paediatric population should provide relevant information. Having considered the data presented, the CHMP noted that there are ongoing PK studies in children that could provide valuable information. The final study results of these clinical trials should be considered before recommending the need of additional studies. Therefore, the CHMP concluded that a PK study should not be requested as a condition at this point in time. The MAHs are reminded that any new information on the use of TXA in children is considered valuable. The ongoing studies could provide some relevant PK data in different age stratum and some pharmacodynamic data, which is considered of interest. The MAHs should present this information to national competent authorities when final results for the studies become available.

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Grounds for amendment of the marketing authorisations of tranexamic acid containing medicinal products listed in Annex I Whereas

Figure: 1. The Committee considered the procedure under Article 31 of Directive 2001/83/EC, for

aprotinin, aminocaproic acid and tranexamic acid (see Annex I).

Figure: 2. The Committee considered all data provided by the MAHs in writing, including data available from literature reviews.

Figure: 3. The Committee considered that evidence from randomised clinical trials and observational studies support the use of tranexamic acid in patients undergoing dental or surgical procedures or at risk of complications from bleeding.

Figure: 4. The Committee considered the available scientific data, including evidence from new studies, on the efficacy of TXA. The CHMP considered also the adverse reactions profile, including new adverse events (some of which serious) associated with the use of TXA.

Figure: 5. In view of the identified serious limitations of the efficacy data, the available new evidence and/or current medical knowledge on the use of TXA, and considering the adverse reactions profile (some of which serious) associated with the use of TXA, the CHMP considered that for some of the therapeutic indications the benefits no longer outweigh the risks and therefore they should be removed.

Figure: 6. The Committee considered that the product information should be updated. In particular, the therapeutic indications were updated to reflect current scientific knowledge on the use of TXA; other changes to the product information were inclusion information on disseminated intravascular coagulation, visual disturbances including impaired colour vision, thromboembolism, haematuria and convulsions as warnings and recommendations.

Therefore the CHMP concluded that the balance of risks and benefits for tranexamic acid is positive under normal conditions of use subject to the revision of the indications as follows: prevention and treatment of haemorrhages due to general or local fibrinolysis in adults and children from one year. Specific indications include: - Haemorrhage caused by general or local fibrinolysis such as: - Menorrhagia and metrorrhagia, - Gastrointestinal bleeding, - Haemorrhagic urinary disorders, further to prostate surgery or surgical procedures affecting the urinary tract, - Ear Nose Throat surgery (adenoidectomy, tonsillectomy, dental extractions), - Gynaecological surgery or disorders of obstetric origin, - Thoracic and abdominal surgery and other major surgical intervention such as cardiovascular surgery, - Management of haemorrhage due to the administration of a fibrinolytic agent. On the basis of the above, the Committee recommended the variation to the terms of the marketing authorisation for the medicinal products containing tranexamic acid referred to in Annex I for which the amendments to the product information are set out in annex III of the opinion. Having considered the detailed grounds for re-examination submitted by the MAH in writing, the CHMP considered that no additional conditions were necessary to ensure the safe and effective use of tranexamic acid.

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Annex III

Summary of Product Characteristics and Package Leaflet

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SUMMARY OF PRODUCT CHARACTERISTICS AND PACKAGE LEAFLET

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SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT Tranexamic acid containing medicinal products [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION [To be completed nationally] 3. PHARMACEUTICAL FORM [To be completed nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prevention and treatment of haemorrhages due to general or local fibrinolysis in adults and children from one year. Specific indications include: - Haemorrhage caused by general or local fibrinolysis such as:

- Menorrhagia and metrorrhagia, - Gastrointestinal bleeding, - Haemorrhagic urinary disorders, further to prostate surgery or surgical procedures affecting the urinary tract,

- Ear Nose Throat surgery (adenoidectomy, tonsillectomy, dental extractions), - Gynaecological surgery or disorders of obstetric origin, - Thoracic and abdominal surgery and other major surgical intervention such as cardiovascular surgery, - Management of haemorrhage due to the administration of a fibrinolytic agent. 4.2 Posology and method of administration Posology Adults Unless otherwise prescribed, the following doses are recommended:

1. Standard treatment of local fibrinolysis: 0.5 g (1 ampule of 5 ml) to 1 g (1 ampule of 10 ml or 2 ampules of 5 ml) tranexamic acid by slow intravenous injection (= 1 ml/minute) two to three times daily

2. Standard treatment of general fibrinolysis: 1 g (1 ampule of 10 ml or 2 ampules of 5 ml) tranexamic acid by slow intravenous injection (= 1 ml/minute) every 6 to 8 hours, equivalent to 15 mg/kg BW

Renal impairment In renal insufficiency leading to a risk of accumulation, the use of tranexamic acid is contra-indicated in patient with severe renal impairment (see section 4.3). For patient with mild to moderate renal impairment, the dosage of tranexamic acid should be reduced according to the serum creatinine level: Serum creatinine μmol/l mg/10 ml

Dose IV Administration

120 to 249 1.35 to 2.82 10 mg/kg BW Every 12 hours 250 to 500 2.82 to 5.65 10 mg/kg BW Every 24 hours > 500 > 5.65 5 mg/kg BW Every 24 hours Hepatic impairment No dose adjustment is required in patient with hepatic impairment.

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Paediatric Population: In children from 1 year, for current approved indications as described in section 4.1, the dosage is in the region of 20 mg/kg/day. However, data on efficacy, posology and safety for these indications are limited. The efficacy, posology and safety of tranexamic acid in children undergoing cardiac surgery have not been fully established. Currently available data are limited and are described in section 5.1. Elderly: No reduction in dosage is necessary unless there is evidence of renal failure. Method of administration The administration is strictly limited to slow intravenous injection. 4.3 Contraindications Hypersensitivity to the active substance or to any of its excipients listed in section 6.1. Acute venous or arterial thrombosis (see section 4.4 Special) Fibrinolytic conditions following consumption coagulopathy except in those with predominant activation of the fibrinolytic system with acute severe bleeding (see section 4.4) Severe renal impairment (risk of accumulation) History of convulsions Intrathecal and intraventricular injection, intracerebral application (risk of cerebral oedema and convulsions) 4.4 Special warnings and precautions for use The indications and method of administration indicated above should be followed strictly: • Intravenous injections should be given very slowly • Tranexamic acid should not be administered by the intramuscular route. Convulsions Cases of convulsions have been reported in association with tranexamic acid treatment. In coronary artery bypass graft (CABG) surgery, most of these cases were reported following intravenous (i.v.) injection of tranexamic acid in high doses. With the use of the recommended lower doses of TXA, the incidence of post-operative seizures was the same as that in untreated patients. Visual disturbances Attention should be paid to possible visual disturbances including visual impairment, vision blurred, impaired colour vision and if necessary the treatment should be discontinued. With continuous long-term use of TXA solution for injection, regular ophthalmologic examinations (eye examinations including visual acuity, colour vision, fundus, visual field etc.) are indicated. With pathological ophthalmic changes, particularly with diseases of the retina, the physician must decide after consulting a specialist on the necessity for the long-term use of TXA solution for injection in each individual case. Haematuria In case of haematuria from the upper urinary tract, there is a risk for urethral obstruction. Thromboembolic events Before use of TXA, risk factors of thromboembolic disease should be considered. In patients with a history of thromboembolic diseases or in those with increased incidence of thromboembolic events in their family history (patients with a high risk of thrombophilia), Tranexamic acid solution for injection should only be administered if there is a strong medical indication after consulting a physician experienced in hemostaseology and under strict medical supervision (see section 4.3). Tranexamic acid should be administered with care in patients receiving oral contraceptives because of the increased risk of thrombosis (See section 4.5.). Disseminated intravascular coagulation Patients with disseminated intravascular coagulation (DIC) should in most cases not be treated with tranexamic acid (see section 4.3). If tranexamic acid is given it must be restricted to those in whom there is predominant activation of the fibrinolytic system with acute severe bleeding. Characteristically, the haematological profile approximates to the following: reduced euglobulin clot lysis time; prolonged prothrombin time; reduced plasma levels of fibrinogen, factors V and VIII, plasminogen fibrinolysin and alpha-2 macroglobulin; normal plasma levels of P and P complex; i.e. factors II (prothrombin), VIII and X; increased plasma levels of fibrinogen degradation products; a normal platelet count. The foregoing presumes that the underlying disease state does not of itself

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modify the various elements in this profile. In such acute cases a single dose of 1g tranexamic acid is frequently sufficient to control bleeding.. Administration of Tranexamic acid in DIC should be considered only when appropriate haematological laboratory facilities and expertise are available. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Simultaneous treatment with anticoagulants must take place under the strict supervision of a physician experienced in this field. Medicinal products that act on haemostasis should be given with caution to patients treated with tranexamic acid. There is a theoretical risk of increased thrombus-formation potential, such as with oestrogens. Alternatively, the antifibrinolytic action of the drug may be antagonised with thrombolytic drugs. 4.6 Fertility, pregnancy and lactation Women of childbearing potential have to use effective contraception during treatment. Pregnancy: There is insufficient clinical data on the use of tranexamic acid in pregnant women. As a result, although studies in animals do not indicate teratogenic effects, as precaution for use, tranexamic acid is not recommended during the first trimester of pregnancy. Limited clinical of the use of tranexamic acid in different clinical haemorrhagic settings during the second and third trimesters did not identify deleterious effect for the foetus. Tranexamic acid should be used throughout pregnancy only if the expected benefit justifies the potential risk. Breastfeeding: Tranexamic acid is excreted in human milk. Therefore, breastfeeding is not recommended. Fertility: There are no clinical data on the effects of Tranexamic acid on fertility. 4.7 Effects on ability to drive and use machines No studies have been performed on the ability to drive and use machines. 4.8 Undesirable effects

The ADRs reported from clinical studies and post-marketing experience are listed below according to system organ class. Tabulated list of adverse reactions Adverse reactions reported are presented in table below. Adverse reactions are listed according to MedDRA primary system organ class. Within each system organ class, adverse reactions are ranked by frequency. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequencies were defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), not know (can not be estimated from the available data).

MedDRA System Organ Class

Frequency Undesirable Effects

Skin and subcutaneous tissue disorders

Uncommon - Dermatitis allergic

Gastrointestinal disorders Common - Diarrhoea - Vomiting - Nausea

Nervous system disorders Not known - Convulsions particularly in case of misuse (refer to sections 4.3 and 4.4)

Eye disorders Not known - Visual disturbances including impaired colour vision

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Vascular disorders Not known - Malaise with hypotension, with or without loss of consciousness (generally following a too fast intravenous injection, exceptionally after oral administration) - Arterial or venous thrombosis at any sites

Immune system disorders Not known - Hypersensitivity reactions including anaphylaxis

4.9 Overdose No case of overdose has been reported. Signs and symptoms may include dizziness, headache, hypotension, and convulsions. It has been shown that convulsions tend to occur at higher frequency with increasing dose. Management of overdose should be supportive. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antihemorrhagics, Antifibrinolytics ATC code: B02AA02 Tranexamic acid exerts an anti haemorrhagic activity by inhibiting the fibrinolytic properties of plasmin. A complex involving tranexamic acid, plasminogen is constituted; the tranexamic acid being linked to plasminogen when transformed into plasmin. The activity of the tranexamic acid-plasmin complex on the activity on fibrin is lower than the activity of free plasmin alone. In vitro studies showed that high tranexamic dosages decreased the activity of complement. Paediatric population In children over one year old: Literature review identified 12 efficacy studies in paediatric cardiac surgery which have included 1073 children, 631 having received tranexamic acid. Most of them were controlled versus placebo. Studied population was heterogenic in terms of age, surgery types, dosing schedules. Study results with tranexamic acid suggest reduced blood loss and reduced blood product requirements in paediatric cardiac surgery under cardiopulmonary bypass (CPB) where there is a high risk of haemorrhage, especially in cyanotic patients or patients undergoing repeat surgery. The most adapted dosing schedule appeared to be: - first bolus of 10 mg/kg after induction of anaesthesia and prior to skin incision, - continuous infusion of 10 mg/kg/h or injection into the CPB pump prime at a dose adapted on the CPB procedure, either according to a patient weight with a dose of 10 mg/kg dose, either according to CPB pump prime volume, last injection of 10 mg/kg at the end of CPB. While studied in very few patients, the limited data suggest that continuous infusion is preferable, since it would maintain therapeutic plasma concentration throughout surgery. No specific dose-effect study or PK study has been conducted in children. 5.2 Pharmacokinetic properties Absorption Peak plasma concentrations of tranexamic acid are obtained rapidly after a short intravenous infusion after which plasma concentrations decline in a multi-exponential manner. Distribution The plasma protein binding of tranexamic acid is about 3% at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is about 9 to 12 liters. Tranexamic acid passes through the placenta. Following administration of an intravenous injection of 10 mg/kg to 12 pregnant women, the concentration of tranexamic acid in serum ranged 10-53 μg/mL while that in cord blood ranged 4-31 μg/mL. Tranexamic acid diffuses rapidly into joint fluid and the synovial membrane. Following administration of an intravenous injection of 10 mg/kg to 17 patients undergoing knee surgery, concentrations in the joint fluids were similar to those seen

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in corresponding serum samples. The concentration of tranexamic acid in a number of other tissues is a fraction of that observed in the blood (breast milk, one hundredth; cerebrospinal fluid, one tenth; aqueous humor, one tenth). Tranexamic acid has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration. Excretion It is excreted mainly in the urineas unchanged drug. Urinary excretion via glomerular filtration is the main route of elimination. Renal clearance is equal to plasma clearance (110 to 116 mL/min). Excretion of tranexamic acid is about 90% within the first 24 hours after intravenous administration of 10 mg/kg body weight. Elimination half-life of tranexamic acid is approximately 3 hours Special populations Plasma concentrations increase in patients with renal failure. No specific PK study has been conducted in children. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. Epileptogenic activity has been observed in animals with intrathecal use of tranexamic acid. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients [To be completed nationally] 6.2 Incompatibilities [To be completed nationally] 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container [To be completed nationally] 6.6 Special precautions for disposal and other handling [To be completed nationally] 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT

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[To be completed nationally]

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PACKAGE LEAFLET

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PACKAGE LEAFLET

Package leaflet: Information for the patient

<Tranexamic acid – containing medicinal products>

<[See Annex I - To be completed nationally]> Read all of this leaflet carefully before you are given 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 nurse. - If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. What is in this leaflet 1. What <Tranexamic acid – containing medicinal products> <Tranexamic acid – containing medicinal products> is and what it is used for 2. What you need to know before you are given <Tranexamic acid – containing medicinal products> 3. How to take <Tranexamic acid – containing medicinal products> 4. Possible side effects 5. How to store <Tranexamic acid – containing medicinal products> 6. Contents of the pack and other information 1. What <Tranexamic acid – containing medicinal products> is and what it is used for <Tranexamic acid – containing medicinal products> contains tranexamic acid which belongs to a group of medicines called antihaemorragics; antifibrinolitics, aminoacids. <Tranexamic acid – containing medicinal products> is used in adults and children above one year of age for the prevention and treatment of bleeding due to a process that inhibits blood clotting called fibrinolysis. Specific indications include: - Heavy periods in women - Gastrointestinal bleeding - Haemorrhagic urinary disorders, further to prostate surgery or surgical procedures affecting the urinary tract - Ear, nose, or throat surgery heart, abdominal, or gynecological surgery bleeding after you have been treated with another medicine to break down blood clots. 2. What you need to know before you are given <Tranexamic acid – containing

medicinal products> Do not take <Tranexamic acid – containing medicinal products> if you:

are allergic to tranexamic acid or any of the other ingredients of this medicine (listed in section 6)

have currently a disease leading to blood clots have a condition called ‘consumption coagulopathy’ where blood in the whole

body starts to clot have kidney problems. have a history of convulsions.

Due to the risk of cerebral oedema and convulsions, intrathecal and intraventricular injection and intracerebral application are not recommended. If you think any of these apply to you, or if you are in any doubt at all, tell your doctor before taking <Tranexamic acid – containing medicinal products>. Warnings and precautions Tell your doctor if any of these apply to you to help him or her decide if <Tranexamic acid – containing medicinal products> is suitable for you:

If you have had blood in your urine <Tranexamic acid – containing medicinal products> it may be lead to urinary tract obstruction.

If you have a risk of having blood clots.

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If you have excessive clotting or bleeding throughout your body (disseminated intravascular coagulation), <Tranexamic acid – containing medicinal products> may not be right for you, except if you have acute severe bleeding and blood test have shown the process that inhibits blood clotting called fibrinolysis is activated.

If you have had convulsions, <Tranexamic acid – containing medicinal products> should not be administered. Your doctor must use the minimal dose possible to avoid convulsions following treatment with <Tranexamic acid – containing medicinal products>

If you are on a long-term treatment with X, attention should be paid to possible disturbances of colour vision and if necessary the treatment should be discontinued. With continuous long-term use of <Tranexamic acid-containing medicinal products> solution for injection, regular ophthalmologic examinations (eye examinations including visual acuity, colour vision, fundus, visual field etc.) are indicated. With pathological ophthalmic changes, particularly with diseases of the retina, your doctor must take a decision after consulting a specialist on the necessity for the long-term use of <Tranexamic acid-containing medicinal products> solution for injection in your case.

Other medicines and <Tranexamic acid – containing medicinal products> Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription, vitamins, minerals, herbal medicines or dietary supplements. You should specifically tell your doctor if you take: other medicines that help blood to clot called antifibrinolytic medicines medicines that prevent blood clotting, called thrombolytic medicines oral contraceptives Pregnancy and breast-feeding Ask your doctor for advice if you are pregnant or breast-feeding before taking <Tranexamic acid – containing medicinal products>. Tranexamic acid is excreted in human milk. Therefore, the use of <Tranexamic acid – containing medicinal products> during breast-feeding is not recommended. Driving and using machines No studies have been performed on the ability to drive and use machines. 3. How to take Use in Adults <Tranexamic acid – containing medicinal products>solution for injection will be given to you by slow injection into a vein. Your doctor will decide the correct dose for you and how long you should take it. Use in children If <Tranexamic acid – containing medicinal products> solution for injection is given to a child from one year, the dose will be based on the child’s weight. Your doctor will decide the correct dose for the child and how long he/she should take it. Use in elderly No reduction in dosage is necessary unless there is evidence of renal failure. Use in patients with kidney problem If you a kidney problem, your dose of tranexamic acid will be reduced according to a test performed on your blood (serum creatinine level). Use in patients with hepatic impairment No reduction in dosage is necessary. Method of administration <Tranexamic acid – containing medicinal products> should only be administrated slowly into a vein. <Tranexamic acid – containing medicinal products> must not be injected into a muscle. If you are given more <Tranexamic acid – containing medicinal products> than the recommended dose

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If you are given more <Tranexamic acid – containing medicinal products> than the recommended dose you may experience a transitory blood pressure lowering. Talk to a doctor or pharmacist immediately. 4. Possible side Effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Side effects reported with <Tranexamic acid – containing medicinal products> are: The following side effects have been observed with <Tranexamic acid – containing medicinal products> Common (may affect up to 1 in 10 users)

effects on the stomach and intestines: nausea, vomiting, diarrhoea

Uncommon (may affect 1 to 10 in 1000 users) effects on the skin problems : rash

Not know (frequency cannot be estimated from the available data)

malaise with hypotension (low blood pressure), especially if the injection is given too quickly

blood clots effects on the nervous system: convulsions effects on the eyes : vision disturbances including impaired color vision effects on the immune system : allergic reactions

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. How to store <Tranexamic acid – containing medicinal products> [To be completed nationally] 6. Contents of the pack and other information What <Tranexamic acid – containing medicinal products> contains [To be completed nationally] What <Tranexamic acid – containing medicinal products> looks like and contents of the pack [To be completed nationally] Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}> This leaflet was last revised in <{MM/YYYY}> <{month YYYY}>. [To be completed nationally]