PUBLIC ASSESSMENT REPORT Decentralised Procedure Tranexamsäure Carino 100 mg/ml Injektionslösung Procedure Number: DE/H/3730/001/DC Active Substance: Tranexamic acid Dosage Form: Solution for injection Marketing Authorisation Holder in the RMS, Germany: Carinopharm GmbH Publication: 23.03.2020 This module reflects the scientific discussion for the approval of Tranexamsäure Carino 100 mg/ml Injektionslösung. The procedure was finalised on 13.03.2014. TABLE OF CONTENTS I. INTRODUCTION ......................................................................................................................... 4 II. EXECUTIVE SUMMARY ....................................................................................................... 4 II.1 Problem statement ..................................................................................................................... 4 II.2 About the product ..................................................................................................................... 4 II.3 General comments on the submitted dossier .......................................................................... 6 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles .. 7 III. SCIENTIFIC OVERVIEW AND DISCUSSION ................................................................... 7 III.1 Quality aspects ........................................................................................................................... 7 III.2 Non-clinical aspects ................................................................................................................... 8 III.3 Clinical aspects .......................................................................................................................... 8 IV. BENEFIT RISK ASSESSMENT ........................................................................................... 11 V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION ................................................................................................................................. 12 V.1 Proposed list of follow-up measures and specific obligations / positive benefit risk assessment ............................................................................................................................................ 12 Tranexamsäure Carino 100 mg/ml Injektionslösung DE/H/3730/001/DC Public Assessment Report Page 2/12 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Tranexamsäure Carino 100 mg/ml Injektionslösung product(s) in the RMS INN (or common name) of the active Tranexamic acid substance(s): Pharmaco-therapeutic group B02AA02 (ATC Code): Pharmaceutical form(s) and Solution for injection 100mg/ml strength(s): Reference Number(s) for the DE/H/3730/001/DC Decentralised Procedure Reference Member State: Germany Member States concerned: DK; FI; NO; SE; UK Marketing Authorisation Holder Carinopharm GmbH (name and address) Bahnhofstr. 18 31008 Elze Germany Names and addresses of Haupt Pharma Wülfing GmbH manufacturer(s) responsible for Bethelner Landstr. 18 batch release in the EEA 31028 Gronau Germany Tranexamsäure Carino 100 mg/ml Injektionslösung DE/H/3730/001/DC Public Assessment Report Page 3/12 I. INTRODUCTION Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for Tranexamsäure Carino 100 mg/ml Injektionslösung in the treatment of “Prevention and treatment of haemorrhages due to general or local fibrinolysis in adults and children from one year.“ is approved since the applicant commits to perform a number of post- authorization follow-up measures to be reported back to the RMS and CMS within predefined timeframes. A preliminary list of such follow-up measures is presented in section V of this report. II. EXECUTIVE SUMMARY II.1 Problem statement Not applicable. II.2 About the product Tranexamic acid was originally approved in France in 1969 and has been marketed in this country since 1971. The product is now approved in over 30 countries through national procedures and is currently marketed in most of them (HMA 2009, Martindale 2012). Tranexamic acid was approved as Cyklokapron Injection in 1987 in the UK (Pharmacia 2011) and as Cyklokapron Injektionslösung in 2005 in Germany (Pfizer 2010). An oral tablet formulation of tranexamic acid was approved in 1983 in the UK (Meda 2011). In the USA, tranexamic acid was originally approved as parenteral and oral formulations (Cyclokapron) by the FDA in 1986 (Gold-Standard 2012). After discontinuation of the oral formulation, a second oral formulation (Lysteda) was approved by the FDA for the treatment of cyclic heavy menstrual bleeding in 2009. With Germany as the Reference Member State in this Decentralised Procedure, Carinopharm GmbH applied for the Marketing Authorisations for TRX Carino in DK, FR, NO, SE, and UK. Mode of action: Tranexamic acid is a synthetic lysine derivative and an antifibrinolytic agent that is able to form a reversible complex with plasminogen. Through binding to plasminogen, tranexamic acid prevents the binding of plasminogen to the surface of fibrin, thus retarding fibrinolysis. The left diagram in Figure 1 shows the activation of plasminogen on the fibrin surface. Plasminogen binds to fibrin at a lysine-binding site and is changed to plasmin, its activated form. Plasmin degrades fibrin into fibrin-degradation products. In the right diagram, tranexamic acid (or aminocaproic acid) blocks the lysine-binding site on plasminogen, which is essential for binding to fibrin, and thereby prevents the activation of plasminogen on the surface of fibrin, although plasmin generation does occur. When the binding site of plasmin is blocked by tranexamic acid, inactivation by α2-antiplasmin cannot proceed. Tranexamsäure Carino 100 mg/ml Injektionslösung DE/H/3730/001/DC Public Assessment Report Page 4/12 Figure 1 Antifibrinolytic action of tranexamic acid and aminocaproic acid (Mannucci 1998) Comparisons of the binding potencies of tranexamic acid and EACA in fibrinolytic test systems have shown tranexamic acid to be more potent by a factor of between 6 and 10 (Dunn and Goa 1999). Tranexamic acid competitively inhibits the activation of trypsinogen by enterokinase and, at concentrations 4 times greater, noncompetitively inhibits the proteolytic action of trypsin. The drug also weakly inhibits thrombin. The noncovalent interactions between plasminogen/plasmin and other macromolecules such as fibrin are mediated by a series of 5 triple disulphide-bonded plasmin(ogen) domains called kringles, each of which has a single binding site for lysine analogues (Dunn and Goa 1999). Both tranexamic acid and EACA appear to interact with kringle 5 (Anonick et al. 1992). Tranexamic acid add binds with high affinity (dissociation constant Kd =1.1 µM) to one lysine binding site on plasminogen and with low affinity (Kd = 750 µM/L) to the four or five other sites (McCormack 2012).Tranexamic acid almost completely blocks the binding of plasminogen or the heavy chain of plasmin to fibrin, primarily through binding to the high-affinity lysine binding site of plasminogen. Although plasminogen may still be converted to plasmin in the presence of a plasminogen activator, such as tPA, after binding to tranexamic acid, it can no longer interact with and digest fibrin. Tranexamic acid also blocks the binding of α2-antiplasmin to plasmin and its inactivation of plasmin. Pharmacological classification: Tranexamic acid is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin, by binding to specific sites of both plasminogen and plasmin, a molecule responsible for the degradation of fibrin, which is a protein that forms the framework of blood clots. In contrast to Aprotinin it has no plasmin neutralizing efficacy and acts as an indirect antifibrinolytic agent. ATC-Code: B02AA02 Claimed indication and recommendation for use (including a possible risk management strategy) and posology. Tranexamic acid is indicated for the “prevention and treatment of haemorrhages due to general or local fibrinolysis in adults and children from one year. Specific indications include: Tranexamsäure Carino 100 mg/ml Injektionslösung DE/H/3730/001/DC Public Assessment Report Page 5/12 - 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.” Tranexamic acid’s posology in Adults differs with respect to the tpye of hyperfibirnolytic bleeding: The following doses are recommended: 1. Standard treatment of local fibrinolysis: 0.5 g (1 ampoule of 5 mL) to 1 g (1 ampoule of 10 mL or 2 ampoules 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 ampoule of 10 mL or 2 ampoules of 5 mL) tranexamic acid by slow intravenous injection (= 1 mL/minute) every 6 to 8 hours, equivalent to 15 mg/kg BW Dose reduction in patients with renal impairment is recommended, while no dose reduction