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

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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

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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.

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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 K d =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:
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- 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 is
necessary in elderly patients or patients with hepatic impairment.

In the paediatric population children from 1 year, treated for current approved indications, the
recommended 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.

II.3 General comments on the submitted dossier

This application is for a 'generic' form of Tranexamic Acid as a Solution for Injection. It is an abridged
application submitted under Article 10(1) of Directive 2001/83/EC as amended, according to which in
derogation of Article 8(3)(i) "[t]he applicant shall not be required to provide the results of
toxicological and pharmacological tests or the results of clinical trials". An abridged application is
appropriate since the product is a 'generic medicinal product' as Defined by article 10.2(b) of directive
2001/83/EC as amended of the reference product Cyklokapron.
As such it was necessary to show that the finished Tranexamic Acid for Injection product in this
application is essentially similar to the innovator finished product. On this basis, the whole
information on clinical (and pharmaco-toxicological) experience can be transferred from the originator
product to the product of this application.

The degree of scientific and clinical interest in tranexamic acid is reflected by more than 2,000
publications referenced in the Medline database, and the coherence of scientific assessments is
evidenced by corresponding monographs on tranexamic acid in current pertinent pharmaceutical
compendia (Gold-Standard 2012, Martindale 2012b) and by its updated Summary of Product
Characteristics (EMA 2012a) following a recent review of fibrinolytic agents by the European
Medicines Agency (EMA) (EMA 2012b.
As the applied product is given intravenously, bioavailability is 100% and demonstration of
bioequivalence to other products in a bioequivalence trial is dispensable.

The applicant followed the relevant CHMP guidance documents. In particular, the product information
was completely harmonized with the published recommendation of CHMP as a result for an Art.31
procedure, recently finalized.
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There is no need for paediatric development and development in other special populations such as the
elderly, male/female and ethnic minorities as in general information available after several decades is
sufficient to conclude. Some open issues with respect to administration in the paediatric population
might be clarified during on-going academic clinical studies on this field of research.

In conclusion, the current stage of knowledge concerning tranexamic acid is sufficiently reflected in
the documentation submitted for this application.

The active substance is not considered a new active substance.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical
principles

The RMS has been assured that acceptable standards of GMP are in place for these product types at all
sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer
authorisations issued by inspection services of the competent authorities as certification that
acceptable standards of GMP are in place at those sites.

GLP: not applicable

GCP: not applicable

III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Drug substance
The drug substance Tranexamic acid is described in the Ph. Eur. monograph no. 875.
The manufacturer of the drug substance has granted a Certificate of Suitability to the Monograph
“Tranexamic acid” from the EDQM.
Tranexamic acid is controlled in accordance with the Ph. Eur. monograph “Tranexamic acid” and
additional requirements regarding microbiological quality. Batch results of the drug substance
demonstrate compliance with the requirements of the Ph. Eur. Monograph.
Stability data have been provided for the drug substance. A retest period of 24 months in the
designated packaging material is documented for tranexamic acid.

Drug Product
The drug product has been developed as a generic medicinal product with respect to the originator
Cyclokapron-Injection 100mg/ml solution for injection from Pharmacia Limited.
It is an aqueous solution for intravenous use, which contains 100mg of the drug substance Tranexamic
acid per ml. The excipients are water for injections and hydrochloric acid (for pH adjustment if
necessary). Two presentations are proposed: Glass ampoules with a nominal volume of 5ml, resp.
10ml.
The manufacturing process has been described and the critical steps are identified. The manufacturing
process involves dissolving of Tranexamic acid, which is freely soluble in water, in water for
injections and adjustment of the pH, if necessary. The solution is filtered using a suitable membrane
filter with a nominal pore size of 0.2 µm and is then filled into ampoules. The product is sterilised in
its final container according to the standard method of the Ph. Eur. with moist heat at 121°C for 15
minutes.

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No process validation data of the manufacturing process are provided, which is considered acceptable
as the manufacturing process can be regarded as a standard method of manufacture and the critical
process parameters are evaluated. For manufacture of batches of the proposed production scale (240 l
or 550 l) a validation scheme is submitted.
Product specifications and validations of the analytical methods have been provided. Two batches of
each presentation in pilot scale met the requirements of the release specification.
The drug product is filled into OPC-ampoules consisting of colourless glass of type I according to the
Ph. Eur. with a nominal volume of 5ml, resp. 10ml.
The conditions used in the stability study are in accordance with the ICH stability guideline.
Stability data of the a. m. two batches of each presentation in pilot scale are provided. Up to now the
stability data cover a storage time of 24 months under long term and 6 months under accelerated
conditions.
On the basis of the currently submitted stability data a shelf life 36 months is accepted, since the
applicant has committed himself to submit the stability results covering the complete shelf life via
variation procedure as soon as these stability results will be available.
A stability commitment on production scale batches in accordance with the relevant stability
Guideline is provided.
Conclusion:
The chemical-pharmaceutical documentation and Expert Report are of sufficient quality in view of the
present European regulatory requirements.
Three Follow-up measures and Specific obligations are listed in section V.1 ‘Final list of follow-up
measures and specific obligations / positive benefit risk assessment’.

III.2 Non-clinical aspects

Pharmacology, pharmacokinetics and toxicology of Tranexamic acid for intravenous injection are well
known. No new nonclinical data have been provided and non is required.
Concerning local tolerance, reference can be made to clinical data and experience with Tranexamic
acid, because the qualitative and quantitative composition of the finished product is identical with the
Originator Cyclocapron.

An Environmental Risk Assessment has not been provided, which is accepted (generic substitution,
product for prescription).

Non-clinical section of the product information is in line with the updated SmPC of the originator
product Cyclocapron, dated December 2012, and in accordance with the latest version of the Guideline
on SmPC.

There are no outstanding issues from the non-clinical point of view.

III.3 Clinical aspects

Tranexamic acid is a lysine analogue used for several decades in Europe and worldwide in the
bleeding linked to local or general fibrinolysis. This product is authorised in the majority of European
countries through national procedure; however the authorised indications are different between
countries.
The use of antifibrinolytic medicinal product is closely linked to the necessity of blood transfusion.
The benefit of blood transfusions is clearly recognized in life-threatening situations of critical blood
loss. Thus antifibrinolytic agents and blood transfusion can be considered complementary in the
management of blood loss. The risk benefit relation for Tranexamic acid was recently again reviewed

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in the EU and CHMP concluded that in the indication currently applied for TXA Carino the risk
benefit is positive.
An EU-harmonized wording for the product information including those indication in which data is
sufficient to assess a positive benefit-risk relation, was recently approved by CHMP. The
recommended wording is in full accordance with the applied SmPC and PIL for this procedure.

Pharmacokinetics

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 litres.
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
micrograms/mL while that in cord blood ranged 4-31 micrograms /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 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 urine as 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.

Pharmacodynamics
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.

Clinical efficacy
In adults, the clinical benefit of tranexamic acid used parenterally to reduce blood loss during surgery
or other hemorrhagic circumstances and the need of blood transfusions has been appropriately
demonstrated by randomised clinical trials and meta-analysis versus placebo or active comparator
(aprotinin) in the following indications linked to general or local fibrinolysis: menorrhagia and
metrorrhagia, gastrointestinal bleeding, haemorrhagic urinary disorders, ENT, cardiovascular,
abdominal or gynaecological surgery and for haemorrhage due to the administration of a fibrinolytic
effect.
Moreover, based on the review of the paediatric data during the recent article 45 procedure, a positive
benefit-risk profile has been identified in paediatric cardiac surgery for children over one year old.
These data did not lead to a specific indication but were considered sufficient for mentioning the use
of TXA in paediatric cardiac surgery in section 5.1 of the SmPC.
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However, with refer to CHMP’s opinion the concerns still remain regarding several indications
already authorised in some member states, due to the lack of robust clinical data to sustain such use:
orthopedic surgery, hereditary angioneurotic oedema, prevention and treatment of hemorrhages in
association with leukaemia, hemorrhage associated with disseminated intravascular coagulopathy,
allergic dermatoses, hyphema, and a specific use prevention of bleeding in patients with congenital
bleeding disorders. Consequently, to CHMP’s point of view, these indications should not be
maintained anymore in section 4.1 of the SPC. The applicant has followed CHMP’s recommendation
completely with respect to this issue.

Clinical safety
Risk
As regard to the safety profile of tranexamic acid, worldwide extensive post-marketing experiences is
available. Taking into account the summary of the recently finalized Art.31 procedure the review of
safety data on tranexamic acid provided does not raise the new safety concern, which is not included
in the SmPC. On the whole, the number of reported adverse events seems to be very low given the
long period of patient exposure and the number of vials sold worldwide. No increased risk of mortality
was observed.
The following adverse events of interest have to be stressed: thromboembolic events, convulsions,
cases of impaired colour vision and other visual disturbances. Moreover tranexamic acid should be
given with caution in patients on oral contraceptives due to the increased risk of thrombosis.

Pharmacovigilance system
The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed
Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File
fully complies with the new legal requirements as set out in the Commission Implementing Regulation
and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan

Table 1. Summary of safety concerns

Summary of safety concerns

Important identified risks  Arterial and venous thrombosis

 Convulsions
 Visual disturbances (including vision blurred
and impaired colour vision)
 Anaphylaxis/severe hypersensitivity
reactions
Important potential risks  Accumulation/Overdosage in severe renal
impairment
 Prolonged shock in patients with
disseminated intravascular coagulation (DIC)
 Urethral obstruction in patients with
haematuria
 Off-label use (intrathecal, intraventricular or
intracerebral application)
Missing information  Safety in pregnancy
 Information on interaction with other
medicinal products
The Applicant has provided an RMP (version 4.0) in full compliance with GVP module V.
Neither additional pharmacovigilance measures nor additional risk minimisation measures were
proposed for the safety concerns which is acceptable. The RMP including the summary for public is
approvable.

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Periodic Safety Update Report (PSUR)
Tranexamic acid is included in the EURD list with currently no need for generics to submit routine
PSURs. The MAH should therefore only submit PSURs if indicated in the EURD-list.

Common renewal date

A proposed common renewal date of 5 years after finalisation of the procedure was accepted.

Legal status
Medicinal product subject to medical prescription.

User Test
The RMS agrees with the applicant that a readability test is dispensable as the product information is
in full accordance with CHMP’s recently published proposal for the PL of Tranexamic acid products.

IV. BENEFIT RISK ASSESSMENT

The application contains an adequate review of published clinical data. From a clinical point of view
the efficacy and safety of Tranexamic acid is well-established since it’s initial approval in France in
1969. As Tranexamic acid is administered intravenously bioavailability is 100 %, no demonstration of
bioequivalence is necessary.
The applied therapeutic indications are in full accordance with those included in the final SmPC and
PIL of the finalized Art. 31 procedure for Tranexamic acid and other antifibrinolytics in the EU.

From quality point of view Tranexamsäure Carino 100 mg/ml Injektionslösung can be approved.

The benefit-risk relation in these applied and EU-harmonized indications is positive.

Furthermore, SmPC and PIL of this procedure are now in full accordance with the harmonized
proposal for TXA product information in the EU following the recent finalization of an Art. 31
procedure for Antifibrinolytics.

Insofar, the wording of the product information is fully acceptable.

The application is approved. For intermediate amendments see current product information.

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V. PROPOSED CONDITIONS FOR MARKETING
AUTHORISATION AND PRODUCT INFORMATION

V.1 Proposed list of follow-up measures and specific obligations / positive benefit
risk assessment

Follow-up measures:
Area1 Description
Quality: 1. The ongoing stability studies will be continued as
scheduled. Once the marketing authorisation will have
been granted two production scale batches of each
ampoule size (5 ml and 10 ml OPC ampoules) will
become the subject of an identical study (only testing in
the original container). Thereafter one batch per year and
ampoule size will be tested according to a reduced
schedule.
2. The applicant should commit himself to present the
results covering the proposed shelf life of the finished
products via separate variation procedure as soon as
possible.
1. Areas: Quality, Non-clinical, Clinical, Pharmacovigilance

Specific Obligations:

Area1 Description
Quality: Stability commitment for production batches
(à 240 litres and 550 litres).
1. Areas: Quality, Non-clinical, Clinical, Pharmacovigilance

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