Regarding amendments to the package leaflets of medicinal products containing tranexamic acid

In accordance with paragraph 8 of Section IV of the Procedure for Expert Evaluation, the applicant must amend the instructions for medical use of the medicinal product upon receipt of new data, including bringing the instructions for medical use into line with the approved instructions for medical use of the original (reference) medicinal product, and ensure that the information on the medicinal product corresponds to current scientific knowledge.

The previous publication can be found on the website of the State Expert Center of the Ministry of Health of Ukraine at the following link:

https://www.dec.gov.ua/materials/zminy-informacziyi-z-bezpeky-likarskyh-zasobiv-shho-mistyat-traneksamovu-kyslotu-tranexamic-acid-za-rezultatamy-zasidannya-komitetu-z-oczinky-ryzykiv-u-farmakonaglyadi-prac-vid-27-30-zh/?role=applicant

https://www.dec.gov.ua/materials/zminy-informacziyi-z-bezpeky-likarskyh-zasobiv-shho-mistyat-traneksamovu-kyslotu-tranexamic-acid-za-rezultatamy-zasidannya-komitetu-z-oczinky-ryzykiv-u-farmakonaglyadi-prac-vid-27-30-zh-2/?role=doctors

The Pharmacovigilance Risk Assessment Committee (PRAC), based on the evaluation of periodic safety update reports (PSURs) for medicinal products containing tranexamic acid, PSUSA/00003006/202503, reached the following conclusions.

Risk of medication errors with intravenous forms of tranexamic acid associated with an incorrect route of administration of the medicinal product

In view of the available data on adverse reactions, including fatal cases, that occurred because of the wrong route of administration of a medicinal product by the intrathecal route, the PRAC considers that the instructions for medical use of medicinal products containing tranexamic acid for intravenous use should inform healthcare professionals and raise awareness of the nature of medication errors that have occurred in the post-marketing period with the use of tranexamic acid, and of the associated harm, especially with regard to intrathecal administration. It is also considered that healthcare professionals should be given recommendations on measures to minimize the risk of the wrong route of administration. In view of the risk of serious health consequences and fatal cases when medicinal products not intended for epidural use are administered by this route, one more contraindication should also be added to the existing ones regarding epidural administration of the medicinal product. In addition, in view of the role of medicinal product packaging in conveying important safety information, it is recommended to amend the information on the outer packaging in order to emphasize the details of the correct route of administration.

PRAC has concluded that the registration materials of medicinal products containing tranexamic acid for intravenous use should be amended accordingly.

Acute renal cortical necrosis

Given the data in the literature on acute renal cortical necrosis and spontaneous reports, including in some cases a close temporal relationship, and given the likely mechanism of action, PRAC considers that a causal relationship between the use of tranexamic acid and the development of acute renal cortical necrosis is at least reasonably possible. PRAC concluded that the information for medical use of medicinal products containing tranexamic acid should be changed accordingly.

Fixed drug eruption

In view of the available data on fixed drug eruption from the literature and spontaneous reports, including in some cases a close temporal relationship, a positive reaction to withdrawal of the medicinal product (de-challenge) and/or a positive reaction to re-administration (re-challenge), as well as the likely mechanism of action, the PRAC considers that a causal relationship between the use of tranexamic acid and the development of fixed drug eruption is, at a minimum, quite probable. The PRAC concluded that the instructions for medical use of medicinal products containing tranexamic acid should be amended accordingly.

Having considered the PRAC recommendations, the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) agrees with the overall conclusions of the PRAC and the grounds for the recommendations.

Based on the scientific conclusions on tranexamic acid, the CMDh considers that the benefit/risk balance of medicinal products containing tranexamic acid remains unchanged, provided that the proposed amendments are made to the instructions for medical use.

Changes to be made to the relevant sections of the instruction for medical use (new text underlined and in bold, deleted text struck through).

Tranexamic acid for intravenous use

Section "Dosage and Administration"

Warnings and precautions should be added as follows:

Route of administration

TRANEXAMIC ACID MUST BE ADMINISTERED ONLY INTRAVENOUSLY and must not be administered intrathecally or epidurally* (see sections “Contraindications” and “Special warnings and precautions for use”).

IN ORDER TO REDUCE THE RISK OF FATAL MEDICATION ERRORS ASSOCIATED WITH THE INCORRECT ROUTE OF ADMINISTRATION OF TRANEXAMIC ACID, IT IS STRONGLY RECOMMENDED TO LABEL SYRINGES CONTAINING TRANEXAMIC ACID (see sections “Contraindications”, “Special warnings and precautions for use”, and “Special precautions for disposal and other handling of the medicinal product”).

*This sentence should be in bold type

“Contraindications” section

The contraindications should be changed as follows:

Intrathecal, epidural, and intraventricular injections, as well as intracerebral administration (risk of cerebral edema, seizures, and fatal outcome).

“Special precautions for use” section

The following warning should be added:

Risk of medication errors due to incorrect route of administration.

<Name of the medicinal product> is intended exclusively for intravenous administration. Intrathecal, epidural, intraventricular, and intracerebral administration of <Name of the medicinal product> is contraindicated (see section “Contraindications”). Serious adverse reactions, including fatal cases, have been reported with accidental intrathecal administration of tranexamic acid. These include severe pain in the back, gluteal muscles, and lower extremities, myoclonus and generalized seizures, as well as cardiac arrhythmias.

Care should be taken to ensure the correct route of administration of <Name of the medicinal product>. Healthcare professionals should be aware of the possibility of confusing <Name of the medicinal product> with other injectable products, which may lead to accidental intrathecal administration of <Name of the medicinal product>. This applies in particular to intrathecally administered injectable medicinal products that may be used during the same procedure as tranexamic acid.

Syringes containing <Name of the medicinal product> must be clearly labeled, indicating the intravenous route of administration.

Section “Special precautions for disposal and other handling of the medicinal product”

The warning should be added as follows:

Healthcare professionals are strongly advised to label syringes with <Name of the medicinal product> when drawing up the medicinal product from <X> for clear identification and the correct route of administration, to help prevent inadvertent medication errors during administration to the patient.”

Information to be stated on the outer packaging

If such wording or its equivalents are absent, the following wording should be added (the placement, layout, and color of the text are to be agreed with the national competent authorities):

For intravenous use only. NOT intended for intrathecal/epidural use.

All dosage forms of tranexamic acid

“Adverse reactions” section

If the adverse reaction “Acute renal cortical necrosis” is already listed in the “Adverse reactions” section with a different frequency, the existing frequency should be left unchanged.

The following adverse reaction should be added to the SOC “Renal and urinary disorders” with frequency “not known”, if such wording or an equivalent is not already present:

Acute renal cortical necrosis

If the adverse reaction “Fixed drug eruption” is already listed in the “Adverse reactions” section with a different frequency, the existing frequency should be retained.

The following adverse reaction should be added to SOC “Skin and subcutaneous tissue disorders” with the frequency “not known”:

Fixed drug eruption

TO ANALYZE THE PUBLISHED INFORMATION AND SUBMIT THE RELEVANT APPLICATION FOR AMENDMENTS TO THE REGISTRATION MATERIALS, THE APPLICANT MUST USE THE ORIGINAL TEXT AVAILABLE AT THE FOLLOWING LINKS: