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Use of tranexamic acid for skin whitening and melasma therapy: a product review.

INTRODUCTION

Tranexemic acid is a competitive inhibitor of plasmin activation, commonly used as a hemostatic agent due to its anti-fibrinolysis action is also promoted as a systemic skin whitening agent particularly as oral or intradermal injections for melasma. Tranexamic acid has become a phenomenon in Malaysia as skin whitening and melasma therapy. Tranexamic acid capsule and can be bought at online resellers without valid prescription.

MALAYSIAN MEDICINE ADVERTISEMENT BOARD GUIDELINES

According to Medicine Advertisement Board (MAB), [1] any advertisements published should have information that is accurate, balanced, be capable of substantiation, fair, informative, objective, reliable, truthful, unambiguous, and up-to-date.

Advertisements published should not contain any misleading or unverifiable information either directly or by implication that is likely to induce unjustifiable medical use or to give rise to undue risks. It is also important that advertisements do not exploit the lack of knowledge and abuse the trust given by the general public. Any approved advertisements by MAB must display KKLIU number. The name, address, and contact number of the advertiser must be clearly stated on the page.

MAB prohibit the advertisement of controlled medicine, poison, and products containing poison pursuant to schedule 1 of the Malaysian Poison Act 1952 unless it is specifically exempted.

Testimonials can be included in the advertisements. However, the individual who provides the testimony must genuinely exist and responsible. The individual must also be accountable to the advertisement and the testimonials given as per say of the indications being approved. Advertisements with testimonial must display the statement: "The effect of the product may vary among individuals."

Any claims regarding the advertised products must be based on the updated evaluation of all evidence and must reflect the evidence accurately and clearly. References of this substantial evidence must be included. All claims should be capable of substantiation either by reference to approved labeling or by scientific evidence from scientifically proven investigations. Such evidence must be readily available and can be reproduced on request.

Hyperboles claims cannot be used to imply or claim or infer the superiority of the advertised product. General public should not be led to overestimate the value of the product by exaggeration or unrealistic claims or statements made by advertisers. Advertisements should not contain exaggerated, improper and misleading claims or visuals to show changes in the human body.

Care should be given to ensure all claims used are related to the approved indication and the degree of severity for which the product is indicated. Claims that the products are free from any side effects should not be implied inside the advertisements.

Even though there are strict and comprehensive guidelines by MAB on advertisements, internet resellers whom selling tranexamic acid capsule illegally never comply with any of these guidelines. Resellers claimed that tranexamic acid can become such a supremacy whitening agent with the false testimonial and hyperboles claiming. There is clearly no KKLIU number and there are no enough data to show the effectiveness of oral tranexamic acid in treating melasma and hyperpigmentation. Putting the illegal advertisement of TransCap on the internet and publicize it to the general public are clearly against the MAB law.

METHODOLOGY

An electronic search of PubMed, MEDLINE and Cochrane Library using the following criteria were carried out [Table 1].

Efficacy and safety

A clinical trial study was conducted by Na et al. with 25 women for 8 weeks in Seoul, South Korea. Volunteers were instructed to take 250 mg tranexamic acid tablets three times a day and apply a tranexamic acid topical agent twice a day for 8 weeks. This study found out that tranexamic acid will reduce epidermal pigmentation that related with melasma and also reversed melasma-related dermal changes, such as vessel number and increased numbers of mast cells. [2]

A clinical trial study carried out by Wu et al. enrolled 74 volunteers in China. Tranexamic acid tablets were prescribed at a dosage of 250 mg twice daily for a therapeutic period of 6 months. All the volunteers were monitored for more than 6 months after the treatment. The effects of treatment were evaluated by two physicians independently and by the patient based on the improvement of pigmentation and reduction in melasma size. The study concluded that oral administration of tranexamic acid is an effective and safe therapy for the treatment of melasma. However, further research on the long-term usage of tranexamic acid is needed (level evidence II). [3]

Preliminary clinical research was studied in Beijing, China with a total number of 35 melasma patients. The total duration of the study was 16 weeks. After evaluation of the testing results, patients were asked to take two tablets of 250 mg tranexamic acid after meal, three times a day for 16 weeks. The patients were advised to avoid excessive sun exposure and to apply the same broad-spectrum sunscreen with a sun protection factor 30. The study concluded that oral compound tranexamic acid is a potentially new and promising therapeutic option. However, a large-scale and multicenter study will be needed to define its long-term benefits and any potential additional adverse effects. [4]

A prospective, interventional, randomized controlled trial was conducted among 260 melasma patients in Nepal. Patients were divided into two groups, control group and intervention group. Each group consists of 130 patients. First group (Group A) was given routine treatment measures and oral tranexamic acid whereas second group (Group B) was treated only with routine topical measures. Capsule tranexamic acid was prescribed at a dose of 250 mg twice a day for 3 months and cases were followed for 3 months. The response was evaluated on the basis of melasma assessment severity index (MASI). Mean scores between the two groups were then compared. Statistically, significant decrease in the mean MASI from baseline to 8 and 12 weeks was observed. The study then suggested that addition of oral tranexamic acid provides rapid and sustained improvement in the treatment of melisma. However, it is not safe to use it for a long period in view of its anti-hemorrhagic property causing side effects such as cerebrovascular accidents, myocardial infarction, pulmonary embolism and venous thromboembolism. It is contraindicated in patients with acquired defective color vision, an active intravascular clotting condition, and hypersensitivity to tranexamic acid. [5]

POTENTIAL RISK TO GENERAL POPULATION

Tranexamic acid was listed under Group B inside Malaysian regulatory classification. [6] Group B medicines can only be prescribed by a registered medical practitioner, dentist, or veterinary surgeon, as the case may be and with the prescription in the correct form as required by the law.

This means tranexamic acid can only be sold with a valid prescription from a registered medical practitioner, dentist, or veterinary surgeon. However, tranexamic acid, a prescription drug is sold to the general public without any valid prescription and supervision from medical healthcare through online. Such action can result in various adverse effects as the usage of tranexamic acid is not being monitored by licensed medical practitioners and can be fatal.

Even though tranexamic acid is already registered in Malaysia as a poison B prescription drug, the approved indications are for hemorrhage associated with excessive fibrinolysis and abnormal bleeding. A tranexamic acid indication as melasma therapy is not approved, and there are not enough scientific data and clinical trials that can support the use of oral administration of tranexamic acid as a whitening agent and melasma therapy for the public's interest. [7,8]

Tranexamic acid with its anti-hemorrhagic property, if being used for long duration can result in side effects such as cerebrovascular accidents, myocardial infarction, pulmonary embolism, and venous thromboembolism. [6] Tranexamic acid is contraindicated in patients with active intravascular clotting condition, acquired defective color vision, thromboembolism, cerebral edema and hypersensitive to tranexamic acid. Tranexamic acid concomitant use with combination hormonal contraceptives can increase the risk of thromboembolism and thrombosis. [9]

The usage of tranexamic acid has been associated with visual disturbances including impaired color vision, visual impairment, and blurring of vision. For patients who are to be treated with tranexamic acid for several weeks, an ophthalmic check-up is advisable, if possible, before treatment is initiated and regularly during treatments. Patients with irregular menstrual bleeding should not use tranexamic acid until the cause of the irregularity has been establish. [8,9]

The safety issues and contraindication were not highlighted by the internet resellers. Claims that Tranexamic acid is safe to be used for all ages and pregnant women are plain hubris. This illegal trend of selling tranexamic acid freely in social network, especially Facebook and Instagram without proper consultation or medical investigation from medical practitioners is illegal and unaccepted.

The recommendations for tranexamic acid are listed in Table 2.

CEDAC has four different types of recommendations: (1) Unrestricted listing, (2) list in a manner similar to other drugs in the class, (3) list with criteria, (4) do not list.

PBAC makes four types of recommendations (1) unrestricted listing, (2) restricted benefit, (3) authority required (the equivalent of prior approval), (4) do not list.

CONCLUSIONS

The need for white and fair skin is a worldwide phenomenon, and it is greatly exploited by both the cosmetic and dermatologic industries.

Topical use of tranexamic acid has been used as a skin whitening agent in numerous leave-on products since 2002, although to which degree is currently unidentified. [8] Use of oral administration of tranexamic acid for melasma therapy has been studied, mostly in Asian countries and even though results from these studies show positive results, there is not enough controlled study and randomized clinical trials were done, especially in other ethnics group for example, Africans and Caucasians that will reflect the world population. The data available are not scientifically proven to demonstrate the role of tranexamic acid as an effective treatment for melasma therapy and whitening agent.

The safety for the use of tranexamic acid in cosmetic products has been examined by the Council of Europe. [10] It was concluded that due to the lack of data it was not possible to reach a conclusion on the use of tranexamic acid in cosmetic products, especially with systematic usage.

Therefore, firm regulations should be imposed to prohibition the use of these agents until well-conducted randomized controlled trials are available ensuring the safety and efficacy of these agents. Internet resellers that are selling prescription drugs should be brought to justice.

DOI: 10.4103/2045-080X.183037

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

For reprints contact: reprints@medknow.com

Financial support and sponsorship

This work was supported by Research Acculturation Grant Scheme: RAGS/1/2014/SKK07/UITM//7. The authors would like to express their gratitude to Ministry of Higher Education and Universiti Teknologi MARA (UiTM), Malaysia for financial support for this research.

Conflicts of interest

There are no conflicts of interest.

REFERENCES

[1.] Ministry Of Health M. Guideline on Advertising of Medicines and Medicinal Products to General Public: Medicine Advertisements Board in MAB; 2015.

[2.] Na JI, Choi SY, Yang SH, Choi HR, Kang HY, Park KC. Effect of tranexamic acid on melasma: A clinical trial with histological evaluation. J Eur Acad Dermatol Venereol 2013; 27:1035-9.

[3.] Wu S, Shi H, Wu H, Yan S, Guo J, Sun Y, et al. Treatment of melasma with oral administration of tranexamic acid. Aesthetic Plast Surg 2012; 36:964-70.

[4.] Li Y, Sun Q, He Z, Fu L, He C, Yan Y. Treatment of melasma with oral administration of compound tranexamic acid: A preliminary clinical trial. J Eur Acad Dermatol Venereol 2014; 28:393-4.

[5.] Karn D, Kc S, Amatya A, Razouria EA, Timalsina M. Oral tranexamic acid for the treatment of melasma. Kathmandu Univ Med J (KUMJ). 2012; 10:40-3.

[6.] MIMS. Tranexamic Acid; 2015. Available from: http:// www.mims.com/Malaysia/drug/info/Transamin/. [Last cited on 2015 Aug 23].

[7.] NPCB. Tranexamic Acid 250; 2015. Available from: http:// www.portal.bpfk.gov.my/risalah-maklumat-ubat-untuk-pengguna-rimup/item/transamin-capsule. [Last cited on 2015 Aug 23].

[8.] Norway FSA. Risk Profile Tranexamic Acid; 2012. Available from: http://www.mattilsynet.no/kosmetikk/ stoffer_i_kosmetikk/risk_profile_tranexamic_acid. 9965/ binary/Risk%20Profile%20Tranexamic%20acid. [Last cited on 2015 Sep 23].

[9.] Australian G. Australian Public Assessment Report for Tranexamic Acid Department of Health and Ageing: Therapeutic Goods Administration; 2010. Available from: http://www.file:///C:/Users/home/Downloads/ auspar-cyklokapron%20(1).pdf. [Last cited on 2015 Dec].

[10.] Europe Co. Active Ingredients Used in Cosmetics: Safety Survey: Council of Europe Publishing; 2008.

Halimi Syafiqah Nadiah (1), Masood Hannah (2), Kah Seng Lee (3), Suhaidah Mohd Jofrry (1,4), Long Chiau Ming (1,4)

(1) Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, (4) Vector-borne Diseases Research Group (VERDI), Pharmaceutical and Life Sciences CoRe, Universiti Teknologi MARA, Shah Alam, Selangor, (2) Department of Pharmacy, Hospital Tuanku Ampuan Najihah, Negeri Sembilan, Malaysia, (3) School of Pharmacy, Curtin University, Perth, Australia

Address for correspondence:

Halimi Syafiqah Nadiah, Level 11, FF1 Building, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia.

E-mail: syanadia23@gmail.com
Table 1: Search criteria and results

Criterion                              Search result

Key words used                         Oral, systemic, tranexamic
                                         acid, tren, transamin,
                                         transcap, melasma, whitening,
                                         lightening, hyperpigmentation
Filters                                Humans
Years searched                         All
Total number of articles reviewed      13
Relevant full text articles reviewed   5
Relevant abstracts reviewed            13

Table 2: Recommendations

Body/country    Drug: Tranexamic acid   Recommendation/reason

CEDAC, Canada   CEDAC registered        Hereditary angioneurotic
                tranexamic acid in      oedema Increased local
                February 2, 1983        fibrinolysis when the
                                        diagnosis is indicative of
                                        hyperfibrinolysis, as with
                                        conization of the cervix,
                                        dental extraction in patients
                                        with coagulopathies (in
                                        conjunction with
                                        antihemophilic factor)
                                        epistaxis, hyphema, and
                                        menorrhagia (hypermenorrhea)

PABC,           Tranexamic acid was     Tranexamic acid 500 mg are
Australia [9]   registered by           currently register for the
                Therapeutic Goods       indications Hereditary
                Administration (TGA)    angioneurotic edema
                in the year 1971        Short-term use in the
                                        treatment of hyphemia and in
                                        patients with established
                                        coagulopathies who are
                                        undergoing minor surgery
                                        Menorrhagia

MHRA, United    Medicines and           Local fibrinolysis: For
Kingdom         Healthcare products     short-term use in prophylaxis
                Regulatory Agency       and treatment in patients at
                registered tranexamic   high risk of peri- and
                acid in August 07,      post-operative hemorrhage
                1972 Re-                following: Prostatectomy,
                registration:           conization of the cervix,
                November 1,2001         surgical procedures and
                                        dental extractions in
                                        hemophiliacs General
                                        fibrinolysis: Hemorrhagic
                                        complications in association
                                        with thrombolytic therapy,
                                        hemorrhage associated with
                                        disseminated intravascular
                                        coagulation with predominant
                                        activation of the
                                        fibrinolytic system

NFSA,           The Norwegian Food      The Norwegian medicinal
Norway [8]      Safety Authority        products agency considered
                approved as facial      tranexamic acid a medicinal
                mask and facial cream   remedy. Because of that up
                3% in 2012              till 2008 topical products
                                        containing this substance was
                                        considered medicine--meaning
                                        a topical product containing
                                        it as automatically
                                        classified a medicine.
                                        Applications for allowance to
                                        use the substance for other
                                        purposes (cosmetics) were
                                        rejected. This regime has
                                        since been lifted The NFSA
                                        consider tranexamic acid is
                                        safe for use in face cream
                                        and facial mask at a
                                        concentration of 3%, but
                                        should be prohibited in all
                                        other cosmetic products
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Author:Nadiah, Halimi Syafiqah; Hannah, Masood; Lee, Kah Seng; Jofrry, Suhaidah Mohd; Ming, Long Chiau
Publication:Archives of Pharmacy Practice
Article Type:Report
Date:Jan 1, 2016
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