Review Article

Oral Tranexamic Acid to treat Melasma: A Literature Review

Maria Júlia Miqueo Canuto Verussa1*, Denise Steiner1

Dermatologists of Universidade de Mogi das Cruzes, São Paulo, Brazil.

*Corresponding Author : Maria Júlia Miquelão Canuto Verussa, Dermatologists of Universidade de Mogi das Cruzes, São Paulo, Brazil. E-mail : mariajuliamik@gmail.com

Citation : Verussa MJMC, Steiner D (2019) Oral tranexamic acid to treat melasma : a literature review. J Dermatol Surg Res Ther 2019: 51-58.

Received Date: 28 March, 2019; Accepted Date:26 April, 2019; Published Date: 14 May, 2019

Abstract

Background

Melasma is an acquired chronic pigmentation disorder associated with significant morbidity, which negatively affects an individual’s quality of life. Increasing knowledge of the etiopathogenesis of melasma has resulted in expansion of the therapeutic arsenal against this condition, and the role of tranexamic acid (TA) is being investigated in these patients. This article includes a review of the published literature that describes the role of oral TA in the treatment of melasma.

Methods

A literature search was performed to identify articles reporting the effect of TA in patients with melasma. The PubMed, Scopus, Medline, Embase, and Cochrane databases were searched using the keywords "melasma" and "tranexamic acid".

Results and conclusion

Fourteen studies discussing the role of oral TA in the treatment of melasma were selected. Oral TA is safe and effective in treating melasma. The published literature revealed that oral TA alone or concomitant with other therapeutic modalities safely and effectively treats melasma.

Key words

Tranexamic Acid; Melasma; Treatment

Introduction

Melasma is an acquired chronic pigmentation disorder associated with significant morbidity, which negatively affects an individual’s quality of life [1]. Clinical features include symmetrical hypermelanosis of skin over sun-exposed areas of the body, particularly the cheeks, forehead, nose, and the supralabial region [2]. This condition is commonly observed in women with darker skin types, although it can occur in both sexes and in individuals of all ethnicities, with all skin phototypes [3]. The exact pathogenesis of melasma is unclear; however, a complex interplay between several contributors including environmental and genetic factors is implicated in its development [4]. Treatment of melasma can be challenging and includes multimodality therapeutic interventions including use of photoprotective agents, topical and/or oral skin lighteners, and resurfacing procedures [5].

Increasing knowledge of the etiopathogenesis of melasma has resulted in an expansion of the therapeutic arsenal against this condition, and the role of tranexamic acid (TA) is being investigated in these patients. In 1979, Sadako [6] first described the systemic administration of TA to treat melasma in Japan. Since then, topical, oral, and injectable TA is increasingly being used for this condition [7]. TA inhibits melanin synthesis in melanocytes by interfering with the interaction of melanocytes and keratinocytes through plasminogen/plasmin system inhibition [8]. This article includes a review of the published literature discussing the role of oral TA in the treatment of melasma.

Year

Study

Patients

Intervention group

Topical treatment

Treatment duration

Oral TA side effects

Conclusion

2012

Karn et al.

260

TA 500 mg daily + sunscreen and hydroquinone

sunscreen and hydroquinone

3 months

No reported

Oral TA provides rapid and sustained improvement in the melasma treatment.

2013

Na JI et al.

22

TA 750 mg daily + with 2% topical TA

2% topical TA + 2% topical niacinamide

2 months

No serious adverse events were observed throughout the study period.

TXA oral and topical agents improved epidermal pigmentation and erythema of melasma, also reversed melasma?related dermal changes.

2015

Padhi and Pradhan

40

TA 250 mg daily + fluocinolone based triple combination cream

fluocinolone based triple combination cream

2 months

One patient presented oligomenorrhoea. other systemic side effects were not reported.

Addition of oral tranexamic acid to of fluocinolone based triple combination cream results in a faster and sustained improvement.

2016

Lajevardi et al.

88

TA 500 mg daily + hydroquinone 4%

hydroquinone 4%

3 months

10.4 patients with side effects, such as severe abdominal pain, flank pain, edema of the hands and feet, nausea, vomiting, and headache

Oral TA can enhance the efficacy of hydroquinone 4% cream

 Table 1. Oral tranexamic acid and topical treatment.

 

Methods

A literature search was performed to identify articles discussing the role of TA in the treatment of melasma. The PubMed, Scopus, Medline, Embase, and Cochrane databases were searched using the keywords "melasma" and "tranexamic acid". The literature search was not time bound and only original reports in English describing systemically administered TA to treat melasma were included. Retrospective and cross-sectional studies were excluded.

Results

Fourteen studies discussing the role of oral TA to treat melasma were selected. For didactic purposes, we categorized the selected articles into 6 groups as follows: 1) Oral TA and topical treatment (Table 1).

2) Oral TA vs. TA microinjections (Table 2).

Year

Study

Patients

Oral TA

Microinjection TA

Duration

Oral TA side effects

Conclusion

2017

Sharma et al.

100

TA 500mg daily

TA 4mg/ml

3 months

Six patients (15.4%) reported hypomenorrhea that improved after the study period. Two patients had epigastric discomfort during the initial 4 weeks, resolved with ranitidine 150 mg twice daily.

TA appears to be an effective and safe treatment for melasma, irrespective of its route of administration.

 

2018

Khuruana et al.

64

TA 500mg daily

TA 4mg/ml

3 months

Two patients (6.25%) had gastrites.

One Patient had oligomenorrhea.

TA provides rapid and sustained improvement in the treatment of melasma.

Table 2. Oral tranexamic acid versus tranexamic acid microinjections. 

3) Oral TA concomitant with laser therapy (Table 3).

Year

Study

Patients

Oral TA

Light / Laser therapy

Duration

Oral TA side effects

Conclusion

2013

Cho HH, Choi M, Cho S, Lee JH

51

TA 500 mg daily + intense pulsed light and laser therapy

intense pulsed light and quality-switched neodymium-doped yttrium aluminum garnet (QSNY) laser

2 – 8 months

No patients complained of noticeable adverse effects

TA may improve clinical efficacy in light / laser therapy.

2013

Shin JU, Park J, Oh SH, Lee JH

48

TA 375 mg daily

quality-switched neodymium-doped yttrium aluminum garnet (QSNY) laser

2 months

Two individuals randomized to the combination group reported medication-associated heartburn, and one complained of nausea.

TA may prove a safe and eficiente treatment option for melasma in combination with low-fluence QSNY laser therapy.

Table 3. Oral TA associated with laser. 

4) Prospective studies investigating the administration of oral TA alone (Table 4).

Year

Study

Patients

Oral TA

Duration

Oral TA side effects

Conclusion

2012

Wu and colleagues

74

TA 500 mg daily

6 months

5.4% reported gastrointestinal effects. 58% presented hypomenorrhoea

Oral TA is an effective and safe therapy for the treatment of melasma.

2014

Li et al.

32

TA 1500 mg daily

4 months

3 patients reported gastrointestinal issues, 3 with menstrual irregularities, 1 with drosiness, 1 with increased liver function tests

Oral TA seems to be a potentially new and promising therapeutic option.

2018

Nagaraju et al.

30

TA 1000 mg daily

3 months

11 patients with headache, weight gain and hypomenorrhea

Oral TA has an inhibitory action on melanin synthesis and melanocyte proliferation.

 

 

Table 4. Prospective studies with oral TA alone

5) Clinical trials investigating the administration of oral TA vs. placebo (Table 5).

Year

Study

Patients

Oral TA

Placebo

Duration

Oral TA side effects

Conclusion

2018

Del Rosario et al.

39

500 mg daily

Placebo capsules

3 months

35% with diarrhea and náusea, 10% with altered menstruation

Oral TA appears to be an effective treatment for moderate-to-severe melasma with minimal side effects.

2018

Colferai et al.

37

500 mm daily

Placebo capsules

  1. months

Mild side effects occurred in 63.6% of patients on TA vs. 36.3% on placebo, without statiscal significance between groups. one patient discontinued the medication due to moderate myalgias.

Oral TA was effective in 50% of patients according to four methods of evaluation when compared to placebo.

 Table 5. Clinical trials with oral TA and placebo.

6) Multicenter prospective study utilizing varying doses of oral TA.

Oral and topical tranexamic acid treatment

Karn et al. [9] (2012) performed a prospective randomized controlled trial including 260 patients with melasma in Nepal. Patients were categorized into 2 groups consisting of 130 patients each. One group of patients received TA at a dose of 250 mg twice daily along with the use of a sunscreen and hydroquinone. The other group received only the same topical treatment for 3 months. Response to treatment was evaluated at the 6-month follow-up using the Melasma Area and Severity Index (MASI). The first group showed a statistically significant reduction in the mean MASI score from baseline values at 8 and 12 weeks, whereas the second group showed a reduced mean score only at the 8-week follow-up. Notably, 82.3% of the patients in the first group reported a good-to-excellent response to treatment, whereas only 40.8% of the patients in the second group reported a good-to-excellent response to treatment. The authors concluded that oral TA administration leads to rapid and sustained improvement in melasma.

Na J et al. [10] (2013) reported a clinical study of 22 women in South Korea who received oral TA at a dose of 750 mg daily along with 2% topical TA. Skin pigmentation and erythema were recorded using the Mexameter® at each visit, and skin biopsies were performed in 8 women before and 8 weeks after treatment. The mean lesional melanin index and erythema index decreased significantly after treatment. Histopathological analysis showed a significant reduction in epidermal pigmentation and also reversal of melasma-associated dermal changes, such as increased vascularity and an increased number of mast cells.

Padhi and Pradhan [11] (2015) compared the efficacy of fluocinolone-based triple combination cream (FBTCC) alone (group A) with FBTCC administered concomitantly with oral TA at a dose of 250 mg daily (group B) among 40 Indian patients (20 patients/group) for 8 weeks. Treatment response was recorded using MASI scores at baseline and at 4 and 8 weeks. Intergroup comparison showed a more rapid statistically significant reduction in pigmentation in group B than in group A, and the medication remained effective throughout the 6-month follow-up.

A recent randomized controlled trial performed by Lajevardi et al. [12] (2016) in Iran included 88 patients. The authors compared the efficacy of orally administered TA (500 mg daily) plus 4% hydroquinone (intervention group) with 4% hydroquinone alone (control group) administered for 3 months. At the end of 6 months, the overall mean MASI score in the intervention group was 1.8 points lower than that in controls; however, the relapse rate was not significantly different. Five patients developed adverse effects, and of these 5, 3 reported severe abdominal and flank pain, edema of the hands and feets, nausea and vomiting, and headache, all of which resolved completely and spontaneously after the discontinuation of TA therapy. Treatment satisfaction was higher in the intervention than in the control group (moderate-to-complete satisfaction reported in 82.2% vs. 34.95% patients, respectively).

Comparison of oral tranexamic acid vs. tranexamic acid microinjections

In 2017, Sharma et al. [13] performed a study in India that investigated 100 patients to compare the efficacy of different routes of administration of TA. Patients were categorized into 2 equal groups and investigated for 12 weeks. Group A received oral TA at a dose of 250 mg twice daily. Group B received intradermal microinjections of TA at a dose of 4 mg/mL every 4 weeks. Eighty patients completed the study. MASI scores reduced by 77.9 points in Group A and by 79.0 points in Group B. The authors concluded that TA appears to be effective and safe treatment for melasma, regardless of the route of administration.

Khurana et al. [14] (2018) performed a similar study in India to compare the oral administration of TA with microinjections of TA. Their study included 2 groups of 32 patients each who were followed-up for 3 consecutive months. The intralesional group received localized microinjections of TA at a dose of 4 mg/mL on a monthly basis, whereas the oral group received oral TA at a dose of 250 mg twice daily. Improvement in the area of distribution of melasma and the MASI score were observed in 57.5% of patients in the oral group vs. 43.5% of patients in the intralesional group. All 32 patients in the oral group (100%) showed >50% improvement, and 8 of these patients showed >75% improvement. In the intralesional group, 17 (53%) patients showed >50% improvement, and 3 of these patients showed >75% improvement. Thus, the oral group showed a more significant response than the intralesional group. The authors proposed that the efficacy of microinjections could be enhanced by increasing the frequency and/or the concentration of the preparation.

Administration of oral tranexamic acid combined with laser therapy

Lee JH et al. reported 2 prospective studies describing the use of oral TA combined with laser therapy in Korea [15,16]. The first was a controlled trial that investigated 51 patients with melasma to determine the clinical efficacy and safety of oral TA as an adjuvant to intense pulsed light (IPL) and laser therapy. In this study, group A received oral TA at a dose of 500 mg daily (administered between 2 and 8 months), IPL, and low-fluence quality-switched neodymium-doped yttrium aluminum garnet (QSNY) laser, and group B received only IPL and QSNY. The MASI score showed a statistically significant reduction after treatment in both groups. However, the reduction was significantly higher in group A than in group B. In the second study, 48 patients underwent 2 sessions of QSNY therapy. These patients were classified into 2 groups; Group A received oral TA at a dose of 125 mg thrice a day for 8 weeks in addition to laser therapy, and Group B received only laser therapy. Twenty-three patients from Group A and 21 patients from Group B completed the study. MASI scores were evaluated by 2 blinded dermatologists. It was observed that patients receiving combination therapy showed a significantly greater reduction in MASI scores than patients receiving only laser therapy. The authors concluded that oral TA combined with laser therapy may improve the clinical efficacy of IPL or of laser-based melasma treatment.

Prospective studies investigating the role of oral tranexamic acid alone

In 2012, Wu et al. [17] investigated 74 women in China who received oral TA at a dose of 250 mg twice daily for 6 months and were followed-up for 6 months after treatment. Outcomes were evaluated by 2 physicians independently and by patients themselves based on the area of distribution of melasma and improvement in pigmentation (poor [<30%], fair [>30%], good [>60%], and excellent [>90%]). After 6 months of therapy, improvement was observed in 95.9% of the patients (10.8% reported excellent, 54% reported good, and 31.1% reported fair results). Although adverse effects including gastrointestinal discomfort (5.4%) and hypomenorrhea (8.1%) occurred, no severe complications were observed.

Li et al. [18] performed a prospective study in China in 2014 that investigated 35 patients who received oral TA at a dose of 500 mg thrice a day for 4 months. Notably, 32 patients completed the study. A significant improvement in the color and size of skin lesions was observed based on a 5-point scoring system using the Skin Tone Color Scale at baseline, 4, 8, 12, and 16 weeks. Improvement occurred in 85% of the patients in 4 weeks, in 97% of the patients in 8 and 12 weeks, and in 100% of the patients in 16 weeks. These patients also reported an improved quality of life. Although mild adverse effects occurred in a few patients, these did not require discontinuation of medication.

In 2018, Nagaraju et al. [19] reported a clinico-immuno-histopathological study to investigate the efficacy of oral TA in patients with refractory melasma. Thirty patients with refractory melasma received oral TA at a dose of 500 mg twice daily for 3 months and underwent 2 months of follow-up upon completion of the treatment. The modified MASI (mMASI) scores and melasma quality of life (MELASQOL) questionnaire were evaluated at baseline and after treatment. Excellent response determined by the mMASI score was observed in only 1 patient, moderate and good improvement in 14 patients each, and mild improvement in 1 patient. Notably, no patient reported excellent improvement in the MELASQOL score, although good improvement was reported by 3, moderate improvement by 23, and mild improvement by 4 patients. Fourteen patients underwent a skin biopsy. Histopathological and immunohistochemical examinations revealed reduction in the number of mast cells, vascularity, inflammation, edema, as well as pigmentary incontinence. The authors concluded that oral TA inhibits melanin synthesis and melanocyte proliferation.

Clinical trials investigating the role of oral tranexamic acid vs. Placebo preparations

In 2018, 2 clinical trials investigated the role of oral TA vs. placebo in treating melasma. A study from Texas [20] included 39 patients (all patients completed the study). The intervention group received oral TA at a dose of 250 mg twice daily, and the control group received placebo capsules for 3 months. After 3 months, a 49% reduction in the mMASI score was observed in the intervention group vs. 18% reduction in the control group. Notably, patients with severe melasma showed more significant improvement than those with moderate melasma. The second study, a monocentric, randomized, double-blind controlled clinical trial reported from Brazil [21] included 47 patients classified into 2 groups. Group A received oral TA at a dose of 250 mg twice daily, and group B received oral placebo twice daily. Thirty-seven patients who completed the study were evaluated before and after 12 weeks of treatment using photographs, colorimetry, and the MELASQOL and MASI scores. Melasma improved in 50% of patients in Gruop A vs. 5.9% of patients in Group B, which was a statistically significant difference.

Multicenter prospective study using varying doses of oral tranexamic acid

A recent multicenter prospective study performed by Zhu et al. (2019) analyzed the therapeutic effects of varying doses of oral TA on melasma [22]. Patients were randomized to receive oral TA at a daily dose of 500 mg, 750 mg, 1000 mg, or 1500 mg. Photographs were obtained, and the MASI score and melanin index were recorded at baseline and at 1, 2, 6, 12 and 24 months. Clinical photographs showed that all 4 doses were effective, and the efficacy correlated with the dosage and duration of treatment. However, the MASI and melanin index scores did not significantly differ between these doses. The authors concluded that TA is safe and effective to treat melasma and is associated with excellent patient satisfaction and minimal adverse effects.

Discussion

Melasma is an acquired chronic pigmentation disorder associated with significant morbidity, which negatively affects an individual’s quality of life1. The high relapse rate observed in these patients could be attributed to several etiopathogenetic contributors including sun exposure, as well as endocrine and genetic factors4. TA has emerged as a new medication in these patients and has shown promising results with all routes of administration (topical, intralesional, and systemic). Two previous studies and 1 meta-analysis describing the effects of TA in the treatment of melasma were published in 2017–2018; however, these studies evaluated the previous literature up to 2016 [7,23,24]. Our study is the first to focus on oral TA among recent prospective studies. We have evaluated studies that included placebo groups and varying dosage, as well as long-term follow-up.

Oral TA has been used as a safe and effective medication to treat melasma. The mechanism of action of this drug is primarily associated with its property of plasminogen/plasmin inhibition. TA is a synthetic derivative of lysine that blocks the lysine binding sites on the plasminogen molecule, thereby inhibiting the plasminogen activator and preventing the conversion of plasminogen to plasmin. This antifibrinolytic action reduces blood loss [6,7,8]. Plasminogen is present in human epidermal basal cells. Ultraviolet radiation (UVR)-induced melanogenesis occurs secondary to an interaction of melanocytes and keratinocytes through UVR-induced activation of the plasminogen/plasmin system. TA inhibits the plasminogen/plasmin system, which serves as the primary mechanism responsible for hypopigmentation caused by TA [21]. Additionally, it is hypothesized that TA competitively antagonizes tyrosinase owing to the structural similarity between these agents, contributing further to the skin lightening effect [11,15]. Moreover, it has been suggested that inhibition of plasminogen binding to keratinocytes decreases the production of inflammatory mediators such as arachidonic acid and prostaglandins, which are known melanocyte stimulators [8]. A study has shown that TA also decreases mast cell activity and serum levels of vascular endothelial growth factor and endothelin-1, consequently decreasing vascularity and the numbers of mast cells in the dermis in patients with melasma [3].

All previous studies have shown the important role of TA in treating melasma either as a single agent or in combination with other therapeutic modalities. Sunscreen use was described by all studies. The dosage of TA used was 500–1500 mg daily over 1–12 months, which was markedly lower than the dose used for hemostatic purposes (usually 3000 mg daily).

All studies reported that careful history-taking and laboratory tests were performed in patients to investigate the risk factors associated with TA administration. Risk factors included a personal history of deep vein thrombosis, pulmonary embolism, acute myocardial infarction and smoking and a family history of hereditary thrombophilia. These events usually occur with hemostatic doses of TA, and the lower doses administered to patients with melasma usually tend to cause only mild adverse effects. All studies reported that systemically administered TA was well tolerated by patients. Most patients reported headache, oligomenorrhea, and gastrointestinal issues; however, these adverse effects did not necessitate the discontinuation of medication. A study reported that 3 patients presented with severe abdominal and flank pain, edema of the hands and feets, nausea, vomiting, and headache, all of which resolved completely and spontaneously after discontinuation of TA. No study reported severe adverse effects such as thromboembolic events.

Relapse after treatment was reported by most studies, except the multicenter study, which included a longer duration of treatment and follow-up. It was observed that recurrence could be effectively treated with repeat administration of TA [17]. More studies are necessary to evaluate the optimal treatment duration and to gain a better understanding of the relapse rate.

It should be noted that most studies included in the published literature investigating the role of oral TA in patients with melasma have included Asians. Moreover, the sunscreen types and sun exposure varied across studies and, probably, even between treated patients in the same study. Another limitation that must be considered was that the scores used to assess treatment response varied across studies. Further research is warranted to develop optimal protocols for the administration of oral TA in patients with melasma.

Conclusion

The aforementioned studies reported that oral TA can effectively and safely treat melasma at a dosage of 500–750 mg daily, divided into 2 or 3 doses/day, administered for at least 3 months, as a single agent or concomitant with other therapeutic modalities.

 

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