Tranexamic Acid for Melasma: Evaluating the Various Formulations

by Jordan V. Wang, MD, MBE, MBA; Nikita Jhawar, BS; and Nazanin Saedi, MD

Drs. Wang and Saedi are with the Department of Dermatology and Cutaneous Biology at Thomas Jefferson University in Philadelphia, Pennsylvania. Ms. Jhawar is with the Drexel University College of Medicine in Philadelphia, Pennsylvania.

FUNDING: No funding was provided for this study.

DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article.

ABSTRACT: Melasma is a common dermatological condition that can be notoriously difficult to treat. Topical bleaching agents and strict photoprotection, in addition to adjuvant treatment modalities, such as chemical peels and laser treatments, have been shown to provide only minimal improvements in the condition. Recently, tranexamic acid has shown promise. Topical, intradermal, and oral formulations of tranexamic acid have been studied, with oral formulations demonstrating the greatest, albeit temporary, improvement. In this brief review, we discuss the different formulations of tranexamic acid for melasma and offer suggestions for future directions of research.

KEYWORDS: Aesthetics, dermatology; melasma,  skincare, tranexamic acid 

 J Clin Aesthet Dermatol. 2019;12(8):E73–E74

Melasma is a chronic skin condition that disproportionately affects people of Asian, African, and Hispanic descent. Melasma is characterized by hyperpigmentation on sun-exposed facial skin, especially the cheeks, forehead, nose, and supralabial regions.¹ While exact mechanisms remain somewhat unclear, one theory is that ultraviolet light increases plasmin activity in keratinocytes, which leads to an increase in melanocytic-stimulating mediators, such as arachidonic acid and alpha-melanocyte stimulating hormone.² Melasma is often associated with pregnancy, changes in uterine or ovarian hormones, oral contraceptives, hepatopathies, and cosmetic drug use.² Melasma can also negatively influence quality of life and cause substantial psychological and social distress.³

Traditionally, the mainstays of treatment for melasma have been topical bleaching agents and strict photoprotection. Additional adjuvant treatment modalities include chemical peels, dermabrasion, and laser treatments, all of which have demonstrated limited efficacy.^1,4 Recently, there has been an interest in studying the effects of tranexamic acid (TA) in melasma.

TA has been evaluated for the treatment of melasma in various formulations, including topical, intradermal, and oral.¹ TA is a fibrinolytic agent that has antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹  Although reported studies have supported the safety and efficacy of TA,¹ there remains a lack of sufficiently powered clinical studies. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized controlled trials.⁵

Topical and Intradermal TA

The efficacy of topical TA has been assessed by several studies. Five out of six studies, all of which had small sample sizes (n=13–50), demonstrated significant differences in Melasma Area and Severity Index (MASI) scores between before and after treatment.^2,6–11 A variety of topical formulations and regimens were used, including 3% TA cream for 12 weeks, 5% TA gel for 12 weeks, 3% TA solution for 12 weeks, 5% TA liposome for 12 weeks, and 2% TA formulation for 12 weeks.² A review of the studies reported supporting data of TA’s effectiveness in lightening dyschromia and decreasing MASI scores from baseline.² Statistically significant differences were generally not observed between TA formulations and the vehicle, and topical TA appears to be as effective as topical hydroquinone, combination topical hydroquinone and dexamethasone, and intradermal injections of TA.² 

In a study comparing topical to intradermal TA, 18 women were enrolled to receive either twice-daily topical TA or weekly intradermal TA injections.⁶ While subjective improvement was greater in the intradermal group, objective measures for improvement were not significantly different between the groups. Therefore, more robust clinical studies are needed to better evaluate the role of topical TA in melasma and to compare its efficacy to other commonly used agents.

Despite these data, efficacy of intradermal TA treatment still requires further investigation. Only a handful of human studies have been completed, and most lack statistical significance and/or control groups. Lee et al¹² studied 100 women receiving weekly intradermal TA microinjections for 12 weeks. After eight and 12 weeks, MASI scores were decreased. Similarly, Elfar and El-Maghraby¹³ assessed 60 women who received either weekly intradermal TA injections, topical silymarin cream, or glycolic acid peels. While all groups showed improvement in MASI, the intradermal TA group showed the least improvement compared to the other groups.  In a more recent study, Saki et al¹⁴ compared the use of topical hydroquinone to intradermal TA through a randomized, split-face trial that included 37 patients. Each half of the face was treated with either monthly intradermal TA injections or nightly hydroquinone for three months. After four weeks of treatment, TA showed superior effects. However, after 20 weeks, the overall changes were not significant between the two groups. Pazyar et al¹⁵ also compared intradermal TA to hydroquinone cream in their split-face, controlled trial of 49 patients. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there was no significant difference in the decreased MASI scores between the treatments. Additional large, double-blinded, controlled trials are needed to thoroughly assess the role of intradermal TA. 

Oral TA

Conversely, oral TA has begun to show more promise for the treatment of melasma. Nine studies were completed during the years 2011 to 2016. While none of these studies had placebo groups, some reported that oral TA was effective based on patient ratings or improved MASI scores.² Since 2016, three additional clinical trials have been completed. One of the studies, which lacked a placebo group, found that MASI scores improved by 69 percent following oral TA.¹⁶ However, 72 percent of patients experienced a relapse of melasma within two months of stopping the oral TA. This occurred despite the use of combination skin lightening topical products. Del Rosario et al¹⁷ conducted a placebo-controlled trial that demonstrated improved MASI scores after three months of using oral TA (49%) compared to placebo (18%). Again, improvements in those with severe melasma were lost after three months of discontinuation and switching to sunscreen alone. Colferai et al¹ conducted a placebo-controlled trial and found that oral TA was associated with 50-percent improvement at 12 weeks compared to 5.9 percent in the placebo group. Although recent studies have incorporated the use of a placebo group, there remains a need for more rigorous studies. Many of these studies reported a recurrence of dyschromia following cessation of oral TA. Future research should evaluate the most effective methods for maintaining benefits following oral therapy. Overall, oral TA was well-tolerated among patients, with the most common side effects being gastrointestinal-related.^1,16,17 More serious side effects, such as deep vein thrombosis, acute renal cortical necrosis, acute myocardial infarction, and pulmonary embolism were rare, which was likely due to the low dose of oral TA used. However, screening for clotting risk factors via thorough patient history assessment and relevant laboratory screening tests would be prudent, and can include clotting times, protein C, protein S, antiphospholipid antibodies, and factor V Leiden.

Conclusion

Despite our advances with technology and new formulations of medications, melasma remains challenging to treat. Over the years, various formulations of TA have been evaluated as a means of treatment for melasma. While topical and intradermal treatments have not shown impressive results, oral TA has shown promise. Future directions for research should include long-term maintenance of achieved results following the cessation of oral TA, as well as combination therapy with TA and other modalities, such as laser treatments. Newer studies on the horizon have begun to examine laser-assisted drug delivery of topical tranexamic acid.¹⁸ There remains a noticeable need for large-scale, randomized, placebo-controlled trials to validate the effectiveness of TA in melasma and determine the best mode of delivery.

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