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Treatment of Melasma Using Tranexamic Acid: What’s Known and What’s Next
In Collaboration with Cosmetic Surgery Forum

Tranexamic acid is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule. Although the US Food and Drug Administration–approved indications for tranexamic acid include treatment of patients with menorrhagia and reduction or prevention of hemorrhage in patients with hemophilia undergoing tooth extraction, the potential efficacy of tranexamic acid in the treatment of melasma has been consistently reported since the 1980s.1

Tranexamic acid exerts effects on pigmentation via its inhibitory effects on UV light–induced plasminogen activator and plasmin activity.2 UV radiation induces the synthesis of plasminogen activator by keratinocytes, which results in increased conversion of plasminogen to plasmin. Plasminogen activator induces tyrosinase activity, resulting in increased melanin synthesis. The presence of plasmin results in increased production of both arachidonic acid and fibroblast growth factor, which stimulate melanogenesis and neovascularization, respectively.3 By inhibiting plasminogen activation, tranexamic acid mitigates UV radiation–induced melanogenesis and neovascularization. In treated guinea pig skin, application of topical tranexamic acid following UV radiation exposure inhibited the development of expected skin hyperpigmentation and also reduced tyrosinase activity.4,5

The largest study on the use of oral tranexamic acid for treatment of melasma was a retrospective chart review of 561 melasma patients treated with tranexamic acid at a single center in Singapore.6 More than 90% of patients received prior treatment of their melasma, including bleaching creams and energy-based treatment. Among patients who received oral tranexamic acid over a 4-month period, 90% of patients demonstrated improvement in their melasma severity. Side effects were experienced by 7% of patients; the most common side effects were abdominal bloating and pain (experienced by 2% of patients). Notably, 1 patient developed deep vein thrombosis during treatment and subsequently was found to have protein S deficiency.6

Although the daily doses of tranexamic acid for the treatment of menorrhagia and perioperative hemophilia patients are 3900 mg and 30 to 40 mg/kg, respectively, effective daily doses reported for the treatment of melasma have ranged from the initial report of efficacy at 750 to 1500 mg to subsequent reports of improvement at daily doses of 500 mg.1,2,6-8

Challenges to the use of tranexamic acid for melasma treatment in the United States include the medicolegal environment, specifically the risks associated with using a systemic procoagulant medication for a cosmetic indication. Patients should be screened and counseled on the risks of developing deep vein thrombosis and pulmonary embolism prior to initiating treatment. Cost and accessibility also may limit the use of tranexamic acid in the United States. Tranexamic acid is available for off-label use in the United States with a prescription in the form of 650-mg tablets that can be split by patients to approximate twice-daily 325 mg dosing. This cosmetic indication poses an out-of-pocket cost to patients of over $110 per month or as low as $48 per month with a coupon at the time of publication.9

Given the potential for serious adverse effects with the use of systemic tranexamic acid, there has been interest in formulating and evaluating topical tranexamic acid for cosmetic indications.10-13 Topical tranexamic acid has been used alone and in conjunction with modalities to increase uptake, including intradermal injection, microneedling, and fractionated CO2 laser.12-14 Although these reports show initial promise, the currently available data are limited by small sample sizes, short treatment durations, lack of dose comparisons, and lack of short-term or long-term follow-up data. In addition to addressing these knowledge gaps in our understanding of topical tranexamic acid as a treatment option for melasma, further studies on the minimum systemic dose may address the downside of cost and potential for complications that may limit use of this medication in the United States.

The potential uses for tranexamic acid extend to the treatment of postinflammatory hyperpigmentation and rosacea. Melanocytes cultured in media conditioned by fractionated CO2 laser–treated keratinocytes were found to have decreased tyrosinase activity and reduced melanin content when treated with tranexamic acid, suggesting the potential role for tranexamic acid to be used postprocedurally to reduce the risk for postinflammatory hyperpigmentation in prone skin types.15 Oral and topical tranexamic acid also have been reported to improve the appearance of erythematotelangiectatic rosacea, potentially relating to the inhibitory effects of tranexamic acid on neovascularization.3,16,17 Although larger-scale controlled studies are required for further investigation of tranexamic acid for these indications, it has shown early promise as an adjunctive treatment for several dermatologic disorders, including melasma, and warrants further characterization as a potential therapeutic option.

References
  1. Higashi N. Treatment of melasma with oral tranexamic acid. Skin Res. 1988;30:676-680.
  2. Tse TW, Hui E. Tranexamic acid: an important adjuvant in the treatment of melasma. J Cosmet Dermatol. 2013;12:57-66.
  3. Sundbeck A, Karlsson L, Lilja J, et al. Inhibition of tumour vascularization by tranexamic acid. experimental studies on possible mechanisms. Anticancer Res. 1981;1:299-304.
  4. Maeda K, Naganuma M. Topical trans-4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation-induced pigmentation. J Photochem Photobiol B. 1998;47:136-141.
  5. Li D, Shi Y, Li M, et al. Tranexamic acid can treat ultraviolet radiation-induced pigmentation in guinea pigs. Eur J Dermatol. 2010;20:289-292.
  6. Lee HC, Thng TG, Goh CL. Oral tranexamic acid (TA) in the treatment of melasma: a retrospective analysis. J Am Acad Dermatol. 2016;75:385-392.
  7. Kim HJ, Moon SH, Cho SH, et al. Efficacy and safety of tranexamic acid in melasma: a meta-analysis and systematic review. Acta Derm Venereol. 2017;97:776-781.
  8. Perper M, Eber AE, Fayne R, et al. Tranexamic acid in the treatment of melasma: a review of the literature. Am J Clin Dermatol. 2017;18:373-381.
  9. Tranexamic acid. GoodRx website. https://www.goodrx.com/tranexamic-acid. Accessed February 2, 2018.
  10. Kim SJ, Park JY, Shibata T, et al. Efficacy and possible mechanisms of topical tranexamic acid in melasma. Clin Exp Dermatol. 2016;41:480-485.
  11. Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014;19:753-757.
  12. Xu Y, Ma R, Juliandri J, et al. Efficacy of functional microarray of microneedles combined with topical tranexamic acid for melasma: a randomized, self-controlled, split-face study. Medicine (Baltimore). 2017;96(19):e6897.
  13. Hsiao CY, Sung HC, Hu S, et al. Fractional CO2 laser treatment to enhance skin permeation of tranexamic acid with minimal skin disruption. Dermatology (Basel). 2015;230:269-275.
  14. Saki N, Darayesh M, Heiran A. Comparing the efficacy of topical hydroquinone 2% versus intradermal tranexamic acid microinjections in treating melasma: a split-face controlled trial [published online November 9, 2017]. J Dermatolog Treat. doi:10.1080/09546634.2017.1392476.
  15. Kim MS, Bang SH, Kim JH, et al. Tranexamic acid diminishes laser-induced melanogenesis. Ann Dermatol. 2015;27:250-256.
  16. Kim MS, Chang SE, Haw S, et al. Tranexamic acid solution soaking is an excellent approach for rosacea patients: a preliminary observation in six patients. J Dermatol. 2013;40:70-71.
  17. Kwon HJ, Suh JH, Ko EJ, et al. Combination treatment of propranolol, minocycline, and tranexamic acid for effective control of rosacea [published online November 26, 2017]. Dermatol Ther. doi:10.1111/dth.12439.
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From the Department of Dermatology, Stanford University Medical Center, California.

The author reports no conflict of interest.

This review was part of a presentation at the 9th Cosmetic Surgery Forum under the direction of Joel Schlessinger, MD; November 29-December 2, 2017; Las Vegas, Nevada. Dr. Sheu was a Top 10 Fellow and Resident Grant winner.

Correspondence: Sarah L. Sheu, MD, Stanford Dermatology Academic Offices, Stanford Medicine Outpatient Center, 450 Broadway, Pavilion C, 2nd Floor, Redwood City, CA 94063 (slsheu@stanford.edu).

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From the Department of Dermatology, Stanford University Medical Center, California.

The author reports no conflict of interest.

This review was part of a presentation at the 9th Cosmetic Surgery Forum under the direction of Joel Schlessinger, MD; November 29-December 2, 2017; Las Vegas, Nevada. Dr. Sheu was a Top 10 Fellow and Resident Grant winner.

Correspondence: Sarah L. Sheu, MD, Stanford Dermatology Academic Offices, Stanford Medicine Outpatient Center, 450 Broadway, Pavilion C, 2nd Floor, Redwood City, CA 94063 (slsheu@stanford.edu).

Author and Disclosure Information

From the Department of Dermatology, Stanford University Medical Center, California.

The author reports no conflict of interest.

This review was part of a presentation at the 9th Cosmetic Surgery Forum under the direction of Joel Schlessinger, MD; November 29-December 2, 2017; Las Vegas, Nevada. Dr. Sheu was a Top 10 Fellow and Resident Grant winner.

Correspondence: Sarah L. Sheu, MD, Stanford Dermatology Academic Offices, Stanford Medicine Outpatient Center, 450 Broadway, Pavilion C, 2nd Floor, Redwood City, CA 94063 (slsheu@stanford.edu).

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In Collaboration with Cosmetic Surgery Forum
In Collaboration with Cosmetic Surgery Forum

Tranexamic acid is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule. Although the US Food and Drug Administration–approved indications for tranexamic acid include treatment of patients with menorrhagia and reduction or prevention of hemorrhage in patients with hemophilia undergoing tooth extraction, the potential efficacy of tranexamic acid in the treatment of melasma has been consistently reported since the 1980s.1

Tranexamic acid exerts effects on pigmentation via its inhibitory effects on UV light–induced plasminogen activator and plasmin activity.2 UV radiation induces the synthesis of plasminogen activator by keratinocytes, which results in increased conversion of plasminogen to plasmin. Plasminogen activator induces tyrosinase activity, resulting in increased melanin synthesis. The presence of plasmin results in increased production of both arachidonic acid and fibroblast growth factor, which stimulate melanogenesis and neovascularization, respectively.3 By inhibiting plasminogen activation, tranexamic acid mitigates UV radiation–induced melanogenesis and neovascularization. In treated guinea pig skin, application of topical tranexamic acid following UV radiation exposure inhibited the development of expected skin hyperpigmentation and also reduced tyrosinase activity.4,5

The largest study on the use of oral tranexamic acid for treatment of melasma was a retrospective chart review of 561 melasma patients treated with tranexamic acid at a single center in Singapore.6 More than 90% of patients received prior treatment of their melasma, including bleaching creams and energy-based treatment. Among patients who received oral tranexamic acid over a 4-month period, 90% of patients demonstrated improvement in their melasma severity. Side effects were experienced by 7% of patients; the most common side effects were abdominal bloating and pain (experienced by 2% of patients). Notably, 1 patient developed deep vein thrombosis during treatment and subsequently was found to have protein S deficiency.6

Although the daily doses of tranexamic acid for the treatment of menorrhagia and perioperative hemophilia patients are 3900 mg and 30 to 40 mg/kg, respectively, effective daily doses reported for the treatment of melasma have ranged from the initial report of efficacy at 750 to 1500 mg to subsequent reports of improvement at daily doses of 500 mg.1,2,6-8

Challenges to the use of tranexamic acid for melasma treatment in the United States include the medicolegal environment, specifically the risks associated with using a systemic procoagulant medication for a cosmetic indication. Patients should be screened and counseled on the risks of developing deep vein thrombosis and pulmonary embolism prior to initiating treatment. Cost and accessibility also may limit the use of tranexamic acid in the United States. Tranexamic acid is available for off-label use in the United States with a prescription in the form of 650-mg tablets that can be split by patients to approximate twice-daily 325 mg dosing. This cosmetic indication poses an out-of-pocket cost to patients of over $110 per month or as low as $48 per month with a coupon at the time of publication.9

Given the potential for serious adverse effects with the use of systemic tranexamic acid, there has been interest in formulating and evaluating topical tranexamic acid for cosmetic indications.10-13 Topical tranexamic acid has been used alone and in conjunction with modalities to increase uptake, including intradermal injection, microneedling, and fractionated CO2 laser.12-14 Although these reports show initial promise, the currently available data are limited by small sample sizes, short treatment durations, lack of dose comparisons, and lack of short-term or long-term follow-up data. In addition to addressing these knowledge gaps in our understanding of topical tranexamic acid as a treatment option for melasma, further studies on the minimum systemic dose may address the downside of cost and potential for complications that may limit use of this medication in the United States.

The potential uses for tranexamic acid extend to the treatment of postinflammatory hyperpigmentation and rosacea. Melanocytes cultured in media conditioned by fractionated CO2 laser–treated keratinocytes were found to have decreased tyrosinase activity and reduced melanin content when treated with tranexamic acid, suggesting the potential role for tranexamic acid to be used postprocedurally to reduce the risk for postinflammatory hyperpigmentation in prone skin types.15 Oral and topical tranexamic acid also have been reported to improve the appearance of erythematotelangiectatic rosacea, potentially relating to the inhibitory effects of tranexamic acid on neovascularization.3,16,17 Although larger-scale controlled studies are required for further investigation of tranexamic acid for these indications, it has shown early promise as an adjunctive treatment for several dermatologic disorders, including melasma, and warrants further characterization as a potential therapeutic option.

Tranexamic acid is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule. Although the US Food and Drug Administration–approved indications for tranexamic acid include treatment of patients with menorrhagia and reduction or prevention of hemorrhage in patients with hemophilia undergoing tooth extraction, the potential efficacy of tranexamic acid in the treatment of melasma has been consistently reported since the 1980s.1

Tranexamic acid exerts effects on pigmentation via its inhibitory effects on UV light–induced plasminogen activator and plasmin activity.2 UV radiation induces the synthesis of plasminogen activator by keratinocytes, which results in increased conversion of plasminogen to plasmin. Plasminogen activator induces tyrosinase activity, resulting in increased melanin synthesis. The presence of plasmin results in increased production of both arachidonic acid and fibroblast growth factor, which stimulate melanogenesis and neovascularization, respectively.3 By inhibiting plasminogen activation, tranexamic acid mitigates UV radiation–induced melanogenesis and neovascularization. In treated guinea pig skin, application of topical tranexamic acid following UV radiation exposure inhibited the development of expected skin hyperpigmentation and also reduced tyrosinase activity.4,5

The largest study on the use of oral tranexamic acid for treatment of melasma was a retrospective chart review of 561 melasma patients treated with tranexamic acid at a single center in Singapore.6 More than 90% of patients received prior treatment of their melasma, including bleaching creams and energy-based treatment. Among patients who received oral tranexamic acid over a 4-month period, 90% of patients demonstrated improvement in their melasma severity. Side effects were experienced by 7% of patients; the most common side effects were abdominal bloating and pain (experienced by 2% of patients). Notably, 1 patient developed deep vein thrombosis during treatment and subsequently was found to have protein S deficiency.6

Although the daily doses of tranexamic acid for the treatment of menorrhagia and perioperative hemophilia patients are 3900 mg and 30 to 40 mg/kg, respectively, effective daily doses reported for the treatment of melasma have ranged from the initial report of efficacy at 750 to 1500 mg to subsequent reports of improvement at daily doses of 500 mg.1,2,6-8

Challenges to the use of tranexamic acid for melasma treatment in the United States include the medicolegal environment, specifically the risks associated with using a systemic procoagulant medication for a cosmetic indication. Patients should be screened and counseled on the risks of developing deep vein thrombosis and pulmonary embolism prior to initiating treatment. Cost and accessibility also may limit the use of tranexamic acid in the United States. Tranexamic acid is available for off-label use in the United States with a prescription in the form of 650-mg tablets that can be split by patients to approximate twice-daily 325 mg dosing. This cosmetic indication poses an out-of-pocket cost to patients of over $110 per month or as low as $48 per month with a coupon at the time of publication.9

Given the potential for serious adverse effects with the use of systemic tranexamic acid, there has been interest in formulating and evaluating topical tranexamic acid for cosmetic indications.10-13 Topical tranexamic acid has been used alone and in conjunction with modalities to increase uptake, including intradermal injection, microneedling, and fractionated CO2 laser.12-14 Although these reports show initial promise, the currently available data are limited by small sample sizes, short treatment durations, lack of dose comparisons, and lack of short-term or long-term follow-up data. In addition to addressing these knowledge gaps in our understanding of topical tranexamic acid as a treatment option for melasma, further studies on the minimum systemic dose may address the downside of cost and potential for complications that may limit use of this medication in the United States.

The potential uses for tranexamic acid extend to the treatment of postinflammatory hyperpigmentation and rosacea. Melanocytes cultured in media conditioned by fractionated CO2 laser–treated keratinocytes were found to have decreased tyrosinase activity and reduced melanin content when treated with tranexamic acid, suggesting the potential role for tranexamic acid to be used postprocedurally to reduce the risk for postinflammatory hyperpigmentation in prone skin types.15 Oral and topical tranexamic acid also have been reported to improve the appearance of erythematotelangiectatic rosacea, potentially relating to the inhibitory effects of tranexamic acid on neovascularization.3,16,17 Although larger-scale controlled studies are required for further investigation of tranexamic acid for these indications, it has shown early promise as an adjunctive treatment for several dermatologic disorders, including melasma, and warrants further characterization as a potential therapeutic option.

References
  1. Higashi N. Treatment of melasma with oral tranexamic acid. Skin Res. 1988;30:676-680.
  2. Tse TW, Hui E. Tranexamic acid: an important adjuvant in the treatment of melasma. J Cosmet Dermatol. 2013;12:57-66.
  3. Sundbeck A, Karlsson L, Lilja J, et al. Inhibition of tumour vascularization by tranexamic acid. experimental studies on possible mechanisms. Anticancer Res. 1981;1:299-304.
  4. Maeda K, Naganuma M. Topical trans-4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation-induced pigmentation. J Photochem Photobiol B. 1998;47:136-141.
  5. Li D, Shi Y, Li M, et al. Tranexamic acid can treat ultraviolet radiation-induced pigmentation in guinea pigs. Eur J Dermatol. 2010;20:289-292.
  6. Lee HC, Thng TG, Goh CL. Oral tranexamic acid (TA) in the treatment of melasma: a retrospective analysis. J Am Acad Dermatol. 2016;75:385-392.
  7. Kim HJ, Moon SH, Cho SH, et al. Efficacy and safety of tranexamic acid in melasma: a meta-analysis and systematic review. Acta Derm Venereol. 2017;97:776-781.
  8. Perper M, Eber AE, Fayne R, et al. Tranexamic acid in the treatment of melasma: a review of the literature. Am J Clin Dermatol. 2017;18:373-381.
  9. Tranexamic acid. GoodRx website. https://www.goodrx.com/tranexamic-acid. Accessed February 2, 2018.
  10. Kim SJ, Park JY, Shibata T, et al. Efficacy and possible mechanisms of topical tranexamic acid in melasma. Clin Exp Dermatol. 2016;41:480-485.
  11. Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014;19:753-757.
  12. Xu Y, Ma R, Juliandri J, et al. Efficacy of functional microarray of microneedles combined with topical tranexamic acid for melasma: a randomized, self-controlled, split-face study. Medicine (Baltimore). 2017;96(19):e6897.
  13. Hsiao CY, Sung HC, Hu S, et al. Fractional CO2 laser treatment to enhance skin permeation of tranexamic acid with minimal skin disruption. Dermatology (Basel). 2015;230:269-275.
  14. Saki N, Darayesh M, Heiran A. Comparing the efficacy of topical hydroquinone 2% versus intradermal tranexamic acid microinjections in treating melasma: a split-face controlled trial [published online November 9, 2017]. J Dermatolog Treat. doi:10.1080/09546634.2017.1392476.
  15. Kim MS, Bang SH, Kim JH, et al. Tranexamic acid diminishes laser-induced melanogenesis. Ann Dermatol. 2015;27:250-256.
  16. Kim MS, Chang SE, Haw S, et al. Tranexamic acid solution soaking is an excellent approach for rosacea patients: a preliminary observation in six patients. J Dermatol. 2013;40:70-71.
  17. Kwon HJ, Suh JH, Ko EJ, et al. Combination treatment of propranolol, minocycline, and tranexamic acid for effective control of rosacea [published online November 26, 2017]. Dermatol Ther. doi:10.1111/dth.12439.
References
  1. Higashi N. Treatment of melasma with oral tranexamic acid. Skin Res. 1988;30:676-680.
  2. Tse TW, Hui E. Tranexamic acid: an important adjuvant in the treatment of melasma. J Cosmet Dermatol. 2013;12:57-66.
  3. Sundbeck A, Karlsson L, Lilja J, et al. Inhibition of tumour vascularization by tranexamic acid. experimental studies on possible mechanisms. Anticancer Res. 1981;1:299-304.
  4. Maeda K, Naganuma M. Topical trans-4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation-induced pigmentation. J Photochem Photobiol B. 1998;47:136-141.
  5. Li D, Shi Y, Li M, et al. Tranexamic acid can treat ultraviolet radiation-induced pigmentation in guinea pigs. Eur J Dermatol. 2010;20:289-292.
  6. Lee HC, Thng TG, Goh CL. Oral tranexamic acid (TA) in the treatment of melasma: a retrospective analysis. J Am Acad Dermatol. 2016;75:385-392.
  7. Kim HJ, Moon SH, Cho SH, et al. Efficacy and safety of tranexamic acid in melasma: a meta-analysis and systematic review. Acta Derm Venereol. 2017;97:776-781.
  8. Perper M, Eber AE, Fayne R, et al. Tranexamic acid in the treatment of melasma: a review of the literature. Am J Clin Dermatol. 2017;18:373-381.
  9. Tranexamic acid. GoodRx website. https://www.goodrx.com/tranexamic-acid. Accessed February 2, 2018.
  10. Kim SJ, Park JY, Shibata T, et al. Efficacy and possible mechanisms of topical tranexamic acid in melasma. Clin Exp Dermatol. 2016;41:480-485.
  11. Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014;19:753-757.
  12. Xu Y, Ma R, Juliandri J, et al. Efficacy of functional microarray of microneedles combined with topical tranexamic acid for melasma: a randomized, self-controlled, split-face study. Medicine (Baltimore). 2017;96(19):e6897.
  13. Hsiao CY, Sung HC, Hu S, et al. Fractional CO2 laser treatment to enhance skin permeation of tranexamic acid with minimal skin disruption. Dermatology (Basel). 2015;230:269-275.
  14. Saki N, Darayesh M, Heiran A. Comparing the efficacy of topical hydroquinone 2% versus intradermal tranexamic acid microinjections in treating melasma: a split-face controlled trial [published online November 9, 2017]. J Dermatolog Treat. doi:10.1080/09546634.2017.1392476.
  15. Kim MS, Bang SH, Kim JH, et al. Tranexamic acid diminishes laser-induced melanogenesis. Ann Dermatol. 2015;27:250-256.
  16. Kim MS, Chang SE, Haw S, et al. Tranexamic acid solution soaking is an excellent approach for rosacea patients: a preliminary observation in six patients. J Dermatol. 2013;40:70-71.
  17. Kwon HJ, Suh JH, Ko EJ, et al. Combination treatment of propranolol, minocycline, and tranexamic acid for effective control of rosacea [published online November 26, 2017]. Dermatol Ther. doi:10.1111/dth.12439.
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Treatment of Melasma Using Tranexamic Acid: What’s Known and What’s Next
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  • Oral tranexamic acid is an antifibrinolytic agent that can be used off-label for the treatment of melasma.
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