Table of Content

Current Issue

Summer 2021, Vol. 29 No. 2

Hong Kong J. Dermatol. Venereol. (2021) 29, 62-70

Review Article

A review of oral treatments for melasma


SYT Tan 陳瀅俐 and DCW Aw 胡政偉

This article aims to evaluate current literature reporting on the efficacy and safety of oral agents in melasma management. An electronic search of publications via PUBMED database was conducted. The search only included clinical trials in the English language until 1 November 2019. This review is limited by small number of high-quality prospective studies each with small patient numbers. Significant heterogeneity in study design concerning study duration, concurrent treatments and outcome measures was present. Irrespective of melasma duration, oral tranexamic acid 500 mg daily appears to be a safe and effective treatment either as monotherapy or as an adjunct treatment.


Keywords: Dermatology, melasma, tranexamic acid

關鍵詞: 皮膚科、黃褐斑、氨甲環酸


Melasma, also known as chloasma, is a commonly acquired hypermelanosis usually involving the face. The prevalence of melasma is approximately 1% in the general population and 9-50% in those with an increased risk for developing the condition.1 Familial predisposition, ethnicity, darker skin types, pregnancy and varying levels of UV exposure are contributing aetiological factors.2

Melasma is a chronic cosmetic disease with a high impact on quality of life.3 Treatment modalities are multiple, can be complex and are constantly evolving to cater to the unmet needs of patients worldwide.1 Current available treatments for melasma include topical agents, oral medications, device-based and a combination of treatment methods targeting various phases of its pathogenic process such as inflammation, vascularity, photodamage and melanin production and transfer.1 It has been widely recommended that the management of melasma take a multifaceted approach, with first-line treatments comprising UV protection and topical whitening agents.4,5

For half a century now, hydroquinone has been the gold standard in topical agents for the treatment of hyperpigmentary conditions including melasma, backed by robust data proving its efficacy and safety.6,7 Other topical lightening agents for melasma include azelaic acid, kojic acid, ascorbic acid, retinoids, corticosteroids, niacinamide, liquorice, undecylenoyl phenylalanine, 4-N-butylresorcinol, soybean, arbutin, glucosamine and mequinol.8 Chemical peels with glycolic acid, Jessner's solution and retinoic acid are common adjuvant therapies but can occasionally result in rebound melasma or post-inflammatory hyperpigmentation (PIH) especially in dark-skinned individuals. In patients with refractory melasma, laser and light therapies are becoming increasingly popular third-line treatment options but suffer similar pigmentary risks as chemical peels. Commonly used device-based therapies for melasma include intense pulsed light (IPL), Q-switched lasers, pico lasers, non-ablative and ablative lasers.9 Recent years have seen a surging interest in the use of oral agents for melasma. Lauded for convenience, efficacy and safety, such agents include tranexamic acid, Polypodium leucotomos extract and various flavonoids.

Tranexamic acid, which was initially found to inhibit bleeding, was later discovered that through the inhibition of the plasmin/plasminogen pathway, firstly it was able to block the melanocyte-keratinocyte interaction, which in turn inhibited epidermal melanocyte tyrosinase activity; and secondly it decreased the production of inflammatory mediators which stimulate melanocyte activity.10 Tranexamic acid has also been shown to decrease pigmentation caused by UV radiation through blocking UV-induced plasmin activity and arachidonic acid production.11 Furthermore, tranexamic acid interferes with mast cell activity, which is involved in the degradation of type IV collagen and basement membrane components.12,13 Lastly, tranexamic acid stops fibroblast growth factor-induced neovascularisation.14 Polypodium Leucotomos extract, when administered orally is known to reduce UV-induced pigmentation through its antioxidant and photoprotective properties.15,16 Flavonoids, due to their structure, interact with the copper ions of the tyrosinase active site to inhibit the functional capacity of the enzyme.17,18

We aim to review and update on these oral agents for melasma.


A search via PUBMED database was conducted for articles written in the English language until 1 November 2019, with the medical subject headings of "melasma", "chloasma" and "oral treatment". The search only included clinical trials. All papers identified in the PUBMED search were reviewed, and bibliographies were hand-searched for more papers.


Forty-five articles were identified, with twenty-nine papers excluded as they either did not include oral treatments for melasma, or they were irrelevant to the topic of interest. Sixteen manuscripts were reviewed in this paper. The overwhelming preponderance of data was on the use of oral tranexamic acid for melasma and it is summarised in Table 1. Table 2 summarises other oral agents that have been used in melasma. Results in Tables 1 and 2 report only objective results, with subjective results excluded. Concurrent therapies, adverse reactions and side effects have also been excluded from the tables.

Table 1 Tranexamic acid (TXA) as oral agent for melasma
Study (First author, year) Study design & duration Dose Study outcome
Karn et al. 2012.23 6-month prospective, interventional RCT (treatment for 3 months, then 4-weekly reviews for 3 more months) 250 mg BD MASI
With TXA:
Baseline: 11.08±2.91 8 weeks: 8.95±2.08 (19.2% reduction) 12 weeks: 7.84±2.44 (29.2% reduction)
Without TXA:
Baseline: 11.60±3.40 8 weeks: 9.9±2.61(14.7% reduction) 12 weeks: 9.26±3(20.2% reduction)
Wu et al. 2012.24 12-month cohort study (treatment for 6 months then follow-up for 6/12) 250 mg BD Assessor & patient ratings at 6 months
Excellent: 10.8% Good: 54% Fair: 31.3% Poor: 4.1%
12 months:
9.5% recurrence of varying degrees
Cho et al. 2013.25 8-month retrospective review of medical records 500 mg BD mMASI
With TXA:
Baseline: 11.33±7.07 8 months: 6.21±5.04 Decrease: 43.8%±22.1%; Baseline & 2-3 weeks after IPL treatment: Decrease: 30.1%±21.1%
Without TXA:
Baseline: 11.70±6.72 8 months: 8.93±5.89 Decrease: 23.6%±22.1%; Baseline & 2-3 weeks after IPL treatment: Decrease: 13.6%±14.3%
Na et al. 2013.26 8-week prospective open-label study 250 mg TDS Melanin Index Lesional skin Baseline: 191.48; 4 weeks: 186.14 8 weeks: 184.82; Perilesional skin Baseline: 120.30; 4 weeks: 126.24 8 weeks: 129.70
Erythema Index
Lesional skin Baseline: 272.15; 8 weeks: 255.00 Perilesional skin Baseline: 216.64; 8 weeks: 231.14
Shin et al. 2013.27 8-week prospective RCT 750 mg OD mMASI (intention-to-treat analysis)
With TXA
8 weeks: 2.9 score decrease (8.0±4.3-5.1±3.3); 4 weeks post treatment: 38.1±22.1% reduction
Without TXA
8 weeks: 1.9 score decrease (7.9±3.9-6.0±3.2); 4 weeks post treatment: 21.9±18.5% reduction
Melanin Index at 8 weeks (intention-to-treat analysis)

With TXA
166.5±49.6-157.5±56.9 decrease
Without TXA
163.1±44.6-158.1±28.7 decrease
Aamir et al. 2014.28 12-month prospective, interventional cross-sectional study (6 months treatment then months follow-up) 250 mg BD Recurrence of any variant at 12 months
87% no recurrence, 12% recurrence
Li et al. 2014.29 16-week prospective, open-label study 2 tabs TDS (dose unspecified) V Value (undefined by authors)
(7.16±0.42)/(6.21±0.54); 4 weeks: (7.44±0.32)/(6.77±0.37); 8 weeks: (7.47±0.24)/(6.79±0.31) ; 12 weeks: (7.60±0.22) 0.22)/(7.01±0.28); 16 weeks: (7.67±0.28)/(7.10±0.36)
V Value difference from baseline

4 weeks:
(0.29±0.40)/(0.55±0.50); 8 weeks: (0.30±0.39)/(0.56±0.47); 12 weeks: (0.45±0.36)/(0.82±0.51); 16 weeks: (0.49±0.41)/(0.86±0.57)
Lee et al. 2016.30 54-month retrospective review of medical records 250 mg BD Degree of Improvement
Worsened: 0.4%; Unchanged: 10.0%; Improved: 89.7%; Initial time to response was 2 months and the median duration of treatment was 4 months. 27.2% relapse rate.
Lajevardi et al. 2017.31 6-month parallel-group, double-blind, RCT (3 months treatment followed by 3 months follow-up) 250 mg TDS MASI
With TXA:
Baseline: 14.4±8.4; 1 month: 35% reduction from baseline; 3 months: 51% reduction from baseline; 6 months: relapse rate of 30%
Without TXA:
Baseline: 10.7±6.2; 1 month: 21% reduction from baseline; 3 months: 33% reduction from baseline; 6 months: relapse rate of 26%
Sharma et al. 2017.32 12-week prospective RCT 250 mg BD MASI
With oral TXA:
Baseline: 12.25±4.44; Week 4: 21.29±17.24% reduction; Week 8: 53.32±16.50% reduction; Week 12: 77.96±9.39% reduction
With intradermal TXA:
Baseline: 11.29±6.07; Week 4: 18.27±15.34% reduction; Week 8: 51.32±17.20% reduction; Week 12: 79.00±9.64% reduction
Del Rosario et al. 2018.33 6-month prospective RCT (intervention for 3 months, then off intervention for 3 months) 250 mg BD mMASI
With TXA
3 months: 49% reduction - Moderate melasma: 45% reduction; Severe melasma: 51% reduction 6 months: 26% reduction - Moderate melasma: 32% reduction; Severe melasma: 21% reduction
With placebo 3 months: 18% reduction - Moderate melasma: 16% reduction; Severe melasma: 19% reduction 6 months: 19% reduction - Moderate melasma: 13% reduction; Severe melasma: 24% reduction
Melanin Index (MI)
Baseline to 12 weeks:
Greater reduction in Group TXA; 24 weeks: Lower scores than baseline in both groups
Khurana et al. 2019.34 6-month prospective, randomised, open label study (treatment for 3 months followed by follow-up for 3 months) 250 mg BD MASI
With oral TXA
Baseline: 7.48±3.73; 6 months: 3.18±1.93% improved: 57.48; % of patients with worsening of lesions at the 6-month follow-up from baseline: 6.25
With intralesional TXA
Baseline: 4.11±2.69; 6 months: 2.32±2.56% improved: 43.55; % of patients with worsening of lesions at the 6-month follow-up from baseline: 9.37
% Grading of Treatment Response

With oral TXA
>50% improvement: All patients (100%); >75% improvement: 8 patients (25%)
With intralesional TXA
>50% improvement: 17 patients (53%) >75% improvement: 3 patients (9%)

Table 2 Other oral agents for melasma
Study (First author, year) Study design & duration Dose Study outcome
Ni et al. 2002.36 1-month prospective cohort study 25 mg of Pycnogenol (French maritime pine bark) TDS Melasma area (mm2)
Baseline: 68.65±44.06; Day 30: 42.79±35.59;
Decrease: 25.8±20.39
Pigmentary intensity (unit)

Baseline: 2.10±0.71; Day 30: 1.63±0.61;
Decrease: 0.47±0.51
3-point semi-quantitative scale (melasma area & pigmentary intensity collectively)

2: markedly improved (23.33%); 1: effective (56.67%); 0: ineffective (20.00%)
Yamakoshi et al. 2004.37 1-year prospective open design study 67 mg of GSE (54 mg of proanthocyanidin) TDS. There was a mandatory one-month break mid-way in the study. SE = Grape-seed extract L (lightening) value of melasma using reflectance spectrophotometer (measured monthly)
Baseline: 57.84±2.48; 6 months: 59.25±2.31; 12 months: 58.70±2.52
MI (calculated monthly)
Baseline: 0.025±0.005; 6 months: 0.019±0.004; 12 months: 0.021±0.005
Size (length & width) using electronic callipers (measured monthly)

Baseline: L 4.42±0.82 mm W 4.44±0.93 mm; 6 months: L 4.10±0.71 mm W4.07±0.77 mm; 12 months: L 4.26±0.6 mm W 4.17±0.78 mm
Handog et al. 2009.35 8-week prospective RCT comparing oral procyanidin with vitamins A, C, E versus placebo 24 mg procyanidin, 6 mg of Vit A precursor, 60 mg Vit C, and 15 IU of Vit E. BD. MI
Measured at baseline, week 4 and week 8. Decreased significantly across all with procyanidin group participants at weeks 4 and 8. Exact figures unspecified.

Measured at baseline, week 4 and week 8. Decreased significantly in both groups. Exact figures unspecified.
Ahmed et al. 2013.38 12-week prospective RCT comparing Polypodium leucotomos extract versus placebo 240 mg TDS Melanin Index
With Polypodium leucotomos extract
Baseline: 43; Week 6: 35; Week 12: 30.62 (28.8% improvement from baseline)
With Placebo
Baseline: 53; Week 6: 47.5; Week 12: 45.68 (13.8% improvement from baseline)
With Polypodium leucotomos extract
Baseline: 14.4; Week 6: 11.0; Week 12: 11.0
With Placebo
Baseline: 13.2; Week 6: 10.8; Week 12: 10.2

Various scoring systems were used to assess melasma in the studies.

The Melasma Area and Severity Index (MASI) scoring system, as developed by Kimbrough-Green et al, is the most common outcome measure adopted in clinical trials.19 This tool accounts for subjective evaluations of four regions of the face: forehead (30%), right malar region (30%), left malar region (30%) and chin (10%), and considers aspects of area of involvement (A), darkness (D) and homogeneity (H). The area of involvement in each of the four regions is given a score from 0 to 6 (0= no involvement; 1=<10%; 2=10%-29%; 3=30%-49%; 4=50%-69%; 5=70%-89%; and 6=90%-100%), whilst darkness and homogeneity are both scored from 0 to 4 (0=absent; 1=slight; 2=mild; 3=marked; and 4=maximum) for each corresponding region. The MASI score, ranging from 0 to 48, is then calculated using the following algorithm: [0.3(D+H)]A(forehead) + [0.3(D+H)]A(left malar) + [0.3(D+H)A(right malar) + [0.10(D+H)]A(chin).20

The MASI scoring system was assessed for its reliability and validity by Pandya et al and revealed difficulties in assessing individual components of the algorithm, particularly in homogeneity and the chin. As part of the validation process of MASI using ANOVA models, Pandya et al proposed the mMASI scoring system with the exclusion of the homogeneity component to produce a more consistent scoring system. Evaluation of the chin was retained as it is essential to assessment of the face and with only 10% representation of the total score, it was deemed to cause little change to the score. The mMASI score ranging from 0 to 24, was proposed to be calculated as follows: [0.3D]A(forehead) + [0.3D]A(left malar) + [0.3D)A(right malar) + [0.10D]A(chin).20

A narrow-band reflectance spectrophotometer is used to measure the Melanin Index (MI) and Erythema Index (EI). The spectrophotometer reflects light onto the subjects' skin and a Red-Green-Blue sensor assesses the intensities of each light reflected back, which is then used to calculate the MI and EI scores as follows:21

Studies in this paper that adopted the MI and EI outcome measurements used either the Mexameter® or the Minolta CM-2600d spectrophotometers.

Lightening (L*) value, which assesses the skin's darkness (0) or lightness value (100) was adopted in one study using the Minolta CM-2600d spectrophotometer.


This review included twelve studies (ten prospective, two retrospective) on oral TXA comprising of 1380 participants.23-34 The largest pool of 561 participants came from a retrospective review by Lee et al.30 Participants were mainly Asians, but also included cases of Hispanic and Middle Eastern ethnicity. A few studies examined the characteristics of the melasma in subjects;23,28,32,34,35 not unexpectedly, the predominant pattern was epidermal followed by mixed and then dermal. Supplementation of 500 mg oral TXA to mainstream therapies such as hydroquinone, intense pulsed light and Q-switched Nd:YAG laser doubled the effectiveness in treating melasma, as suggested in one retrospective study and two prospective randomised controlled trials. Notwithstanding the disparity in daily dosages adopted (three studies looked at 750 mg while nine looked at 500 mg), all papers reported significant improvements from baseline across all outcome measures. The longest duration of oral tranexamic acid was studied by Aamir.28 Adverse effects were uncommon but the most frequently reported were menstrual (irregularities were observed in no higher than 18.2% of subjects in any paper) and gastrointestinal disturbances (highest observed incidence was 22.7% in a 6-month prospective open-label study).33 We try to ascertain the lowest effective dose by comparisons within individual outcome measures.

Four studies reported with the MASI scoring system.31-34 Comparison between efficacy outcomes at the third month were conflicting over the two doses.23,31,32 At six months, participants on 750 mg/day demonstrated a greater relapse rate than those on 500 mg/day, perhaps contributed by Fitzpatrick skin type, melasma duration and distribution (relapse rates of 30% and 6.25% respectively).31,34 It is important to note that the former study was double-blinded whereas the latter was open-label. Interestingly, two studies that compared oral and intralesional tranexamic acid demonstrated superiority in MASI improvements at weeks 4, 8 and 24 with oral treatment.32,34

Three studies used the mMASI scoring system.25,27,33 Score reductions were 2.9 at two months with 750 mg/day,27 and 5.12 at eight months,25 and 4.2 at three months with 500 mg/day.33 As studies looked at different timeframes from baseline, it was difficult to decisively conclude on the more efficacious dosage. Three studies reported with the MI scoring system.26,27,33 At the two-month mark, MI scores reduced by 6.66,26 and 9 (p=0.23)27 with 750 mg/day. The 500 mg/d group saw greater MI score reductions than placebo although values were unspecified.33

Five studies reported mean melasma duration, with four reporting ranges between three and six years and one study reporting a duration of 13 years. Participants demonstrated significant improvements at 3 and 6 months, suggesting that a longer melasma duration did not have any impeding effect on drug efficacy.

Four studies investigating non-TXA oral agents (Polypodium leucotomos extract, the proanthocyanidins family including the French maritime pine bark and Vitamins A, C and E) were identified.35-38 The efficacy of the oral agents was assessed by looking at outcome measures such as MASI, MI and melasma area, pigmentary intensity and L values; clinical evaluations and patient self-assessments. Only two were placebo controlled. Although an overall trend towards improvement with active intervention was observed, patient self-assessments in the controlled studies failed to report significant improvements. In the three studies on proanthocyanidins family, dosages and outcome measures adopted varied widely rendering it difficult to make any meaningful conclusion on the efficacy of this class of supplement in treatment of melasma.35-37


This review is primarily limited by the small number of high-quality prospective studies, each with small patient numbers. Except for the study by Del Rosario, all the prospective tranexamic acid studies were not controlled with placebo, and only included patients without previous interventions. Indirect head-to-head comparisons made in the discussion must be interpreted with a high degree of caution due to significant heterogeneity of study designs. Wide variations were noted in study duration and outcome measures. Data on concurrent treatments suffered from lack of clarity in dosing regimens and consistency in dosing. Caucasians and Afro-Caribbeans were excluded from all studies. Therapeutic compliance to interventional and adjuvant therapies was not evaluated in any study.


Oral tranexamic acid at 500 mg/day is shown in this review to be a safe and effective treatment for melasma. As the therapy has been shown to be highly promising, large-scale multicentre double-blind placebo-controlled studies on oral tranexamic acid for melasma in all ethnicities using validated objective (mMASI) and patient-centred (MelasQOL) scoring systems, preferably with long-term (beyond six months) extension studies on the safety and maintenance of efficacy of oral tranexamic acid should be considered.


1. Ogbechie-Godec OA, Elbuluk N. Melasma: an Up-to-Date Comprehensive Review. Dermatol Ther (Heidelb)2017;7:305-18.

2. Moin A, Jabery Z, Fallah N. Prevalence and awareness of melasma during pregnancy. Int J Dermatol 2006;45:285-8.

3. Harumi O, Goh CL. The Effect of Melasma on the Quality of Life in a Sample of Women Living in Singapore. J Clin Aesthet Dermatol 2016;9:21-4.

4. Rivas S, Pandya AG. Treatment of melasma with topical agents, peels and lasers: an evidence-based review. Am J Clin Dermatol 2013;14:359-76.

5. Sarma N, Chakraborty S, Poojary SA, Rathi S, Kumaran S, Nirmal B, et al. Evidence-based Review, Grade of Recommendation, and Suggested Treatment Recommendations for Melasma. Indian Dermatol Online J 2017;8:406-42.

6. Nordlund JJ, Grimes PE, Ortonne JP. The safety of hydroquinone. J Eur Acad Dermatol Venereol 2006;20:781-7.

7. Tse TW. Hydroquinone for skin lightening: safety profile, duration of use and when should we stop? J Dermatolog Treat 2010;21:272-5.

8. Grimes PE, Ijaz S, Nashawati R, Kwak D. New oral and topical approaches for the treatment of melasma. Int J Womens Dermatol 2019;5:30-6.

9. Trivedi MK, Yang FC, Cho BK. A review of laser and light therapy in melasma. Int J Womens Dermatol 2017;3:11-20.

10. Maeda K, Tomita Y. Mechanism of the Inhibitory Effect of Tranexamic Acid on Melanogenesis in Cultured Human Melanocytes in the Presence of Keratinocyte-conditioned Medium. J Health Sci 2007;53:389-96.

11. Maeda K, Naganuma M. Topical trans-4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation-induced pigmentation. J Photochem Photobiol 1998;47:136-41.

12. Reichel CA, Lerchenberger M, Uhl B, Rehberg M, Berberich N, Zahler S, et al. Plasmin Inhibitors Prevent Leukocyte Accumulation and Remodeling Events in the Postischemic Microvasculature. PLoS ONE 2011;6:e17229.

13. Iddamalgoda A, Le QT, Ito K, Tanaka K, Kojima H, Kido H. Mast cell tryptase and photoaging: possible involvement in the degradation of extra cellular matrix and basement membrane proteins. Arch Dermatol Res 2008;300:69-76.

14. Bastaki M, Nelli EE, Dell'Era P, Rusnati M, Molinari-Tosatti MP, Parolini S, et al. Basic Fibroblast Growth Factor-Induced Angiogenic Phenotype in Mouse Endothelium. Arterioscler. Thromb. Vasc Biol 1997;17:454-64.

15. Middelkamp-Hup MA, Pathak MA, Parrado C, Goukassian D, Rius-Díaz F, Mihm MC, et al. Oral Polypodium leucotomos extract decreases ultraviolet-induced damage of human skin. J Am Acad Dermatol 2004;51:910-8.

16. Middelkamp-Hup MA, Pathak MA, Parrado C, Garcia-Caballero T, Rius-Díaz F, Fitzpatrick TB, et al. Orally administered polypodium leucotomos extract decreases psoralen-UVA-induced phototoxicity, pigmentation, and damage of human skin. J Am Acad Dermatol 2004;50:41-9.

17. Şöhretoğlu D, Sari S, Barut B, Özel A. Tyrosinase inhibition by some flavonoids: Inhibitory activity, mechanism by in vitro and in silico studies. Bioorg Chem 2018;81:168-74.

18. Jacob V, Hagai T, Soliman K. Structure-Activity Relationships of Flavonoids. Curr Org Chem 2011;15:2641-57.

19. Kimbrough-Green CK, Griffiths CEM, Finkel LJ, Hamilton TA, Bulengo-Ransby SM, Ellis CN, et al. Topical Retinoic Acid (Tretinoin) for Melasma in Black Patients: A Vehicle-Controlled Clinical Trial. Arch Dermatol 1994;130:727-33.

20. Pandya AG, Hynan LS, Bhore R, Riley FC, Guevara IL, Grimes P, et al. Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol 2011;64:78-83.e1-2.

21. Khalid AT, Moore CG, Hall C, Olabopo F, Rozario NL, Holick MF, et al. Utility of sun-reactive skin typing and melanin index for discerning vitamin D deficiency. Pediatr Res 2017;82:444-51.

22. Fullerton A, Fischer T, Lahti A, Wilhelm KP, Takiwaki H, Serup J. Guidelines for measurement skin colour and erythema. A report from the Standardization Group of the European Society of Contact Dermatitis. Contact Dermatitis 1996;35:1-10.

23. 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.

24. 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.

25. Cho HH, Choi M, Cho S, Lee JH. Role of oral tranexamic acid in melasma patients treated with IPL and low fluence QS Nd:YAG laser. J Dermatolog Treat 2013;24:292-6.

26. 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.

27. Shin JU, Park J, Oh SH, Lee JH. Oral tranexamic acid enhances the efficacy of low-fluence 1064-nm quality-switched neodymium-doped yttrium aluminum garnet laser treatment for melasma in Koreans: a randomized, prospective trial. Dermatol Surg 2013;39(3 Pt 1):435-42.

28. Aamir S, Naseem R. Oral tranexamic acid in treatment of melasma in Pakistani population: a pilot study. Journal of Pakistan Association of Dermatologists 2014;24.

29. 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.

30. Lee HC, Thng TG, Goh CL. Oral tranexamic acid (TA) in the treatment of melasma: A retrospective analysis. J Am Acad Dermatol 2016;75:385-92.

31. Lajevardi V, Ghayoumi A, Abedini R, Hosseini H, Goodarzi A, Akbari Z, et al. Comparison of the therapeutic efficacy and safety of combined oral tranexamic acid and topical hydroquinone 4% treatment vs. topical hydroquinone 4% alone in melasma: a parallel-group, assessor- and analyst-blinded, randomized controlled trial with a short-term follow-up. J Cosmet Dermatol 2017;16:235-42.

32. Sharma R, Mahajan VK, Mehta KS, Chauhan PS, Rawat R, Shiny TN. Therapeutic efficacy and safety of oral tranexamic acid and that of tranexamic acid local infiltration with microinjections in patients with melasma: a comparative study. Clin Exp Dermatol 2017;42:728-34.

33. Del Rosario E, Florez-Pollack S, Zapata L, Jr., Hernandez K, Tovar-Garza A, Rodrigues M, et al. Randomized, placebo-controlled, double-blind study of oral tranexamic acid in the treatment of moderate-to-severe melasma. J Am Acad Dermatol 2018;78:

34. Khurana VK, Misri RR, Agarwal S, Thole AV, Kumar S, Anand T. A randomized, open-label, comparative study of oral tranexamic acid and tranexamic acid microinjections in patients with melasma. Indian J Dermatol Venereol Leprol 2019;85:39-43.

35. Handog EB, Galang DA, de Leon-Godinez MA, Chan GP. A randomized, double-blind, placebo-controlled trial of oral procyanidin with vitamins A, C, E for melasma among Filipino women. Int J Dermatol 2009;48:896-901.

36. Ni Z, Mu Y, Gulati O. Treatment of melasma with Pycnogenol® Phytother Res 2002;16:567-71.

37. dkoshi J, Sano A, Tokutake S, Saito M, Kikuchi M, Kubota Y, et al. Oral intake of proanthocyanidin-rich extract from grape seeds improves chloasma. Phytother Res 2004;18:895-9.

38. Ahmed AM, Lopez I, Perese F, Vasquez R, Hynan LS, Chong B, et al. A randomized, double-blinded, placebo-controlled trial of oral Polypodium leucotomos extract as an adjunct to sunscreen in the treatment of melasma. JAMA Dermatol 2013;149:981-3.