記住我
Kiran Godse1, Rashmi Sarkar2, Venkataram Mysore3, Manunath M Shenoy4, Manas Chatterjee5, Rajetha Damisetty6, Swapnil Shah7, Maya Vedamurthy8, Sanjeev Aurangabadkar9, Chakravarthi Srinivas10, Anil Ganjoo11, Sudip Das12, Anant Patil13
1 From the Department of Dermatology, Dr. DY Patil Medical College, Navi Mumbai, Maharashtra, India
2 Dermatology at Lady Hardinge, Medical College and Associated Hospitals, Delhi University, New Delhi, Delhi, India
3 Consultant Dermatologist, Venkat Center for Skin ENT and Plastic Surgery, Bengaluru, Karnataka, India
4 Department of Dermatology, Yenepoya Medical College, Yenepoya University, Mangalore, Karnataka, India
5 Brig Med 14 Corps and Consultant Dermatologist, Leh, Ladakh, India
6 Consultant Dermatologist, Mohana Skin and Hair Clinic, Hyderabad, Telangana, India
7 Consultant Dermatologist, Solapur, Maharashtra, India
8 Consultant Dermatologist, Apollo Hospitals, Chennai and RSV Skin and Research Centre, Chennai, Tamil Nadu, India
9 Consultant Dermatologist, Skin and Laser Clinic, Begumpet, Hyderabad, Telangana, India
10 Dermatology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
11 Department of Dermatology and Venereology, Saroj Hospital and Heart Institute, New Delhi, Delhi, India
12 Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
13 Department of Pharmacology, Dr. DY Patil Medical College, Navi Mumbai, Maharashtra, India
Correspondence Address:
Anant Patil
Department of Pharmacology, Dr. DY Patil Medical College, Navi Mumbai - 400 701, Maharashtra
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ijd.ijd_266_22
Abstract
Melasma, a chronic pigmentary skin condition mainly affecting the face, remains a challenge despite the availability of several options for treatment. Many melasma patients are not satisfied with treatment outcomes. Tranexamic acid (TXA), an anti-fibrinolytic drug has shown promising results in patients with melasma. Evidence from several clinical studies has surfaced on efficacy and tolerability of TXA in these patients. It can be used as monotherapy or adjuvant with other therapies. Currently, there is no published consensus or guideline document for its use in the treatment of melasma. TXA is available for oral use, topical use as well as an injection. In this article, a consensus of Indian experts is prepared based on the available literature and experience with use of oral TXA in melasma. This review article might help clinicians for use of oral TXA appropriately while treating melasma.
Keywords: Adverse event, anti-fibrinolytic agent, evidence, treatment outcome
Introduction 
Melasma, a chronic, acquired pigmentary disorder due to dysfunction in melanogenesis affecting exposed body parts, mainly the face is one of the common reasons of patients to consult dermatologists.[1] Patients may develop localized hyperpigmentation of skin. The condition is associated with significant psychological disturbance resulting in impaired quality of life.[2] Although several treatment options including hydroquninone, tretinoin and corticosteroid combinations, non-steroidal topical formulations for demelanization, chemical peels and lasers, and intense pulse light are available, they do not show promising results in many patients, making treatment unsatisfactory and challenging.[1],[3],[4] Treatment can be frustrating both to the physician as well as patients.[5] Therefore, clinicians still look forward to newer and better treatment options for melasma.[3]
Tranexamic acid (TXA)
TXA, an anti-fibrinolytic agent, through inhibition of plasminogen activator pathway in skin, is proposed to act by preventing melanocytes activation due to ultraviolet (UV) light, hormones, and injured keratinocyte.[6]
Vascular proliferation is considered to have an important role in the development melasma.[7] Reduction in the activity of melanocyte tyrosinase by reducing prostaglandins and decreased angiogenesis in dermal blood vessels by inhibition of vascular endothelium growth factor are other proposed mechanisms of TXA in melasma.[6]
TXA is used in different formulations for the treatment of melasma.[1],[2] It acts by inhibiting plasminogen activator which convers plasminogen to plasmin.[1]
TXA is available in different formulations including tablet, injection, and topical application. TXA tablets are available for oral use in the strengths of 250 mg and 500 mg. Combination of 250 mg with proanthocyanadin is also available.
Oral formulation (tablets) of TXA is approved by the US FDA for the treatment of cyclic heavy menstrual bleeding.[8] TXA injection is approved in hemophilia for short-term to reduce or prevent bleeding and decrease the requirement for replacement therapy during and after tooth extraction.[9] Considering its mechanism, several researchers have evaluated efficacy of TXA in melasma. Oral, topical, as well intradermal formulations have been evaluated for its efficacy and safety in patients with melasma. It has been used either alone or along with other therapy such as laser.[2] However, its use in melasma is not approved by US FDA or Indian regulatory authority, Drug Controller General-India (DCGI).
Despite of several published studies, and its use off-label in clinical practice currently, there is no consensus or published guideline for use of TXA in melasma. With this background, this review and experience-based consensus of Indian experts is prepared to evaluate currently available evidence with TXA and its place in the treatment of melasma.
Materials and Methods A draft document was prepared based on the available published evidence retrieved through PubMed/Medline, Google Scholar and Cochrane Database. Search words included “melasma” “tranexamic acid” “trial” “study” words in the title. References of relevant articles were also included for review. Clinical trials, prospective studies, retrospective analysis, review articles, systematic reviews, meta-analysis, case series, and case reports were considered for this review. Studies from India as well as other countries were included for analysis of evidence. After screening of all articles, evidence from clinical studies with oral TXA is summarized. Suggestions from the experts were incorporated and draft was circulated among experts for final approval.
Results A total of 25 clinical studies published from 2012 to 2022 involving more than 2000 patients were retrieved. The details of these studies along with results are summarized in [Table 1]. We have summarized the results in two sections; prospective studies and retrospective studies based on the years of publications of these articles.
Evidence from prospective studies
Wu, et al. (2012)[10] evaluated use of oral TXA given in the dose of 250 mg BD for 6 months and follow-up was done for more than 6 months. The investigators evaluated the response in the form of improvement in pigmentation and decrease in melasma size. Good to excellent response was observed in about 65% patients. Adverse events in the form of gastrointestinal discomfort and hypomenorrhea were reported in this study. A total of 9.5% patients developed recurrence of melasma.[10] In the same year, Karn, et al.[11] published a larger randomized trial in which patients were divided into two groups. One group was treated with routine measures along with oral TXA 250 mg given twice daily for 3 months. Whereas patients in the other group were treated only with routine topical treatments. There was significant reduction in MASI at 8 and 12 weeks with TXA while in the group of patients treated only with topical measures, there was significant improvement only at 8 weeks, but not at 12 weeks. Another study[12] evaluated effects of oral plus topical TXA for 8 weeks with histological examination. They reported significant decrease in mean lesional melanin index (MI) scores along with decrease in epidermal pigmentation, vessel numbers, and mast cell counts. Cho, et al.[13] have evaluated oral TXA along with intense pulse light and laser therapy. Adjuvant therapy significantly reduced modified melasma area severity index (mMASI) in both groups, i.e., with intense pulse light as well as laser therapy.
Shin, et al.[14] compared effects of two sessions of low-fluence 1064-nm quality-switched neodymium-doped yttrium aluminum garnet (QSNY) laser alone versus laser plus oral TXA for 8 weeks. They reported significant reduction in mMASI score after 4 weeks of second treatment in both groups. In the combination group, more patients had grade 3 or more improvement. In another study, Agamia, et al.[15] compared efficacy of oral TXA Oral TXA versus oral TXA and Q-switched Nd: YAG laser (1064-nm wavelength). The authors concluded that addition of oral TXA may enhance efficacy and decrease side effects of laser therapy. Behrangi, et al.[16] recently reported their observations of microinjections (4 mg/ml) of TXA and Q-switched 1064 laser every 2 weeks versus oral TXA 250 mg three times a day and Q-switched 1064 laser every 2 weeks. Significant reduction in MASI score was observed in both groups. There was no significant difference in adverse events between two group. A study comparing oral TXA 250 mg thrice daily plus HQ 4% versus HQ 4% cream only showed significantly lower MASI score in combination group compared to control arm after 6 months without significant difference in the relapse rate or adverse events between two groups. Importantly, significantly higher treatment satisfaction was noted in combination group.[17] In another study, Shihab, et al.[18] reported that combination of oral TXA and topical hydroquinone is more effective than hydroquinone alone. In another small single-center placebo-controlled study, oral TXA 250 mg twice daily given for 12 weeks resulted in significant improvement (50% vs 5.9%; P < 0.005). Both groups used tinted sunscreen (SPF 50). There were no severe side effects with TXA therapy.[1]
In moderate to severe melasma, oral TXA 250 mg BD provided 49% reduction in mMASI score versus 18% in the control group at 3 months. After 3 months of stopping therapy, there was 26% reduction in mMASI score in TXA group compared to baseline versus 19% in placebo group.[19] Zhu, et al.[20] 2019 reported efficacy with all four doses (oral TXA 500 mg, 750 mg, 1,000 mg, or 1,500 mg) without significant difference. In another prospective study (n = 100), combination of oral plus topical 3% TXA provided significantly better results than oral TXA with 20% azelaic acid.[21] Minni et al. conducted evaluated efficacy or oral TXA plus topical fluocinolone-based combination cream (FbTC) versus topical FbTC alone. At 12th week, there was marked improvement in 65.6% patients in the first group as compared to 27.1% in group of patients receiving topical fluocinolone-based combination cream. Recurrence at 24 weeks in the first group was much lower as compared to comparator arm (18.03% vs 64.4%).[5]
In a recent study, oral TXA has been shown to decrease dermal blood flow in melasma and normal skin, but more reduction in the former.[22] Akl, et al. (2021)[23] studied efficacy of oral TXA 250 mg OD plus liposomal azelaic acid 20% cream or hydroquinone 4% cream. There was significant improvement with liposomal azelaic acid than hydroquinone 4%. Liposomal azelaic acid 20% was more significantly tolerable than comparator. Elkamshoushi, et al.[24] studied oral TXA 250 mg twice daily for three months alone versus combination of either topical hydroquinone 4% or low-fluence 1064 nm Q-switched Nd: YAG laser in mixed melasma. There was significant reduction of telangiectasia in all groups. However, relatively early and better cosmetic results were seen with combination of hydroquinone 4% and oral TXA. Another study compared oral TXA 250 mg twice daily, intradermal TXA 100 mg/mL and intradermal TXA 4 mg/mL given every 2 weeks for 8 weeks. Significant reduction in the mMASI and MI was seen in all groups. There was no statistically significant difference in three groups for changes in mMASI, melanin index (MI), and erythema index (EI).[25]
Padhi and Pradhan[26] compared topical therapy versus oral TXA 250 mg given twice daily plus fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 2% combination cream given once daily for 8 weeks. In this study, there was significantly faster reduction in pigmentation with oral TXA plus triple combination therapy. In a study involving, 100 patients Sharma, et al.,[27] reported equal efficacy with oral TXA 250 mg twice daily and intradermal microinjections of TXA 4 mg/mL every 4 weeks for 12 weeks. Khurana et al.[28] reported more improvement in MASI score with oral TXA than microinjections. Recurrence at 6 months follow-up was higher in the microinjection group. Recently, Sahu, et al.[3] compared efficacy of oral TXA 250 mg twice daily versus topical TXA and modified Kligman's regimen for 8 weeks along with sunscreen. Slightly, more efficacy was observed with modified Kligman's regimen followed by oral TXA. Topical TXA had lowest efficacy.
Evidence from retrospective studies
Lee, et al.[29] reported results of retrospective analysis in 561 patients. Improvement was noted in 503 (89.7%). Patients without family history of melasma demonstrated better response. Incidence of adverse events was 7.1%. Deep vein thrombosis was reported in one patient. This patient had familial protein S deficiency. Oral TXA has also reported to provide moderate to excellent improvement in 81.25% vitiligo patients with melasma on face.[31] Tan, et al.[32] refractory melasma (n = 25) with mean age 47.2 years Oral TXA 250 mg BD with pre-existing combination topical therapy. They also reported significant improvement in MASI scores after treatment as compared to baseline. A recently published meta-analysis reported effectiveness of oral TXA with well tolerated response in patients with melasma.[32]
Discussion Large number of clinical studies with different designs and from several countries have evaluated effects of oral TXA in melasma. Most of the studies retrieved were prospective in nature. Only three studies were retrospective in design.[29],[30],[31]
A study evaluating TXA doses from 500-1500 mg have showed no significant difference in efficacy.[20] Usual doses of TXA in studies range from 250 mg twice daily or thrice daily. Most commonly used dose is 250 mg twice daily. TXA has been used alone as well as adjuvant with other traditional or experimental therapies in patients with melasma. It has been shown to be effective in moderate to severe melasma.[19] Oral TXA has been studied along with sunscreen,[1] topical hydroquinone (HQ),[17],[18],[23] topical TXA or topical azelaic acid,[21] liposomal azelaic acid 20%[23] topical fluocinolone-based combination cream (FbTC)[5] laser[14],[15],[16] and intense pulse light.[13] Duration of therapy ranges from 4 weeks to about 6 months.
Clinical studies discussed in the previous section have not only showed clinical benefits, but also histological improvements in patients with melasma.[12] Reduction of dermal blood flow in melasma affected areas has also been demonstrated.[22] Evidence from Indian studies[1],[26],[27],[28] is also promising. Exact duration of therapy is not known. Recurrence has been reported after discontinuation of therapy. Results of retrospective studies are also in accordance with those from randomized clinical trials.[29],[30],[31] Adverse event profile from different clinical studies does not raise serious concerns. Gastrointestinal adverse events and hypomenorrhea are seen in few patients.
Adverse events and contraindications for use of oral TXA
Gastrointestinal adverse events and hypomenorrhea are reported adverse events with TXA.[10] Oral TXA should be stopped if patients receiving develops visual or ocular symptoms or severe allergic reaction.[8] TXA should be avoided in patients with hypersensitivity reactions to it, women receiving combination hormonal contraception and those with history, risk, or active thromboembolic disease.[8]
TXA is not approved for the treatment of melasma by USFDA or Drug Controller General, India (DCGI). Clinicians should inform this to the patient and obtain informed consent before using it for melasma treatment.
Expert consensus statements for use of oral tranexamic acid for the treatment of melasma are provided in [Box 1].
Conclusion Despite availability of several treatment options, outcomes of melasma are not satisfactory in many patients. Several clinical studies show that oral TXA is effective and well tolerated when given for the treatment of melasma. In order to avoid recurrence, in addition to oral TXA, other adjuvant therapies and sun protection should be advised to patients with melasma.
Financial support and sponsorship
Akumentis Healthcare Ltd supported the writing of this manuscript.
Conflicts of interest
There are no conflicts of interest.
References 
留言 (0)