Effectiveness and Safety of Intradermal Tranexamic Acid Injection as an Adjunctive Treatment for Melasma in Skin Type IV–V: A Double-blind Randomized Controlled Trial

J Clin Aesthet Dermatol. 2025;18(7):30–34.

by Vashty Amanda Hosfiar, MD; Irma Bernadette S. Sitohang, MD, PhD, Prof; and Githa Rahmayunita, MD

All authors are with the Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia at Dr. Cipto Mangunkusumo Hospital in Jakarta, Indonesia.

FUNDING: No funding was provided for this article.

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

Abstract: Objective: Melasma is an acquired pigmentary disorder for which tranexamic acid (TA) injection has shown promising results in earlier studies. This study aimed to evaluate the effectiveness and safety of intradermal TA as an adjuvant therapy for melasma in individuals with Fitzpatrick Skin Type IV–V. Methods: We conducted a double-blind, randomized, split-face controlled trial of 34 female patients with melasma. All subjects were randomized to receive either 10mg of intradermal TA or placebo injection on the right or the left side of their face. The primary outcome was improvement of melasma lesions assessed by modified Melasma Area and Severity Index (mMASI) score and mexameter examination which includes Melanin Index (MI) and Erythema Index (EI). Measurements were done at baseline and every two weeks for 12 weeks. Additionally, side effects of therapy and subject satisfaction assessment with patient global assessment (PtGA) were also documented. Results: This study showed the reduction of mMASI score was larger and faster in intervention group compared to control group whereas the reduction of MI and EI was not significantly different between both groups. The majority of subjects did not experience any serious side effects. The subjects in the treatment group also reported significantly higher proportion of very good response compared to control group. Limitations: This was a single-center study with a small sample size and the inability to control confounding variables. Conclusion: Based on our results, intradermal TA injection appears to be an effective and safe adjuvant therapy for melasma in individuals with Fitzpatrick Skin Type IV–V. Keywords: Melasma, tranexamic acid, modified melasma area and severity index, melanin index, erythema index

Introduction

Melasma is an acquired pigmentation disorder in the form of brownish macules with irregular edges caused by dysfunction of melanogenesis.^1,2 Various intrinsic and extrinsic factors play a role in the pathogenesis of melasma, including genetic predisposition, exposure to ultraviolet (UV) light and visible light, hormonal influences, pregnancy, cosmetics use, photosensitizing drugs, and stressful conditions.^3,4

Diagnosis of melasma is mainly established based on clinical and dermoscopic findings. Several differential diagnoses should be considered, such as ochronosis, Riehl melanosis, lichen planus pigmentosus, and ashy dermatosis.⁵

Various studies have examined the effectiveness of tranexamic acid (TA) therapy for melasma. Oral tranexamic acid has been shown to improve melasma lesions. Intradermal TA has been studied for melasma lesions. However, these studies have yielded mixed results.⁶ This study aims to evaluate the effectiveness and safety of intradermal TA as an adjunctive treatment for patients with melasma with Fitzpatrick Skin Type IV–V.

Methods

A double-blind, randomized, split-face controlled trial was conducted at a single center in Jakarta, Indonesia. This study was approved by the Ethics Committee of Faculty of Medicine Universitas Indonesia. Subjects were consecutively recruited from February 2021 to May 2021. Female subjects aged 18 to 60 years old with Fitzpatrick Skin Type IV–V who were diagnosed with melasma were included in this study. Exclusion criteria were 1) pregnancy and breastfeeding, 2) use of oral contraceptives within six months, 3) use of topical or systemic melasma therapy within two weeks, 4) history of superficial peeling within four weeks, 5) history of dermabrasion within six months, 6) use of photosensitizer drugs, 7) history of thrombosis or currently using antithrombotic or anticoagulant drugs, 8) history of TA allergy, and 9) presence of COVID-19 symptoms. Written informed consent was obtained from all participants prior to the study. Sample size calculation with consideration of 80 percent statistical power and 10 percent dropout resulted in a minimum of 30 subjects in each arm.

Eligible subjects were randomized to receive either 10mg of intradermal TA injection or placebo on one side of the face with 1:1 ratio. The drugs were prepared by a pharmacologist. The allocation sequence was generated with a computer by an analyst. The allocation sequence was concealed from the investigators and subjects. All subjects were given SPF 33 sunscreen cream and 4% hydroquinone cream to be applied on the face daily. All subjects were advised to practice sun avoidance during study.

At the first visit, clinical and mexameter examination were performed on all subjects. Modified Melasma Area and Severity Index (mMASI) score was calculated from each side of the face due to the nature of split-face study. Mexameter (Courage-Khazaka Electronic, Koln, Germany) was used to measure erythema index (EI) and melanin index (MI). EI and MI were defined as the difference of the redness and pigmentation readings between involved and adjacent uninvolved skin respectively. All subjects were given a diary to record daily cream usage and symptoms.

At Weeks 2, 4, 6, 8, 10 and 12, all subjects received followed up. mMASI score, EI, and MI were measured at each visit. At Weeks 2, 4, 6, 8, and 10, all subjects were given the same intervention as the baseline according to the allocation sequence. At Week 12, all subjects were asked to complete a satisfaction questionnaire which was patient global assessment (PGA).

The primary outcome included the improvement of melasma lesions measured by mMASI score, EI, and MI. The secondary outcome was the incidence of side effects and subject satisfaction result. Data were analyzed using SPSS® for Windows version 21.0 (SPSS Inc., Chicago, Illinois) with intention-to-treat analysis. Continuous data were presented as mean differences and standard deviations (SD) if the data were normally distributed or median and minimum-maximum value if the data were not, whereas categorial data were presented as frequency. An independent t-test or Mann-whitney test was performed depending on the normality of the data. A chi-square test was performed for secondary outcomes. P-value<0.05 was considered significant.

Results

A total of 34 subjects were recruited into the study. Two subjects were excluded due to use of anticoagulant drugs and oral contraceptive. Hence, 32 patients were randomized into intervention or control group. During the study, one patient had to use anticoagulant drugs and dropped out from the study.

Sociodemographic and clinical characteristics of patients at baseline are shown in Table 1. mMASI score, MI, and EI of the control and intervention group at the baseline are shown in Table 2.

Both control and intervention groups showed decreasing mMASI scores at Weeks 2, 4, 6, 8, 10, and 12 (Figure 1). Further analysis showed a significant greater reduction of mMASI score in intervention group compared to control group at Week 2 (P=0.001), Week 8 (mean difference (MD)=-0.64; 95% Confidence Interval (CI)=-1.25–-0.03; P=0.041), and Week 12 (MD=-0.82; 95% CI=-1.42–-0.21; P=0.009).

Both control and intervention groups showed decreasing MI at Week 2, 4, 6, 8, 10, and 12 (Figure 2). However, further analysis showed there was no significant difference of MI reduction between each measurement. Similarly, both control and intervention groups showed decreasing EI at Weeks 2, 4, 6, 8, 10, and 12 (Figure 3) without significant difference in EI reduction between both groups at each measurement.

There were no serious side effects reported by the patients. However, there were mild side effects such as pain at the site of injection that vanished in 24 hours and moderate side effects such as pain or hematoma that persisted for three days. The proportion of side effects between two groups was not significantly different (P=0.552). In addition, patient’s satisfactory assessment showed that the very good response was significantly higher in intervention group compared to control group (74.2% vs. 6.5%; P=< 0.001).

Discussion

TA is an antifibrinolytic drug with antiplasmin effect. It can inhibit the release of paracrine melanogenic factors which results in inhibition of melanocyte stimulation. Various studies have shown that topical TA therapy is effective in epidermal melasma but the response is poor in dermal or mixed melasma. Intradermal TA injection can reach mid-dermis so that it can be useful for deeper pigmentary disorders.⁷

This study showed that mMASI score improved faster and greater in intervention group compared to control group. This finding is consistent with Payzar et al⁸ study which reported that TA injection showed a significant faster decrease in mMASI score compared to hydroquinone at Week 8. Similarly, Shihab et al⁹ reported that administration of oral TA as adjunctive treatment reduced mMASI score faster than standard treatment alone at Week 2 and 12. However, this study also showed the reduction of mMASI did not differ significantly between both groups at Week 4, 6, and 10 which might be caused by high UV exposure. This is was influenced by the geographical location of Indonesia, which is a tropical country with significant UV exposure.¹⁰ In addition, most of our subjects were actively working so the UV exposure increased during outdoor daily activities.

Despite showing decreasing trend of MI and EI at each measurement, the decrease of MI and EI was not significantly different between intervention and control groups. Several possible explanations could rationalize these findings. For both MI and EI, mexameter examination only obtained melanin and erythema data from one spot, while mMASI score was obtained through assessment of half of the face. Hence, mexameter examination could not represent the improvement of whole face.⁹ In addition, TA could possibly cause an erythema which could influence the EI measurement.¹¹ A previous study by Nguyen et al¹² showed that oral TA improved EI significantly compared to placebo group. Hence, the different preparations of TA could also possibly play a role in these result. Lastly, EI and MI could also be influenced by environmental factor (eg, light and temperature) and individual factor (eg, the progression of melasma).¹³ In spite of the aforementioned possible mechanisms, the exact mechanisms are still unknown.

Our subjects did not report any serious side effects with no significant difference in the proportion of mild and moderate side effects between both groups. This is in line with studies by Shetty et al¹⁴ and meta-analysis by Feng et al¹⁵ which reported no significant side effects from intradermal TA injection. This is also supported by the dose of intradermal TA injection in our study which was 10mg/mL. This dose is smaller than the recommended dose for preventing blood loss from bleeding, which was 0.5 to 1.5g three times daily resulting in significantly decreased side effects.⁷

Limitations. This study was limited due to it being a single center study with small sample size and the inability to control confounding variables, such as UV exposure, that might alter the results.

Conclusion

Based on our results, intradermal TA injection appears to be a safe and effective adjuvant therapy for patients with melasma with Fitzpatrick Skin Type IV–V. Future multicenter studies with longer follow-up duration and comparison of different TA doses are necessary to establish the most effective dose of intradermal TA injection for melasma.

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