Original Article

A randomized, open‑label, comparative

study of oral tranexamic acid and
tranexamic acid microinjections in patients
with melasma
Vinod K. Khurana, Rachita R. Misri, Swati Agarwal,
Akhilesh V. Thole, Sachin Kumar, Tanu Anand1
Departments of Dermatology, Venereology and Leprosy, and 1Department Of Preventive and Social Medicine,
Hindu Rao Hospital, New Delhi, India

Abstract Correspondence:
Dr. Rachita R. Misri,
Background: Melasma poses a great challenge as its treatment modalities are unsatisfactory. Treatment
2nd Floor OPD Building,
using tranexamic acid is a novel concept. Department of Dermatology,
Aim: This study aimed to compare the therapeutic efficacy and safety of oral tranexamic acid and Venereology and Leprosy,
tranexamic acid microinjections in patients with melasma. Hindu Rao Hospital,
Methods: This is a prospective, randomized, open‑label study with a sample size of 64, 32 in each New Delhi ‑ 110 007, India.
E‑mail: [email protected]
treatment arm. Thirty‑two patients were administered localized microinjections (4 mg/ml) of tranexamic
acid monthly in 1 arm, while in the other arm, 32 were given oral tranexamic acid 250 mg twice a day.
Patients were followed up for 3 consecutive months. Clinical photographs were taken at each visit, and a
modified melasma area and severity index scoring was performed at the beginning and end of treatment.
Results: Improvement in melasma area and severity index score in the oral group was 57.5% as compared
to 43.5% in the intralesional group. All 32 patients in the oral group (100%) showed >50% improvement, out
of which 8 showed >75% improvement. In the intralesional group, 17 (53%) patients had >50% improvement,
of which 3 had >75% improvement. The remaining 15 patients in this group had <50% improvement. Thus,
the oral group showed a more significant response as compared to the intralesional group. No major
adverse effects were observed in both the groups. At 6‑month follow‑up, two patients (6.2%) in the oral
group had recurrence as compared to three patients (9.4%) in the intralesional group.
Limitations: A small sample size was one of the limitations in this study. The dose of tranexamic acid
in microinjections and the frequency of injections could have been increased.
Conclusion: Tranexamic acid provides rapid and sustained improvement in the treatment of melasma.
It is easily available and affordable. Oral route is undoubtedly efficacious, but the results of microinjections,
while encouraging, can probably be enhanced by either increasing the frequency of injections or increasing
the concentration of the preparation.

Key words: Clinical trials preparation, melasma, therapeutic studies, tranexamic acid

This is an open access journal, and articles are distributed under the terms of
the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License,
which allows others to remix, tweak, and build upon the work non‑commercially,
Access this article online as long as appropriate credit is given and the new creations are licensed under
Quick Response Code: Website: the identical terms.
www.ijdvl.com For reprints contact: [email protected]

DOI: How to cite this article: Khurana VK, Misri RR, Agarwal S, Thole AV,
10.4103/ijdvl.IJDVL_801_16 Kumar S, Anand T. A randomized, open-label, comparative study of
oral tranexamic acid and tranexamic acid microinjections in patients
PMID: with melasma. Indian J Dermatol Venereol Leprol 2019;85:39-43.
*****
Received: September, 2016. Accepted: March, 2017.

© 2018 Indian Journal of Dermatology, Venereology and Leprology | Published by Wolters Kluwer - Medknow 39
Khurana, et al. Study of tranexemic acid in melasma

Introduction Table 1: Study used for sample size

Melasma is a common acquired dermatosis characterized
Year Authors Sample Dose of oral Results
by the presence of light‑to‑dark brown macules and patches size tranexamic acid
involving the sun‑exposed areas of the face and neck. This 2008 Mafune 99 ‑ Oral ‑ 750 mg, 2 Statistically significant
disease is commonly observed in women.1 Although the precise et al. TA/100 tablets TID × 8 weeks improvement in TA
cause of melasma is still unknown, some commonly identified Control ‑ placebo group (76.8% vs. 27%)
contributing factors are genetic susceptibility, ultraviolet light TA: Tranexamic acid

exposure, pregnancy, sex hormones, contraceptive pills,

thyroid disease, cosmetics and phototoxic drugs.2

Various treatment modalities are used for melasma. These

include the use of sunscreens, hypopigmenting agents,
superficial peeling agents such as glycolic and lactic acid and
laser therapy.1,3‑5 Newer studies have found that tranexamic
acid, a hemostatic agent, has hypopigmentary effect on
melasma lesions and also prevents ultraviolet‑induced
pigmentation.2,6,7 In addition to its hemostatic effects,
tranexamic acid exhibits anti‑allergic and anti‑inflammatory
effects on various skin diseases such as angioedema.8 Its
anti‑inflammatory property appears to be related to its
inhibitory effect on melanogenesis.6,8 Tranexamic acid is
reported to improve melasma when injected locally or used
Figure 1: Modified melasma area and severity index scoring
in its oral and topical forms.

Although several treatment modalities are available, Patients were randomly selected for oral and topical therapy
management of this condition is a challenging task for for melasma. Randomization was done by random number
doctors and the results are frequently unsatisfactory, with a allocation. After obtaining written informed consent, history
high recurrence. However, there are many ongoing studies was taken and clinical examination done. The lesion was
aiming to find more effective and safe treatments. also examined under a Woods lamp. Baseline investigations
of liver and renal functions and a coagulation profile were
Methods done, and repeated after 3  months. Modified melasma area
A prospective randomized open‑label study was conducted and severity index scoring system  [Figure  1] was used to
on 64 clinically diagnosed melasma patients. Sample size assess the severity of melasma and to compare the response
was calculated to be a minimum of 14 in each group at alpha in each patient with the initial score to find the percentage
error = 5% and power 80% at 95% confidence interval. Sample improvement. Patients in the oral therapy group were given
size was calculated using the study as shown in Table 1. tablet tranexamic acid (250 mg) twice daily for 3 months. In
the intralesional group, patients were administered intradermal
Patients were selected from among those coming for injections of tranexamic acid. About 2 U of tranexamic acid
treatment of various dermatoses in our outpatient department was drawn in a 40 U/ml 30‑gauge insulin syringe and diluted
during 1‑year period of May 2014–May 2015, after obtaining with normal saline up to 1  ml  (remaining 38 U out of total
approval from the Institutional Ethical Committee. 40 U) to get a concentration of approximately 4  mg/ml of
tranexamic acid.9 Intradermal injections were given at the site
This study included adult men and women with melasma of melasma, after application of topical anesthetic, keeping a
between the age group of 20 and 50  years. Patients with a distance of around 1 cm from each injection, with a maximum
history of bleeding disorders, use of oral anticoagulant drugs of 8  mg in a single sitting. Three such sessions at intervals
or any other photosensitizing drugs such as nonsteroidal of a month were carried out. Various measures for strict
anti‑inflammatory drugs, tetracycline, spironolactone, photoprotection were explained to each patient, for better
phenytoin, carbamazepine, known allergy to tranexamic and sustained improvement. All patients were given the same
acid, other concomitant medical history and the use of other sunscreen (of sun protection factor 50) for the entire 6 months.
depigmenting oral or topical agents in the past 1 month
were exclusion criteria. Additionally, females with a history To assess response, clinical photographs were taken at each
of pregnancy/lactation or use of oral contraceptive pills/ visit; modified melasma area and severity index scores were
hormonal replacement therapy at the time of or during the calculated at the beginning and end of the therapy. Subjective
past 12 months were excluded from the study. Patients with response to treatment, according to patient, was graded at the
a history of any treatment for melasma in the past 6 weeks in end of the study as follows: no response, no improvement;
any form were also excluded from the study. mild response, <25% improvement; moderate response,

40 Indian Journal of Dermatology, Venereology and Leprology | Volume 85 | Issue 1 | January-February 2019

Khurana, et al. Study of tranexemic acid in melasma

25%–<50% improvement; good response, 50%–<75% Improvement in oral group was 57.5% with P < 0.01 (paired
improvement and excellent response, >75% improvement. t‑test: 12.111). In intralesional group, the improvement was
Final response was evaluated according to the melasma area 43.6% with P value of 0.047 (paired t‑test: 2.068).
and severity index scores and subjective patient response.
Any complications and side effects were also noted during All the 32 patients in the oral group (100%) showed >50%
these follow‑ups. For another 3 months after treatment, the improvement, of which 8 showed >75% improvement. In the
patients were examined at monthly intervals to look for any intralesional group, 17 (53%) patients had >50% improvement,
relapse or complication. 3 of whom had >75% improvement. The remaining
15 patients in this group had <50% improvement [Table 5].
Histopathology could not be done due to apprehension of Thus, the oral group showed significantly better response as
patients and as it involved the face. Dermoscopy was not compared to the intralesional group (2 × 2 table; χ2 = 19.592,
available and no previous studies have used it as a tool to df < 1. P <0.01).
assess response to tranexamic acid.
Figures 3 and 4 show examples of clinical improvement in
Statistical analysis was done using SPSS  software some of the patients.
version 20 (IBM Statistical package for the Social Sciences.
IBM SPSS Statistics for Windows, Version  20.0. Armonk, In the oral group, the difference in the mean fall in melasma
NY: IBM Corp.). The difference in mean melasma area and area and severity index score in epidermal type was 2.92
severity index scores in each group was calculated using (standard deviation  ±0.92) and in mixed type was 4.55
paired t‑test. The difference in mean melasma area and (standard deviation  ±2.06). Although the fall in mixed
severity index scores between the two groups was calculated type was more, it did not differ significantly (P = 0.058 by
using Chi‑square test using 2 × 2 table. Mann–Whitney U‑test). In the intralesional group, the mean
fall in melasma area and severity index in epidermal type
Results
Out of 72  patients enrolled in the study, 64  (88.8%)
Table 2: Sex distributon
successfully completed the trial. Forty‑seven  (65.27%)
patients belonged to the age group of 30–50  years. The Study group Women Men Total
number of women was more (54) compared to men (10) in Oral 26 6 32
both the study groups  [Table  2]. All the patients had skin Intralesional 28 4 32
type 4 or 5 [Table 3]. Forty‑four (68.8%) patients had mixed
pattern of melasma, 17 (26.6%) had epidermal and 3 (4.7%)
Table 3: Skin types of patients, type and pattern of melasma
had dermal [Table 3]. The distribution of melasma was either
centrofacial or malar [Table 3]. None of the patients were on Skin type Oral (%) Intralesional (%) Total (%)
any drugs. Fitzpatrick type 4 12 (37.5) 15 (46.87) 27 (42.18)
Pattern of melasma
Mean melasma area and severity index score of the patients Centrofacial 19 (59.37) 8 (25) 27 (42.18)
at the beginning and end of the trial with percentage Type of Melasma
improvement is shown in Table 4 and graphically in Figure 2. Epidermal 6 (18.75) 11 (34.37) 17 (26.56)
Mean decrease in melasma area and severity index score in Dermal 3 (9.37) 0 3 (4.68)
oral group was significantly higher than in the microinjection Mixed type of melasma 23 (71.87) 21 (65.63) 44 (68.75)
group  (Mann–Whitney U‑test: P < 0.001, df  =  62).
Table 4: Mean melasma area and severity index scores,
percentage improvement and P value in both groups
Study Pre‑MASI Post‑MASI Percentage of P
group improvement
Oral group 7.48±3.73 3.18±1.93 57.48 <0.01
Intralesional 4.11±2.69 2.32±2.56 43.55 0.047
MASI: Melasma area and severity index

Table 5: Percentage grading of treatment response

Response percentage Oral (%) Intralesional (%)
0‑25 0 4 (12.5)
25‑50 0 11 (34.38)
50‑75 24 (66.66) 14 (43.75)
Figure 2: Graph showing comparison of decrease in melasma area and severity
index score in oral and intralesional groups 75‑100 8 (33.33) 3 (9)

Indian Journal of Dermatology, Venereology and Leprology | Volume 85 | Issue 1 | January-February 2019 41

Khurana, et al. Study of tranexemic acid in melasma

Figure 3: Patient treated with oral tranexamic acid – before and after treatment Figure 4: Patient treated with intralesional tranexamic acid – before and
after treatment
was 3.12 (standard deviation ±4.99) and in mixed type was
1.01  (standard deviation  ±4.81). Here too, the fall was not Limited studies are found in literature regarding the use of
statistically significant (P = 0.31 by Mann–Whitney U‑test). tranexamic acid in melasma. In 1979, Nijor was the first to
study and report on the action of tranexamic acid in melasma.13
No major side effects were observed except for mild pain and In 1985, Hajime et  al. showed that forty patients aged 20–
erythema in the intralesional group patients, which lasted for 60 years had their melasma reduced in severity with 1–1.5 g
2–3 days. In the oral group, two patients (6.25%)  had gastritis daily oral tranexamic acid in 10 weeks’ time.14 In 1988,
and one patient  (3.12%)  had oligomenorrhea at the end of 11 patients with melasma were treated with oral tranexamic
3 months. There was no change in coagulation parameters at acid 0.75–1.5  g/day.15 All had decreased severity; however,
the end of 3 months. pigmentation recurred after some months of cessation of
therapy. Zhu and Yang16 and Liu et  al.17 each gave 250 mg
At 6  months of follow‑up,    6.25%   in the oral group tranexamic acid 3  times a day along with Vitamin C and E
had recurrence with darkening of the lesions and in the for duration of 6–8 weeks. Both the groups showed significant
intralesional group   9.37%  had repigmentation of lesions at reduction in pigmentation with tolerable gastrointestinal
symptoms and no abnormality in coagulation parameters. They
the end of 6 months.
also found that increasing the treatment duration was more
effective than increasing the dose of tranexamic acid. In 2008,
Discussion
Mafune et  al. used 750 mg oral tranexamic acid two tablets
Tranexamic acid (trans‑4‑aminomethylcyclohexanecarboxylic
3 times daily.18 In 2013 Cho et al. performed the first controlled
acid) is a plasmin inhibitor used to prevent abnormal
trial by administering 500 mg/day as an adjuvant to patients
fibrinolysis to reduce blood loss.10 Ultraviolet irradiation
treated with intense pulse light or neodymium‑doped yttrium
induces plasminogen activator synthesis and plasmin activity aluminum garnet laser, as compared to patients who received
in cultured keratinocytes. Plasmin‑activated precursors the same treatment without tranexamic acid.19 Six‑month
of secretory phospholipase A2 which participates in the treatment led to significantly higher improvement without any
production of arachidonic acid from membrane phospholipids systemic side effects, in the tranexamic acid group.
is a precursor to prostaglandins E2 and leukotrienes which
can lead to melanogenesis.11 Plasmin also leads to release of The usual effective dose for melasma is 250–500 mg 2–3 times
basic fibroblast growth factor which is a potent melanocyte daily, which is much lower than the dose to reduce bleeding. Our
growth factor. Hence, tranexamic acid prevents binding of study is in agreement with other many studies where successful
plasminogen to keratinocyte which results in less arachidonic lightening was observed following oral tranexamic acid
acid and diminished ability to produce prostaglandins and administration, with some side effects of  gastritis (6.25%)  and
subsequently reduces melanogenesis in melanocyte.12 By oligomenorrhea (3.12%)   which disappeared after cessation
injecting intradermally, it may be possible to treat the dermal of therapy. Commonly reported side effects include nausea,
and mixed types of melasma. diarrhea, orthostatic reactions, disturbances in color vision,
42 Indian Journal of Dermatology, Venereology and Leprology | Volume 85 | Issue 1 | January-February 2019
Khurana, et al. Study of tranexemic acid in melasma

occasionally anaphylactic shock and acute renal cortical melanocyte by sunlight, hormonal influence through the
necrosis. Thrombotic incidents have been reported at doses inhibition of plasminogen activator system.
ranging from 1.5 to 6 g/day.12 After 6‑month follow‑up period,
recurrence was seen in two patients (6.25%)  which could be Declaration of patient consent
effectively treated again using tranexamic acid therapy. The authors certify that they have obtained all appropriate
patient consent forms. In the form, the patients have given their
Localized microinjection, also known as mesotherapy, consent for their images and other clinical information to be
is a widely used technique in medicine. It aims at directly reported in the journal. The patients understand that their names
applying an adequate amount of medication at the given site and initials will not be published and due efforts will be made
thus avoiding oral medications. This allows lower dosage of to conceal their identity, but anonymity cannot be guaranteed.
drugs to be used. In our study, we used monthly intradermal
injections of tranexamic acid on the affected area with Financial support and sponsorship
significant decrease in melasma area and severity index scores Nil.
with no significant side effects. In 2006, Lee et al. showed
Conflicts of interest
that 85 patients who completed weekly intradermal injections
There are no conflicts of interest.
of tranexamic acid for 12 weeks had significant decrease in
their melasma area and severity index scores.2 Budamakuntla
et al. compared weekly intradermal injections of tranexamic References
1. Grimes  PE. Melasma. Etiologic and therapeutic considerations. Arch
acid in one arm with microneedling with tranexamic acid in Dermatol 1995;131:1453‑7.
the second arm and found significant decrease in melasma 2. Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, Kim MY, et al. Localized
area and severity index scores in both the groups.9 There are intradermal microinjection of tranexamic acid for treatment of melasma in
Asian patients: A preliminary clinical trial. Dermatol Surg 2006;32:626‑31.
no standard guidelines for giving intralesional injections of 3. Rendon  M, Berneburg  M, Arellano  I, Picardo  M. Treatment of
tranexamic acid for melasma. In our study, we gave monthly melasma. J Am Acad Dermatol 2006;54 5 Suppl 2:S272‑81.
injections instead of weekly ones, as mentioned in the above 4. Prignano F, Ortonne JP, Buggiani G, Lotti T. Therapeutical approaches
two studies, to see if we get an appreciable response with this in melasma. Dermatol Clin 2007;25:337‑42, viii.
5. Gupta AK, Gover MD, Nouri K, Taylor S. The treatment of melasma: a
technique, since repeated injections are quite traumatic for review of clinical trials. J Am Acad Dermatol 2006;55:1048‑65.
the patient, due to multiple pricks and visits to the doctor. We 6. Maeda  K, Naganuma  M. Topical trans‑4-aminomethylcyclohexanec
got a good response of 43.6% which is statistically significant arboxylic acid prevents ultraviolet radiation‑induced pigmentation.
but this was less than the response achieved by the oral route. J Photochem Photobiol B 1998;47:136‑41.
7. Kondou S, Okada Y, Tomita Y. Clinical study of effect of tranexamic
acid emulsion on melasma and freckles. Skin Res 2007;6:309‑15.
We compared the safety and efficacy of treatment in both these 8. Maeda K, Tomita Y. Mechanism of the inhibitory effect of tranexamic
methods of drug delivery. The melasma area and severity acid on melanogenesis in cultured human melanocytes in the presence
index scores showed a significant decrease in baseline to the of keratinocyte‑conditioned medium. J Health Sci 2007;53:389‑96.
9. Budamakuntla  L, Loganathan  E, Suresh  DH, Shanmugam  S,
end of 12th week in both the arms. The scores showed better Suryanarayan  S, Dongare  A, et al. A  randomised, open‑label,
improvement in patients on oral tranexamic acid than those comparative study of tranexamic acid microinjections and tranexamic
receiving intralesional injections, and this was statistically acid with microneedling in patients with melasma. J  Cutan Aesthet
significant. This can be attributed to lower dosages of the Surg 2013;6:139‑43.
10. Shimizu M, Naito T, Okano A, Aoyagi T. Trans‑4 aminomethylcyclohex
injected drug, as well as decreased frequency of injections. On anecarboxylic acid as a potent antiplasmin agent. Chem Pharm Bull
comparing the differences between the fall in melasma area (Tokyo) 1965;13:1012‑4.
and severity index score between epidermal and mixed types 11. Akashima  A, Yasuda  S, Mizuno  N. Determination of the action
of melasma, there was no difference, thus showing it to be spectrum for UV‑induced plasminogen activator synthesis in mouse
keratinocytes in vitro. J Dermatol Sci 1992;4:11‑7.
equally effective in all types of melasma. All scores remained 12. Tse  TW, Hui  E. Tranexamic acid: An important adjuvant in the
almost the same during the next 3 months of follow‑up. treatment of melasma. J Cosmet Dermatol 2013;12:57‑66.
13. Nijor  T. Treatment of melasma with tranexamic acid. Clin Res
Based on our study, we suggest oral tranexamic acid 250 mg 1979;13:3129‑31.
14. Hajime  M, Mineo  T, Yoshio  T. Oral administration therapy with
2 times daily for at least 3 months. Prolonged prescription
tranexamic acid for melasma. Nishinihon J Dermatol 1985;47:1101‑4.
period should have a better effect rather than increasing the 15. Higashi N. Treatment of melasma with oral tranexamic acid. Skin Res
dose. Increasing the frequency of intralesional injections to 1988;30:676‑80.
once a week rather than a month would increase the efficacy. 16. Zhu  HJ, Yang  XH. The clinical study of acidum tranex‑amicum on
melasma. Pharm Program 2001;3:178‑81.
It would be also interesting to observe if increasing the
17. Liu H, Kou CC, Yeung CW. Effectiveness of tranexamic acid in treating
concentration of intralesional tranexamic acid from 4  mg/ melasma and observation of its safety. Chin J Med Aesthet Cosmetol
ml would increase the efficacy of the results. Further studies 2005;11:361‑3.
with larger number of patients are required. On the basis of 18. Mafune  E, Morimoto  Y, Iizuka  Y. Tranexamic acid and melasma.
Farmacia 2008;44:437‑42.
the above findings, tranexamic acid can be used as a safe 19. Cho  HH, Choi  M, Cho  S, Lee  JH. Role of oral tranexamic acid in
effective therapeutic agent for the treatment of melasma. melasma patients treated with IPL and low fluence QS Nd:YAG laser.
It is the only modality that can prevent the activation of J Dermatol Treat 2013;24:292‑6.

Indian Journal of Dermatology, Venereology and Leprology | Volume 85 | Issue 1 | January-February 2019 43