Journal of Cosmetic and Laser Therapy, 2012; 14: 150–154

ORIGINAL RESEARCH REPORT

Topical 5% tranexamic acid for the treatment of melasma in Asians:

A double-blind randomized controlled clinical trial

PINYAPAT KANECHORN NA AYUTHAYA1, NUCHA NIUMPHRADIT1,

ARANYA MANOSROI2 & ARTIT NAKAKES1
1Phramongkutklao Hospital – Dermatology, Bangkok, Thailand, and 2Division of Pharmaceutical Science,
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Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand

Abstract
Background: Topical tranexamic acid has been claimed to lighten melasma without serious adverse effects. However, con-
trolled studies assessing the efficacy and safety of topical tranexamic acid (TA) for the treatment of melasma is limited.
Objective: To assess in a double blind, randomized, prospective study, the efficacy of topical 5% tranexamic acid versus
vehicle for treatment of melasma. Methods: Twenty-three women with bilateral epidermal melasma enrolled in a split-face
trial lasting 12 weeks. Patients blindly applied topical 5% tranexamic acid and its vehicle, to the designated sides of the
face twice daily in addition to the assigned sunscreen each morning. Pigmentation and erythema were measured objectively
using a mexameter and Melasma Area and Severity Index (MASI), in addition to physician and patient global assessments.
For personal use only.

Results: Twenty-one patients completed the study. Eighteen out of twenty-three patients (78.2%) showed decrease in the
melanin index on either or both sides of the face by the end of 12 weeks compared to baseline. The MASI scores were also
significantly reduced on both tested sides. However, lightening of pigmentation induced by TA gel was neither superior nor
different (p ⬎ 0.05) compared to its vehicle although erythema was significant on the TA-applied site (p ⬍ 0.05). Conclusions:
Although lightening of pigmentation was obtained, the results were not significant between the two regimens. However,
topical TA produced erythema.

Key Words: tranexamic acid, whitening, melasma

Introduction
Melasma is a commonly acquired pigmentary disor-
der characterized by the development of tan-brown
macules and patches of the face and occasionally the
neck of Hispanic and Asian women. The etiology of
melasma, although multifactorial, remains poorly
understood. Apart from racial and genetic suscepti-
bility, pregnancy, sun exposure, hormonal therapy
(estrogen and progesterone), cosmetics and certain
drugs have been regarded as attributes (1–4) to
melasma.
Presently, there is no universally effective proce-
dure or agent for melasma treatment despite various
therapeutic modalities already available such as laser
ablation, chemical peeling or depigmenting agents
that are used to lighten melasma to some degree.
Other than conservative measures such as prevention
of eliciting factors, hydroquinone, the most commonly
used topical depigmenting agent, is effective at high
concentration (4–5%). However, cosmetically unac-
ceptable side effects such as leukoderma, erythema
and ochronosis can occur (4).
Tranexamic acid (TA), that is, trans-4-aminom-
ethyl cyclohexane carboxylic acid, is a hydrophilic
agent used as an antifibrolytic agent for over 30 years.
Studies in human melanocyte and keratinocyte cul-
tures have revealed that TA inhibits melanin synthe-
sis in melanocytes by interfering with the interaction
of melanocytes and keratinocytes through inhibition
of plasminogen/plasmin system (5). TA was claimed
to have anti-inflammatory and whitening effects
when administered either systemically or topically
(6,7). However, systemic tranexamic acid is not
completely safe with reports of serious complications
such as deep venous thrombosis, pulmonary embo-
lism, cerebral artery thrombosis and embolism, and

Correspondence: Pinyapat Kanechorn Na Ayuthaya, MD, Phramongkutklao Hospital – Dermatology, 315 Rajavithi Rd. Bangkok 10400, Thailand.
E-mail: jewenator@gmail.com

(Received 4 January 2012 ; accepted 12 April 2012 )

ISSN 1476-4172 print/ISSN 1476-4180 online © 2012 Informa UK, Ltd.
DOI: 10.3109/14764172.2012.685478

coronary artery thrombolism (8–12). On the other
hand, TA should be safer when used topically due to
the absence of systemic absorption (13–15). Recently,
Lee et al. reported intralesional localized micro-in-
jection of TA as a potentially new, effective and safe
therapeutic modality for melasma (16). Despite lim-
ited controlled trials with objective measurements for
testing the lightening abilities of topical TA, it is
popular as a cosmetic ingredient and available com-
mercially in combined formulas with other whitening
agents. We therefore assess, in a double blind, ran-
domized, prospective study, the efficacy of topical
5% tranexamic acid as a whitening agent. We chose
a TA-incorporated liposome gel formulation due to
prior studies of the formulation’s high stability, small
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size, slow leakage, and prolonged and sustained
release profile in our study (17,18).
Methods
Patients eligible for the study were Thai women, aged
18–45 years, with bilateral symmetrical epidermal or
mixed melasma, confirmed by enhancement of
lesions with a Wood’s lamp. The study was approved
by the Ethics Committee of Phramongkutklao Hos-
For personal use only.
pital. Informed consents were obtained. Exclusion
criteria included patients with dermal melasma,
pregnant or breast feeding women, those on hor-
monal therapy or contraception, those with history
of coexisting endocrinopathies, known allergy to
tranexamic acid, allergy to sunscreen ingredients,
previous topical treatment for melasma within 2
weeks, on systemic tranexamic acid within 3 months,
or on oral retinoic acid derivatives within 1 year prior
to the study.
After cleansing, the degree of pigmentation on
both sides of the face was recorded using the mex-
ameter (Model MX 16, Courage ⫹ Khazaka elec-
tronic GmbH, Cologne, Germany). A third reading
was taken from the suprasternal notch, which was
exposed to sunlight but not to the treatments, as a
control. The mexameter provides reproducible,
objective measurement of pigment based on the
absorption spectra of light and has an accuracy
of ⫹ 5%. Readings range from 1 to 1000, with 1 rep-
resenting white and 1000 representing black. A linear
analog scale was marked at baseline and at weeks 4,
8 and 12 as each visit’s reading was recorded.
Standard photographs and the Melasma Area
and Severity Index (MASI) score were recorded at
baseline and at weeks 4, 8 and 12. The MASI is an
index devised to more accurately quantify the sever-
ity of melasma and changes during therapy. The
index was modified by Kimbrough-Green et al., who
based it on a similar scoring system devised for pso-
riasis. The MASI is calculated based on the area (A)
of involvement, the darkness (D) of melasma and the
homogeneity (H) of the hyperpigmentation. The
Tranexamic acid, whitening, melasma 151
right forehead (rf), right malar region (rm) and right
chin (rc) correspond to 15%, 30% and 5% of the
total face, respectively. The same regions are mea-
sured on the left side, giving a total facial surface area
of 100%. The area of involvement in each of these
six areas is given a numerical value of 0–6 (0 indi-
cates no involvement; 1, 0–9%; 2, 10–29%; 3, 30–
49%; 4, 50–69%; 5, 70–89%; and 6, 90–100%). The
severity of melasma is also determined by measuring
2 additional variables i.e. darkness (D) and homoge-
neity (H), rated on a scale from 1 to 4 (0 indicates
absent; 1, slight; 2, mild; 3, marked; and 4, maxi-
mum). The MASI score is calculated by adding the
sum of the severity ratings for darkness and homo-
geneity, multiplied by the value of the area of involve-
ment, for each of the six facial areas. The values for
each side are then totaled; for example, the MASI
for melasma on the right and left would be:
MASI(Rt) ⫽ 0.15(D rf ⫹ H rf)A rf ⫹ 0.3(D rm ⫹ H rm)
Arm ⫹ 0.05(Drc ⫹ Hrc)Arc and MASI(Lt) ⫽ 0.15(Dlf ⫹
H lf)A lf ⫹ 0.3(D lm ⫹ H lm)A lm ⫹ 0.05(D lc ⫹ H lc)A lc ,
respectively.
Each blinded subject was given a supply of 5%
tranexamic acid formula and vehicle in identical
tubes designated ‘right’ and ‘left’ to apply to the side
of the face assigned twice daily. Sun protection factor
60 cream (Spectraban™ 60, Stiefel Laboratories
(Thailand) Co. Ltd.) as provided for application to
the entire face 15 minutes after applying the medica-
tions every morning. For each participant, the MASI
scores and mexameter readings for the sides treated
with 5%TA gel and vehicle gel were compared with
the corresponding readings for the same area at base-
line and monthly until completion of the trial. The
p ⬍ 0.05 was considered a statistically significant
effect.
The various MASI and mexameter values
obtained data sets were analyzed using a paired t-test
while the others used the Wilcoxon signed rank test.
All tests were two-sided. The final visit included a
global evaluation by two masked investigators and
the patient.
Results
Twenty-five patients were enrolled in the study. Three
subjects dropped out due to lack of compliance
whereas one had unexpected pregnancy. Therefore,
21 patients completed the study and data for analy-
sis were obtained from these subjects. Demographic
data given in Table I showed the average age of the
patients was 39.3 years (range 32–45 years) and all
had melasma over a year. Over half of the patients
do not apply sunscreen on a regular basis nor had
used any anti-melasma regimen.
Baseline data showed that both sides of the face
of each participant did not differ significantly
in terms of pigmentation and erythema (p ⬎ 0.05).
 152 P. K. N. Ayuthaya et al.

Table I. Patient demographic data. 254 ⫻ 190mm. (72 ⫻ 72 DPI).

Subject Demographics Number of Subjects N ⫽ 25 (%)

Pattern of Melasma
Centrofacial 3 (13)
Malar 23 (100)
Mandibular 2 (8.69)
Duration of melasma (years)
ⱕ1 0 (0)
⬎1 25 (100)
Age (years)
20–30 0 (0)
31–40 16 (64)
41–45 9 (36)
Previous Treatment
None 14 (60.9)
Sunscreen only 11 (47.8)
Hydroquinone 2 (8.69)
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Retinoids 2 (8.69)
Tranexamic acid 0
Peeling 0
Others 0
Figure 2. There was significant improvement in Melanin Indexes
in both groups at 12 weeks compared to baseline. However, results
Figure 1 shows the regression of the mean MASI of the linear analog scale showed no discrimination in pigmentation
score readings, reflecting that although both groups between the TA and vehicle at 12 weeks 254 ⫻ 190 mm (72 ⫻ 72
DPI).
improved significantly during the study, there was no
statistical difference between the results in the TA
and vehicle groups by the end of 12 weeks. holiday, many subjects felt that their complexions
For personal use only.

Similar to the MASI score readings, the melanin
indexes for both groups showed a significant lighten-
ing in pigmentation at 12 weeks as opposed to base-
line (Figure 2). Interestingly, during the 8th week of
the trial, there had been a slight darkening in both
TA and vehicle-tested sides. This phenomenon could
be explained by the fact that it corresponded to the
week of Songkran festival, a national holiday that
most people performed outdoor activities. After the
darkened as a whole. By the end of the trial, the
melanin indexes for both tested sides of the face
decreased to the lowest readings. Again, the results
between the TA and vehicle did not reach statistical
difference. On the other hand the erythema index at
12 weeks on the TA-treated side was higher than at
baseline (p ⫽ 0.05) (Figure 3). Compared with the
vehicle at the end of the trial, the TA-treated side also
revealed more erythema (p ⬍ 0.05).

Figure 1. Improvement seen in clinical Melasma Area and Severity

Index(MASI) scores during the study showed a beneficial effect Figure 3. Erythema index was higher for the TA-treated side as
in both groups (p ⬍ 0.000 for both TA and Control at 12 weeks), shown. In comparison with the control, the erythema on the TA-
but no significant difference between the two groups (p ⫽ 0.15). treated side was not statistically significant at 12 weeks. 254 ⫻ 190
254 ⫻ 190 mm (72 ⫻ 72 DPI). mm. (72 ⫻ 72 DPI).

Physician global evaluation results demonstrated
no significant pigmentary alteration including the
erythema between the TA-treated and control sides
of the face by the end of the study. For patients’
global evaluation of lightening of pigment, 16 out of
21 subjects were not able to distinguish the differ-
ences in pigmentation between both sides of the face.
Among these subjects, 1 out of 21 found excellent
results for both sides of the face, 8 out of 21 felt
moderate lightening on both sides, 5 out of 21 had
marginal results, while 2 achieved no improvement
at all. Four out of 21 subjects found differences in
the pigmentation between both sides of the face but
they were irrelevant (p ⬎ 0.05). None of the patients
detected any redness or darkening on the drug-
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applied areas. All felt comfortable with the treat-
ments except two who experienced minor irritations
on both sides of the face.
Discussion
The outcome of this study showed statistically sig-
nificant lightening in melanin pigmentation on both
the TA-tested side and vehicle-tested side when
compared to baseline. Although lightening of pig-
For personal use only.
mentation noted in the MASI score readings was
considerable at 12 weeks compared to baseline
(p ⬍ 0.05), blinded investigators as well as the sub-
jects, were unable to detect any significant differ-
ences between both sides of the face throughout the
trial. The whitening effect on both sides of the face
might be due to adequate sunscreen application, sup-
ported by the fact that over half (52%) of the par-
ticipants were not familiar with wearing sunscreen in
the past.
Concerning the erythema index recordings, there
was an increase in erythema index only on the TA-
applied side at 12 weeks compared to the baseline
TA and control (p ⬍ 0.05). It was probable that TA
had the potential to produce erythema but had not
been mentioned in earlier studies due to the fact that
the erythema was detected by the mexameter only,
but not to the naked eye.
A prior study mentioned that a concentration as
low as 1% of topical TA was asserted to lighten
melasma (6). In our study, we chose liposomes as a
transporter of TA owing to its property as an excel-
lent carrier of active molecules for pharmaceutical
and cosmetic ingredients. Our final product was
composed of 5% tranexamic acid entrapped in small-
sized hydrogenated soy-phosphatidylcholine choles-
terol charged lipid liposomes formulation that had
been known for its low leakage, high stability, pro-
longed and sustained release profile (17,18). Unfor-
tunately, we were unable to demonstrate the efficacy
of 5%TA for significantly lightening melasma.
Melasma is a common cosmetic problem espe-
cially in women with Fitzpatrick skin types IV to VI
Tranexamic acid, whitening, melasma 153
and can pose a tremendous psychological impact.
Although various factors such as ultraviolet radia-
tion, hormones and genetics play roles in the patho-
genesis of melasma, the exact mechanism remains
unknown (1–4). In melasma, there are increased
proliferation and increased number of melanocytes.
These melanocytes exhibit enlarged perikarya and
increased transfer of melanosomes to the basal and
suprabasal keratinocytes (4). Therapy is based on
(i) sun protection; (ii) inhibition of melanocyte
hyperactivity; (iii) removal of melanin; (iv) disper-
sion of melanin granules. Currently, there are many
hydroquinone-free alternative treatments for
melasma, for example, mulberry extracts, arbutin,
kojic acid, liquiritin, ling-zhi and tranexamic acid
(TA).
Tranexamic acid acts by attaching to the lysine-
binding sites of plasmin and plasminogen. Topical
TA inhibits UV-induced plasmin activity in keratino-
cytes by preventing the binding of plasminogen to
the keratinocytes, thus suppresses the production of
prostaglandins, UV-induced melanogens, through
the suppression of the epidermal plasmin activity.
Eventually, lesser free arachidonic acids and depleted
production of prostaglandins reduces the melanocyte
tyrosinase activity. This might be the mechanism for
the treatment of melasma and improvement of post-
inflammatory hyperpigmentation (5,7). Although
systemic TA has been reported to be safe for the
treatment of melasma (21), the risk- benefit study
must be done on a larger scale.
In conclusion, Topical 5% TA as a monotherapy
appears to be safe but fails to reduce pigmentation
significantly in melasma for darker skin types.
However, our study contains limited number of
participants, and larger controlled trials should be
done to represent the melasma population and por-
tray the effectiveness of TA as a monotherapeutic
whitening agent more accurately. Nevertheless,
novel formulations for topical tranexamic acid and
different mode of administration might achieve sat-
isfactory results. Although in our study topical TA
does not significantly improve the appearance of
melasma in darker skin types, we have not com-
bined TA with other whitening agents to see if TA
produces synergistic properties. Since TA is consid-
ered safe as a topical agent, future clinical studies
may be carried out to disclose its hidden anti-
melasma potential.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the article.
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