Oral Tranexamic Acid for the Treatment of Melasma- A Review

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Oral Tranexamic Acid for the Treatment of Melasma:
A Review
Harini R. Bala, MBBS,* Senhong Lee, MBBS,† Celestine Wong, MBBS,*
Amit.G. Pandya, MD,‡ and Michelle Rodrigues, FACD*xk
BACKGROUND Melasma is a common acquired disorder of hyperpigmentation that commonly affects those with
skin of color. Tranexamic acid (TXA) is a novel treatment for melasma that has a multimodal mechanism of action.
OBJECTIVE To provide a comprehensive review of the literature regarding the evidence on the mode of
action, safety profile, and efficacy of TXA in the treatment of melasma.
MATERIALS AND METHODS The literature was searched for publications on TXA in the treatment of mel-
asma using MEDLINE, Scopus, and Google Scholar.
RESULTS Oral TXA has clearly demonstrated the efficacy for melasma in Asian skin, even in low doses (e.g., 500
mg daily) over short periods (8–12 weeks). It is also a safe therapeutic option, which is easy to administer with few
and mild side effects. Studies have shown that TXA does not increase the thromboembolic risk, although patients
should be screened carefully for contraindications and risk factors prior to commencement of the therapy.
CONCLUSION Oral TXA is a safe and efficacious treatment for refractory melasma. It should be considered in
cases that are unresponsive to topical hydroquinone and combination topical therapy over a period of
approximately 12 weeks and without contraindications to oral TXA.
The authors have indicated no significant interest with commercial supporters.
Melasma is a common, chronic, acquired disorderofpigmentationpresentingwith light,darkbrown
macules on the face.1 Males and females in all racial
subgroups may be affected.2 The significant morbidity of
melasma and its negative impact on quality of life is well
documented.3 Despite this, the paucity of therapeutic
innovation for melasma has been a source of frustration
for both patients and clinicians. Hydroquinone has been
the gold standard for the treatment of melasma for many
decades, but over the past few years, oral tranexamic acid
(TXA), with its demonstrated efficacy and rarity of side
effects, has begun to emerge as the possible new gold
standard therapy for melasma.
The exact etiology of melasma is unknown, but it is
thought to be complex and multifactorial involving
both environmental and genetic influences.3,4 Known
common triggers and exacerbating factors include
pregnancy, hormonal therapy, ultraviolet (UV) radi-
ation, and, in those with richly pigmented skin, visible
light.4–6 Increased numbers of mast cells and vascular
endothelial growth factor have been demonstrated in
lesional skin of those with melasma.4,7,8 Kang and
colleagues9 found melanin throughout all epidermal
layers and an increase in the intensity and the number
of epidermal melanocytes and dermal melanophages
in melasma-affected skin.3 The presence of solar elas-
tosis in lesional skin indicated UV damage, and the
increase of intracellular organelles, such as mito-
chondria, within the lesional melanocytes suggested
greater activity in comparison to normal skin.3,9
Additionally, Noh and colleagues10 studied the
*Skin and Cancer Foundation Inc., Melbourne, Australia; †Department of Medicine, Monash Health, Melbourne,
Australia; ‡Department of Dermatology, University of Texas, Southwestern Medical Center, Dallas, Texas; xDepartment
of Dermatology, The Royal Children’s Hospital, Victoria, Australia; kDepartment of Dermatology, St Vincent’s Hospital,
Victoria, Australia
© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1076-0512 · Dermatol Surg 2018;0:1–12 · DOI: 10.1097/DSS.0000000000001518
1
© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
inflammatory features of melasma in Asian skin and
reported more melanophages, mast cells, and leuko-
cytes in lesional skin.
Elimination of causative factors and photoprotection
is paramount in all patients. The current gold standard
in the United States for the treatment of melasma is
hydroquinone. A previous study demonstrated clear-
ance of melasma with hydroquinone alone in
approximately 40% of patients.11 However, adverse
effects associated with hydroquinone use include irri-
tant dermatitis, allergic contact dermatitis, post-
inflammatory hyperpigmentation, nail bleaching, and
exogenous ochronosis (a rare but permanent bluish
gray discoloration of skin),2,3 making hydroquinone
alternatives highly sought after.
Treatment for melasma is often challenging.3
Tyrosinase is a key enzyme that is involved in the
rate-limiting processes of melanogenesis, and vari-
ous therapies, including hydroquinone, are aimed at
inhibiting this enzyme.12 Conventional first-line
treatments for melasma include various topical
agents, including hydroquinone, retinoids, and
alpha- and beta-hydroxy acids.2 Some of these
treatments, however, are limited by cutaneous side
effects and often only result in partial lightening.2
Second-line agents include physical therapies such
as chemical peels and low-fluence Q-switched
neodymium-doped: yttrium aluminium garnet laser
(QS-Nd:YAG) (known as “laser toning”), but the
need for multiple treatments over several months,
complications after several treatments, and the
financial burden of these therapies are limiting fac-
tors.1,2 The cost and risk-to-benefit ratio, particu-
larly in those with skin of color, needs to be carefully
considered.2
Over the past 5 years, a plethora of literature demon-
strating efficacy and safety of oral TXA in the Asia
Pacific region for the treatmentofmelasmahas surfaced.
Despite promising results with oral TXA for the treat-
ment of melasma in Asian patients, there are no studies
evaluating this therapy in those with Hispanic, Cauca-
sian, Mediterranean, Middle Eastern, or African
American backgrounds. To date, TXA has not been
Food and Drug Administration approved for melasma.
Mechanism of Action and Pharmacokinetics
Tranexamic acidwas discovered to inhibit bleeding by
its effects on the conversion of plasmin and thus sub-
sequently stopping fibrinolysis over 50 years ago.13,14
Its primary use in the 1990s was to induce hemostasis
in surgical procedures and for the treatment of
menorrhagia.15
Aside from haemostatic effects, TXA also displays
both anti-inflammatory and antiallergic properties.16
Tranexamic acid, which is a synthetic derivative of
the amino acid lysine, binds to lysine residues of
plasminogen and prevents its conversion to plasmin
(Figure 1).14,17
Sadako18 were the first to describe TXA for the treat-
ment of melasma in 1979. This was an accidental
finding while attempting to study TXA for the treat-
ment of urticaria. This prompted a study of TXA on
melasma patients.19 Lightening of melasma was seen
after 4 weeks of 1.5 g daily dosing of TXA alongside
Vitamins B, C, and E supplementation.18
Maeda and colleagues20,21 investigated the role of
TXA in human melanocyte and keratinocyte cultures.
Results revealed that TXA inhibits epidermal mela-
nocyte tyrosinase activity by blocking the interaction
of melanocytes and keratinocytes via the inhibition of
the plasminogen/plasmin system.20 In addition, they
suggested that the inhibition of plasminogen binding
to keratinocytes decreases the production of inflam-
matory mediators arachidonic acid and prostaglan-
din, which are known melanocyte stimulators.12,20,21
Tranexamic acid also prevents UV light–induced
plasmin activity, decreases mast cell activity, and
inhibits fibroblast growth factor, subsequently
decreasing vascularity and mast cell numbers in the
dermis.7,21–26 Due to the similarity between TXA and
tyrosinase structurally, it is postulated that TXA also
competitively antagonises the enzyme, adding further
to the lightening effect (Figure 1).26,27
Dosing and Adverse Effects Profile
The primary concernwith the use of TXA formelasma
has been the risk of developingarterial and venous
thromboses. Callender and colleagues34 in 1970
THE USE OF TRANEXAMIC AC ID FOR MELASMA
DERMATOLOG IC SURGERY2
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documented that 1 g of TXA used over the first 4 days
of the menstrual cycle decreased menorrhagia with no
significant difference in side effects between the con-
trol and placebo arms.34 Clinical trials, some con-
ducted over 1 year, led to the approval of TXA for
menorrhagia with only mild side effects reported.
These included nasal and sinus discomfort, back pain,
musculoskeletal pain, oligomenorrhea, and abdomi-
nal cramps, with no evidence of ocular toxicity.15,35
Retinal degeneration has been previously reported in
animal studies with higher doses of TXA.36,37 Theil37
studied TXA in human use for more than 6 years and
found TXA to demonstrate no ocular toxicity, par-
ticularly no retinal damage. Various studies have since
reviewed the use of TXA in hemorrhagic conditions
and have deemed TXA safe with nausea and diarrhea
being the most commonly reported side effects.38
Studies that evaluated intra- or postoperative use of
TXA for hemostasis have yet to find a connection
between TXA and thromboembolic risk, with similar
side effects reported in treatment and control arms.39–41
A long-term follow-up study was conducted in women
who used 3.9 g of TXA per day for 5 days over 29
menstrual cycles.42 Common side effects reported in
this trial included headache, menstrual, and back
pain.42
While there were reported cases of thrombosis with
oral TXA for the use of bleeding, these patients usually
had risk factors identified for hypercoagulability,
which included clotting disorders, history of pulmo-
nary emboli (PE), prolonged immobility, hormone
therapy, drug interactions, active bleeding, cancer,
and surgery43–47 Data evaluation at this point suggests
that TXA does not increase thromboembolic risk, and
treatment has not demonstrated any serious adverse
events in women with menorrhagia.35,48–51 This is
further supported by data from population-based
studies.50 In further details, 23 and 14 trials (TXA vs
control) reported data for deep vein thrombosis (DVT)
and pulmonary embolism, respectively.50 A total of
1,472 and 1,006 patients were included, respectively,
and subsequently randomized to either theTXAgroup
or the control group (who did not receive TXA).50 It
Figure 1. Tranexamic acid, mode of action. Plasminogen (PA) resides in keratinocytes and basal cells.14 Ultraviolet (UV)
radiation stimulates the keratinocyte–PA pathway and thus melanogenesis.14,28 Hormones also stimulate the keratinocyte–
PA pathway.14 Tranexamic acid inhibits pigmentation induced by ultraviolet radiation by various mechanisms including the
following: plasmin increases single chain urokinase PA (Sc-uPA), which increases tyrosinase activity and keratinocyte
growth.19 Tranexamic acid is thought to inhibit this pathway and thus decrease the activity of tyrosinase.16 Tranexamic acid
prevents the binding of plasminogen to the keratinocyte.19 Tranexamic acid reduces the production of prohormone cov-
ertase (PC2). PC2 is involved in the proopiomelanocortin system (PMOC) in producing a-melanocyte–stimulating hormone
(a-MSH). This subsequent decrease in a-MSH despite UV stimulation of the PMOC gene results in lightening of the skin.16,29
Via blocking plasminogen to plasmin, inflammatory mediators such as AA, prostaglandin E2 (PGE2), leukotriene, and
fibroblast growth factor (FGF) are reduced decreasing melanogenesis19,30–33. AA, arachondonic acid; VEGF, vascular
endothelial growth factor; UV, ultraviolet.
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was demonstrated that the risk of developing a DVTs
or apulmonary embolismwasnot increasedwithTXA
treatment.50
Doses of TXAused formelasma in studies to date have
ranged from 500 to 1,500mg daily.18,52 A typical dose
is 250 mg twice daily. Treatment is usually continued
for 8 to 12 weeks.52 This is in contrast to menorrhagia
forwhich the dose is 3.9 to 4 gdaily for up to 5days per
month.35
Contraindications to Tranexamic Acid Therapy
Contraindications to therapy include comorbidities
such as renal dysfunction, malignancy, cardiovascu-
lar, respiratory disease, current anticoagulant therapy,
and history of thromboembolic disease, including
DVT, PE, arterial thrombosis, stroke,and sub-
arachnoid hemorrhage.52,53 Other risk factors for
thromboembolism such as pregnancy, hormonal
contraception or replacement therapy, smoking, and
long distance travel should also be taken into account
when assessing suitability and should be considered as
an exclusion criteria if present.53 Patients must be
screened carefully through careful history for contra-
indications and risks and subsequently given careful
instructions to monitor for side effects prior to initia-
tion of therapy with TXA.
Summary of the Literature
Sadako18 were the first to describe the use of TXA for
the treatment for melasma in 1979 in Japan.
Improvement in melasma was noted in 4 weeks with
doses of 1.5 g daily in combinationwith Vitamins B, C
and E.18 Since then, there has been growing use of
topical, oral, and injectable TXA in Asia.
In 2011, Cho and colleagues27 published the first TXA
study for melasma in the English language. Five hun-
dred milligrams of oral TXA daily was used as an
adjuvant treatment to intense pulsed light (IPL). This
blinded study comprised 51 cases in 2 arms; oral TXA
in combination with IPL and laser versus IPL only.
Both groups were instructed to put on a broad-
spectrum sunscreen during and after treatments. The
modified melasma area and severity index (mMASI)
scores and photographs were evaluated.27 The
mean mMASI score decreased from 11.33 6 7.07 to
6.216 5.04 in the treatment group and 11.706 6.72
to 8.936 5.89 in the control group.27 The results were
statistically significant with no serious side effects
documented.27
In 2012, a 16-week, prospective, open-label study of
35 patients was conducted in Beijing, China.54 A
treatment regimen of TXA dosed 250 mg 3 times per
day was used. All patients were advised to apply
broad-spectrum sunscreen. The study employed
a 5-point scoring scale to evaluate the severity of
melasma. Eighty-five percent of patients experienced
improvement at 4 weeks with 100% response by the
end of the study.54 Mild adverse effects were reported
including slightly elevated alanine transaminase (3%),
gastrointestinal discomfort such as nausea and vom-
iting (12.5%), early menstruation (1, 3%), delayed
menstruation (1, 3%), and drowsiness (1, 3%).
In 2012, another randomized, prospective clinical trial
involving 48 women aged between 18 and 55 years
were recruited from a single site in Seoul, South
Korea.55 Oral TXA combined with low-fluence
QS-Nd:YAG laser was studied for the treatment of
melasma. The participants were divided into 2 arms:
a combination group and a laser treatment group. All
participants were treated with 2 sessions of low-
fluence QS-Nd:YAG laser and were advised to apply
sunscreen. Those in the combination group were also
provided with 8 weeks supply of 750 mg TXA. The
mean MASI score 4 weeks after the second treatment
decreased significantly in both the groups from base
line (combination group: 37.8 + 23.9%vs laser group:
21.9 + 18.5%; p = .02), with the combination group
treated with TXA demonstrating better results. Mild
side effects such as heartburn and nausea were
reported.
A large case series byWuand colleagues,17 conducted
in 2012, involved 74 women in Hangzhou, China.
The efficacy and safety profile of TXAat a dose of 250
mg twice daily for more than 6 months was assessed.
All patients were advised to apply sunscreen. Photo-
graphs were taken every 4 weeks, and 2 independent
assessors performedevaluations.17 An excellent
response was defined as the area of involvement
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decreasing by 90%, good was defined as the area of
involvement decreasing by 60%, fair was defined as
area of involvement decreasing by 30%, and a poor
result was defined as an area of improvement
involving less than 30%. The study results revealed
that more than half of the participants demonstrated
a good response (54%), one-third had a fair response
(31.1%), and more than 10% had an excellent
response. Less than 5% of the participants were
reported to have poor results. Gastrointestinal dis-
comfort (5.4%) and hypomenorrhea (8.1%)were the
reported side effects.17 Melasma recurrence was
observed in 7 cases (9.5%).
In 2013, a case series of 22 women was reported
from Seoul, South Korea.7 The 8-week trial evalu-
ated 250 mg of TXA 3 times per day in conjunction
with twice daily application of 1% TXA topically.7
All subjects were also advised to apply sunscreen.
The mean melanin index scores for lesional skin
decreased significantly, and histological analysis
showed significant reduction of epidermal pigmen-
tation, blood vessel number, and mast cell count.7
Epidermal pigmentation, erythema, and melasma-
related dermal changes, such as vascular angiogen-
esis and increased mast cells counts, also improved.7
All 22 women completed the study with no adverse
effects reported.7
More recently, 40 patients with melasma were
recruited into an open-labeled, randomized, compar-
ative trial comparing 250 mg of TXA twice daily with
triple combination cream (TCC) (Group B) with TCC
alone (Group A).26 All patients were advised to apply
broad-spectrum sunscreen. Treatment response was
evaluated using the melasma severity index. The
comparison between the treatment Group A and
GroupB showed statistically significant results (Group
AMasi at 8weeks 6.9956 6.056 andGroup B 2.196
2.378) at 4 and 8 weeks. No significant side effects
were noted, and all 40 patients completed the trial.26
There were limitations of this study, which included
the absence of information about other topical thera-
pies used and lack of blinding.26
The largest study to date was published in 2016 by Lee
and colleagues.52 In this retrospective study, 561
patients were treated with TXA 250 mg twice daily.
Ninety-five percent of participants were classified as
having treatment-resistant melasma (prior therapy
with no satisfactory clearance).52 Given the retro-
spective nature of this study, not all patients have used
sunblock. Lightening of lesional skin was observed
within 2months of treatment, and 89.7%patients had
documented improvement, 10% remained
unchanged, and 0.4% worsened. Of the patients who
improved, the reported lightening rate was 50%.52
Assessments were made on the physician global
assessments as documented in patient files.52 7.1% of
patients reported mild side effects including abdomi-
nal bloating and headache. One patient developed
a DVT 6weeks into therapy. This was in the setting of
undiagnosed familial protein S deficiency. The study
concluded that TXA at 250 mg twice daily is a valu-
able adjuvant in treatment-resistant melasma. This
study also highlighted the importance of a detailed
history in order to exclude contraindications to
therapy.
The literature is summarized in Table 1.
The role of oral TXA on nonlesional skin remains
unclear. In a large case series, it is found that in some
patients who had both melasma and other hyperpig-
mented lesions (i.e., freckles and senile lentigo), TXA
treatment improved their melasma but not the other
hyperpigmented lesions.17 It was postulated that these
other hyperpigmentation diseases may involve differ-
ent pathogeneses that TXA does not interfere with.17
Interestingly, in another case series, a combination of
topical and oral TXA had reduced the melanin index
score for lesional skin but increased the melanin index
score in perilesional skin.7 The darkening of the per-
ilesional skin was attributed to a change in season,
from spring to summer.7 On the other hand, in the
study conducted by Li and colleagues,54 their study
demonstrated that TXA treatment improved the skin
color for both lesional skin and nonlesional skin. The
former demonstrated marked improvement, while the
latter showed moderate improvement.54 However, it
was not explained in the article whether this obser-
vation could be attributed to seasonal changes. Larger
studies are required to clarify the role of oral TXA on
nonlesional skin.
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TABLE 1. Summary of Studies (Focusing Primarily on English Publications)
Year Study
No. Cases vs
Controls
TXA Arm
(Oral)
Concurrent
Treatment
Control
Arm
Duration
(Wk) Results Side Effects
Additional
Comments
1979 Sadako and
colleagues
(Japan)
12 cases,
0 controls
1.5 g daily Vitamins
B, C, E
— 20 11 cases
demonstrated
an obvious
result
Nil reported Effect was
noted in 4 wk
1985 Hajime and
colleagues56
(Japan)
40 cases,
0 Controls
1–1.5 g daily 10 33 cases had
a reported
decreased
severity
1988 Higashi and
colleagues57
(Japan)
11 cases,
0 controls
0.75–1.5 g
daily
Not indicated
exactly, article
states, “a
couple of mo”
11 cases
reported with
decreased
severity
Nil reported Recurrence of
melasma
noted a few
mo post
cessation of
treatment
2001 Zhu and
colleagues58
(China)
128 cases 30
controls
750 mg daily Vitamins
C and E
Vitamins C and
E
6–8 Improvement:
20% > 95%,
30% > 60%,
33% = 20%–
60%
Mild
gastrointestinal
cases reported
p < .001
Important
findings that
increased
duration was
more effective
than higher
doses of TXA
In addition,
TXA did not
alter the
clotting
profile
2005 Liu and
colleagues59
(China)
176 cases, 70
controls
750 mg/d + Vitamins
C and E
Vitamins C and
E
8 24% > 90%,
40% > 60%
5% of participants
in both treatment
and control
reported
gastrointestinal
symptoms
p < .01
T
H
E
U
S
E
O
F
T
R
A
N
E
X
A
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IC
A
C
ID
F
O
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A
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©
2018
by
the
A
m
erican
S
ociety
for
D
erm
atologic
S
urgery,
Inc.
P
ublished
by
W
olters
K
luw
er
H
ealth,
Inc.
U
nauthorized
reproduction
of
this
article
is
prohibited.
TABLE 1. (Continued)
Year Study
No. Cases vs
Controls
TXA Arm
(Oral)
Concurrent
Treatment
Control
Arm
Duration
(Wk) Results Side Effects
Additional
Comments
2008 Wu and
colleagues60
(China)
256 cases,
0 controls
500 mg daily 24 10.5% > 90%,
19% > 60%,
51%, 30%
4.3% of
participants
reported
gastrointestinal
symptoms
33% response 4
wk; 33% in 8
wk
3.5% reported
menstrual
irregularity
TXA did not
alter the
clotting
profile
2008 Mafune and
colleagues61
99 cases, 100
controls
2.25 g daily Placebo 8 76.8% of
participants
improved
1 transient chest
discomfort
p < .001
2011 Cho and
colleagues27
(Korea)
24 cases, 27
controls
500 mg daily IPL/Nd:YAG
laser
IPL/Nd:YAG 24 A decrease in
mMASI,
43.8% vs
23.6%
Mild headache in 4
patients
p < .005
2012 Shin and
colleagues55
(Korea)
23 cases, 21
controls
750 mg daily
(compound)
Low fluence
QS-Nd:YAG
laser
Low fluence
QS-Nd:YAG
laser
8 A decrease in
mMASI
however no
significant,
decrease in
melanin index
3 patients reported
GIT side effects
TXA increased
the efficacy of
laser and
reduced the
frequency of
laser
treatment
2012 Wu and
colleagues17
(China)
75 cases,
0 controls
250 mg twice
daily
24 (follow up at
6 mo)
Excellent
10.8%, Good
54%, Fair
31.1%, Poor
4.1%
5.4% of patients
reported GIT
effects. 58%
reported
hypomenorrhoea
The recurrence
rate noted in
thetrial was
9.5%
82% of results
were noted in
the first 4 wk
2012 Karn and
colleagues62
(Nepal)
130 cases, 130
controls
250 mg twice
daily
Routine topical
treatment
Routine topical
treatment
12 Statistically
significant
decrease in
MASI in the
control group B
A
L
A
E
T
A
L
0
:0
:M
O
N
T
H
2
0
1
8
7
©
2018
by
the
A
m
erican
S
ociety
for
D
erm
atologic
S
urgery,
Inc.
P
ublished
by
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olters
K
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er
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ealth,
Inc.
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nauthorized
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prohibited.
TABLE 1. (Continued)
Year Study
No. Cases vs
Controls
TXA Arm
(Oral)
Concurrent
Treatment
Control
Arm
Duration
(Wk) Results Side Effects
Additional
Comments
2013 Na J and
colleagues7
(Korea)
25 cases,
0 controls
125 mg twice
daily
2% TXA and 2%
niacinamide
topically
8 No serious effects
noted
Study reported
different
effects on
lesional vs
nonlesional
skin
2013 Li and colleagues54
(China)
35 cases,
0 controls
Compound
TXA (Dai-
ichi pharma
Japan) 3
times daily
16 Moderate
improvement
3 cases reported
GIT side effects, 3
cases with
menstrual
irregularities, 1
case of
drowsiness, and
1 patient with
increased liver
function tests
85% of cases
improved in 4
wk
2014 Aamir and
colleagues63
(Pakistan)
65 cases 250 mg twice
daily
24 15 cases had an
excellent
response, 41
with good and
8 fair
Mild side
effects
including
gastrointestinal
symptoms,
palpitation, and
oligomenorrhea
Study reported
TXA as a safe
and effective
treatment for
melasma
2015 Padhi, Pradhan26
(India)
20 case, 20
controls
250 mg twice
daily
TTC
(fluocinolone
acetonide
0.01%,
tretinoin
0.05%,
hydroquinone
2%) daily
TTC
(fluocinolone
acetonide
0.01%,
tretinoin
0.05%,
hydroquinone
2%) daily
8 54.65% saw
a decrease in
in MASI
(15.425–
6.995), 88%
saw
a decrease in
MASI (from
18.243 to 2.19)
TTC—faster,
more
sustained
effect when
TXA is added
2016 Tan and
colleagues23
(Singapore)
25 250 mg twice
daily
Combination
topical
therapy
Mean
improvement
of 69%.
Significantly
lower MASI
scores
p < .01
Low-dose TXA
is useful for
refractory
melasma
T
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©
2018
by
the
A
m
erican
S
ociety
for
D
erm
atologic
S
urgery,
Inc.
P
ublished
by
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olters
K
luw
er
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ealth,
Inc.
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nauthorized
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is
prohibited.
In 2 studies, subjects withmelasmawere stratified into
various subtypes via Wood’s lamp, that is, epidermal,
dermal, and mixed. Although all subtypes of melasma
responded well to TXA, both studies highlighted that
epidermal melasma tends to demonstrate more sig-
nificant clinical improvement when compared to der-
mal ormixed variants.62,63 The underlyingmechanism
of this phenomenon remains unclear, and further
studies are required to clarify this. It is important to
note that many patients with melasma have a dermal
component even if not clinically visible.
There are studies to support the therapeutic efficacy of
TXA via various route of administration (i.e., oral,
topical and intradermal) for melasma.64 In a study
conducted by Steiner and colleagues,65 it was found
that topical and intradermal TXA were both effective
for the treatment of melasma objectively, without
statistical difference between the 2 groups. However,
no studies have directly compared the efficacy of oral
TXA versus topical or intradermal TXA. Kim and
colleagues66 had recently conducted a meta-analysis
examining the efficacy of TXAmelasma. It was found
that with oral, intradermal, and topical TXA, the
standardized mean reduction inMASI was 2.46 (95%
confidence interval [CI], 1.13–3.8;p< .001; I2 = 71%),
1.42 (95% CI, 0.98–1.87; p < .001; I2 = 72%), and
1.36 (95% CI, 20.17 to 2.9; p = .08, I2 = 74%),
respectively.66 However, further studies will be
required to compare oral TXA versus topical or
intradermal TXA directly.
There is a clear role forTXA in the treatment ofmelasma
given its safe and effective profile. However, its exact
position in the therapeutic ladder for melasma remains
poorly defined. The present standard of care is the triple
combination cream that contains hydroquinone, ste-
roids, and tretinoin. Unfortunately, there was no direct
comparison study to evaluate the effect of oral TXA
versus the combination cream. There is evidence that
oral TXA is effective alone or as an adjunct with other
therapeutic modalities (e.g., topical therapy and laser). It
also has a role in melasma that is resistant to conven-
tional topical therapies.23 Based on the available data in
the literature, it is recommended that oral TXA should
only be used only in cases of melasma that are unre-
sponsive to topical hydroquinone and combination
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BALA ET AL
0 : 0 :MONTH 201 8 9
© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
topical therapyover a period of approximately 12weeks
and if there are no contraindications to oral TXA.
However, large-scale, randomized controlled trials are
warranted to better characterize the role of oral TXA in
the therapeutic ladder of melasma.
Melasma is known to have high relapse rates.52
Multiple studies have revealed that melasma tend to
recur post cessation of TXA treatment.17,23,52,57 In
a case series conducted by Wu and colleagues,17 the
recurrence of melasma was observed in 9.5% of
patients (7 of 74) after 6 months. It was found that
these recurrences could be effectively treated with
a repeat intake of TXA.17 Lee and colleagues also
demonstrated that melasma relapsed in 27.2% of
patients (137 of 503) with a median duration of 7
months upon cessation of oral TXA. The highest
relapse rate was observed in the study by Tan and
colleagues, with 72% of patients relapsed within 2
months post cessation of TXA.23 This could be
explained by the fact that their study only included
patients with recalcitrant melasma not cleared by
conventional topical therapy.23 This suggests that
treatment-resistant cases are more prone to recur-
rence. These studies highlight that TXA treatment
may need to be maintained for a more extended
period, especially in treatment-resistant cases. More
research on the ideal dosage and duration of TXA
intake to result in clearance of melasma without
recurrence is required.
Summary and Future Directions
Tranexamic acid is the first systemic therapy to be
studied for melasma. It has clearly demonstrated the
efficacy for melasma in Asian skin, even in low doses
(e.g., 500mg daily) over short periods (8–12weeks). It
has also established itself as a safe therapeutic option,
which iseasy to administer with few, reversible, and
mild side effects. Studies have shown that TXA does
not increase thromboembolic risk, although patients
should be screened carefully for contraindications and
risk factors prior to commencement of the therapy.
Patients shouldbewell informedof the risks associated
with therapy and counseled adequately prior to the
initiation of therapy. Based on the available data in
the literature, it is recommended that oral TXA
should only be used only in cases of melasma that are
unresponsive to topical hydroquinone and combi-
nation topical therapy over a period of approxi-
mately 12weeks and if there are no contraindications
to oral TXA. However, large-scale, randomized
controlled trials are warranted to better characterize
the role of oral TXA in the therapeutic ladder of
melasma. Despite the plethora of studies now pub-
lished on the successful use of oral TXA for the
treatment of melasma, randomized, double-blinded,
controlled trials and data from centers outside Asia
are clearly needed to document safety and efficacy in
non-Asian patients.
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Address correspondence and reprint requests to: Harini R.
Bala, MBBS, Skin and Cancer Foundation, Level 1, 80
Drummond Street, Carlton, Victoria 3053, Australia, or
e-mail: hbala@skincancer.asn.au
THE USE OF TRANEXAMIC AC ID FOR MELASMA
DERMATOLOG IC SURGERY12
© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
mailto:hbala@skincancer.asn.au