502 Journal of the College of Physicians and Surgeons Pakistan 2019, Vol. 29 (6): 502-504
Melasma is an acquired hyperpigmentation of the skin
that typically affects the sun-exposed areas of the face.
It is most common in women with darker complexions,
who live in areas of intense ultraviolet (UV) radiation
exposure.1,2 Melasma causes considerable cosmetic
disfigurement and psychological distress; quality-of-life
studies have shown a significant negative effect of
melasma on emotional wellbeing, social life, and leisure
activities.3,4 The prevalence of melasma is reported
around the globe. In Brazil, it is about 5-9%, which
remains main cause of demand for dermatological care
in Saudia Arabia, Nepal and Brazil.3-5 The pathogenesis
of melasma is poorly understood. Contributing factors
include darker skin phototype (especially III and IV),
ultraviolet (UV) radiation, hormonal factors (eg, pregnancy,
oral contraceptives), genetic predisposition, cosmetic
use, thyroid dysfunction, and antiepileptic medications.5,6
The diagnosis of melasma is based upon history and the
clinical finding of symmetrically distributed hyper-
pigmented macules and patches on the face.7, 8
Examination under Wood's light may be helpful in
identifying the pattern of pigment deposition.9-11 The
melasma area and severity index (MASI) was created in
an attempt to standardise the subjective evaluation of
melasma in clinical trials.4,5
The treatment of melasma can be challenging because
of its chronic and relapsing nature.12-14 Treatments
include skin-lightening agents, chemical peels, and laser
and light-based therapy.15-18
These include hydroquinone used in strength of 2% and
4%, azelaic acid 15% and 20%, mequinol, kojic acid,
topical retionids 0.25%, 0.5% and 0.1%. All of these
treatment options result in excellent cure rate among
60% to 90%.19-22 Several types of lasers have been
used for the treatment of melasma with variable results.4
Oral and topical tranexamic acid has been used recently
in the treatment of melasma.4,5,11-13
Tranexamic acid is a plasmin inhibitor and lysine
analogue that has been shown to inhibit UV-induced
pigmentation in animal models while azelaic acid is a
naturally occurring, nonphenolic, nine-carbon dicarboxylic
acid that competitively inhibits tyrosinase. Both have
shown variable results for its efficacy in melasma.11,13
Combination of Oral Tranexamic Acid with Topical 3% Tranexamic Acid
versus Oral Tranexamic Acid with Topical 20% Azelaic Acid
in the Treatment of Melasma
Fahmida Malik1, Malik Muhammad Hanif1and Ghulam Mustafa2
Objective: To compare the effect of combination therapies of topical 3% tranexamic acid versus topical 20% azelaic acid
each combined with oral tranexamic acid in the treatment of melasma.
Study Design: Interventional comparative study.
Place and Duration of Study: Department of Dermatology, Sheikh Zayed Hospital, Rahim Yar Khan, from July 2017 to
Methodology: Cases of melasma diagnosed clinically (based upon history and the clinical findings of symmetrically
distributed hyperpigmented macules and patches on the face), aged 12 to 50 years, were selected. The cases were
divided into two groups by simple random sampling method. The cases in group A were treated by oral tranexamic acid
(250 mg twice daily) with topical 3% tranexamic acid (twice daily). In group B, cases had oral tranexamic acid (250 mg
twice daily) with topical 20% azelaic acid (daily) for six months. They were followed every second month upto 6 months
and the efficacy was assessed on the basis of scores on MASI scale.
Results: In 100 patient, there was no significant difference in terms of mean MASI score at 2 and 4 months with p-value
of 0.20 and 0.89, respectively. However, mean MASI score was significantly less in group A (6.06 ±5.06 vs. 10.62 ±7.43)
in group B (p=0.001). In group A, 14 (28%) had excellent response, whereas in group B, 11 (22%) had excellent results.
Conclusion: Combination of oral and topical 3% tranexamic acid is significantly better than oral tranexamic acid with 20%
azelaic acid for treatment of melasma.
Key Words: Melasma, Tranexamic acid, Azelaic acid.
Department of Dermatology1/ Community Medicine2,
Sheikh Zayed Medical College and Hospital, Rahim Yar Khan,
Correspondence: Dr. Fahmida Malik, Department of Dermatology,
Sheikh Zayed Medical College and Hospital, Rahim Yar Khan,
Received: July 13, 2018; Accepted: January 29, 2019
This study was planned to assess the effects of
combination therapy in melasma. The objective of this
study was to compare the effect of combination
therapies of oral tranexamic acid with topical 3%
tranexamic acid versus oral tranexamic acid with topical
20% azelaic acid in the treatment of melasma.
This was an interventional comparative study, conducted
from July 2017 to June 2018 at Department of
Dermatology, Sheikh Zayed Hospital, Rahim Yar Khan.
Sample size was calculated by taking 95% confidence
interval power of study 80% and cure rate in azelaic acid
group taken as 65%; whereas, cure rate in Tranexamic
acid group taken as 90%.16,17
Cases were taken in the range of 12 to 50 years of either
gender of melasma diagnosed clinically based upon
history and the clinical findings of symmetrically
distributed hyperpigmented macules and patches on the
face. Examination under Wood's light was used when
differentiating the pattern of pigment deposition
(assessed by history and medical record) were selected.
The cases being pregnant or nursing women, taking
contraceptive pills at the time of study or past 12
months, any chronic illness, with allergy to any of the
agents used in the treatment and those taking any
topical and systemic treatment for melisma in the last
one month were excluded from this study.
The cases were divided into two groups by simple
random sampling method. MASI scoring done before
starting the treatment. The cases in group A were treated
by oral tranexamic acid (250 mg twice daily); with topical
3% tranexamic acid solution (twice daily) and in group B
with oral tranexamic acid (250 mg twice daily) with
topical 20% azelaic acid (daily at night) for 6 months.
Topical 3% tranexamic acid solution was 3 g tranexamic
acid dissolved in 10-cc ethanol 96o, 10-cc 1.3-butanediol
and distilled water up to 100-cc formulated by Green
Plus Pharma Lahore. Candidates were asked to apply
sunscreen with SPF 60 or more during day time. They
were followed every 2nd month at OPD of dermatology
and the final outcome was seen at 6 months where the
efficacy was assessed on the basis of score on MASI
scale. Follow-up done for 6 months after completion of
treatment by using MASI score.
The data was entered and analysed by using (SPSS)
version 23. Age was compared by using t-test.
Qualitative variables were presented as frequencies and
percentages, while quantitative variables as mean and
standard deviation. Both the groups [Group A oral
tranexamic acid (250mg twice daily) with topical 3%
tranexamic acid solution and Group B oral tranexamic
acid (250 mg twice daily) with topical 20% azelaic acid]
were compared in terms of efficacy by using Chi-square
test taking p-value less than 0.05 as significant.
In the present study, there were a total of 100 cases, 50
in each group. Group A contained 6 (12%) males and 44
(88%) females, in contrast to group B, where they had 7
(14%) males and 43 (86%) females (p=0.76). There was
no significant difference in terms of mean MASI score at
2 and 4 months with p-value of 0.20 and 0.89
However, mean MASI score was significantly less in
group A where it was seen as 6.06 ±5.06 as compared
to 10.62 ±7.43 in group B with p-value of 0.001 as shown
in Table I. There was also no significant difference of
response of patients in terms of satisfaction (Table II)
with p-value of 0.74. Pre-treatment mean MASI score in
group A was 33.7 ±12 versus 34 ±13 in group B
(p=0.74). Mean age in group A was 24 ±6.02 and in
group B was 23.08 ±6.31 (p=0.45).
Melasma is defined as acquired macular hyper-pigmen-
tation, commonly seen in young population and majority of
them are females of child bearing age.14-18 Multiple factors
that influence its presence and precipitation include oral
contraceptive pills, pregnancy, genetics, endocrine
dysfunction, nutritional deficiency, medications, hepatic
dysfunction, and HIV etc. Sun exposure is common
factor for exacerbation of symptoms.19-22
In the present study, the efficacy in terms of MASI score
was significantly better in group A where it was seen as
6.06 ±5.06 as compared to 10.62 ±7.43 in group B with
p-value of 0.04. No such comparison of this combination
done before. However, significant difference in MASI score
was not found at 2 and 4 months follow-up in this study.
In a study of 100 cases of melasma done by Lee et al.
where they had used tranexamic acid intradermal every
week for 12 weeks, found significant improvement in
terms of MASI score at 8 and 12 weeks (p<0.05).15 The
efficacy seen in their study was even higher as compared
to the present one, where it was seen in 76.5% of
subjects. It may be due to the fact that they had longer
follow-up as compared to current study.
Combination therapies for melasma
Table I: Comparison of efficacy in both groups (independent t-test results).
MASI score Treatment group Significance
Group A Group B
At 2 months 21.68 ±10.93 24.32 ±9.82 0.20
At 4 months 14.02 ±9.07 17.04 ±8.47 0.89
At 6 months 6.06 ±5.06 10.62 ±7.43 0.001
Table II: Patient response to treatment in both groups (Chi-square test
Response Treatment group Significance
Group A Group B
Excellent 14 (28%) 11 (22%) 0.74
Good 28 (56%) 29 (58%)
Fair 8 (16%) 10 (20%)
Total 50 50
Journal of the College of Physicians and Surgeons Pakistan 2019, Vol. 29 (6): 502-504 503
Fahmida Malik, Malik Muhammad Hanif and Ghulam Mustafa
504 Journal of the College of Physicians and Surgeons Pakistan 2019, Vol. 29 (6): 502-504
A study of 25 cases done by Fox et al., using tranexamic
acid in the topical emulsion form up to 18 weeks, showed
that the improvement was even better and was observed
in 80% subjects,may be due to long follow-up.16 In both
of these studies, no major side effects were observed.
Karn et al. compared the combination of oral tranexamic
acid with topical hydroquinone with that of topical hydro-
quinone alone.17 It was observed that there was
significant reduction in MASI score in tranexamic acid
group. The efficacy of this can be explained by the factor
that tranexamic acid is temperature-stable, not UV
sensitive, and does not get oxidised easily. Thus, it acts
as an ideal choice for composition in skin lightening
creams. The advantage of it is that it is present in both
oral as well as topical preparations.
Siddique et al. in their study used combination of 20%
azelaic acid with 0.05% tretinoin. Good efficacy was
seen in 38.66% of the cases only. Side effects were also
noted during therapy.18
Mazurek et al. also used different combinations of azelaic
acid for the treatment of melasma, and they showed
better efficacy but none was significantly better as
compared to each other. The best results were seen in a
combination of 20% azelaic acid and mandelic acid,
phytic acid, 4N-butyl resorcinol, and ferulic acid.19
Fatemi et al. used topical solution form of tranexamic
acid. That study introduced the topical TA as an effective
and safe medication for the treatment of melasma.20
Combination of oral and topic 3% tranexamic acid is
significantly better than oral tranexamic acid with 20%
azelaic acid for treatment of melasma.
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