Tranexamic acid, kojic Acid, and niacinamide have been studied either separately or in conjunction for the appearance of hyperpigmentation found in melasma and post inflammatory hyperpigmentation (PIH).1-11
Tranexamic Acid, kojic acid, and niacinamide may be compounded individually, combined, or combined in parts. The combination is commonly compounded as a serum in the following strengths: Tranexamic Acid/Niacinamide/Kojic Acid 3/5/1%.
Melasma is a chronic skin condition that disproportionately affects people of Asian, African, and Hispanic descent. Melasma is characterized by hyperpigmentation on sun-exposed facial skin, especially the cheeks, forehead, nose, and supralabial regions. While exact mechanisms remain somewhat unclear, one theory is that ultraviolet light increases plasmin activity in keratinocytes, which leads to an increase in melanocytic-stimulating mediators, such as arachidonic acid and α-melanocyte stimulating hormone. Melasma is often associated with pregnancy, changes in uterine or ovarian hormones, oral contraceptives, hepatopathies, and cosmetic drug use. Melasma can also negatively influence quality of life and cause substantial psychological and social distress.
Tranexamic acid (TA) has been evaluated for the treatment of melasma through various routes of administration, including topical, intradermal, and oral. TA is an antifibrinolytic agent that has antiplasmin activities. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.
Niacinamide studies have demonstrated a suppression of melanosome transfer resulting in a suppression of cutaneous pigmentation. Niacinamide’s effects also include prevention of photo-immunosuppression, photo-carcinogenesis, anti-inflammatory effects in acne, rosacea and psoriasis. It also increases biosynthesis of ceramides, as well as other stratum corneum lipids with enhanced epidermal permeability barrier function. Moreover, its antiaging effects have been demonstrated in randomized trials.
Kojic Acid (KA) is a natural metabolite produced by fungi that has the ability to inhibit tyrosinase activity in the synthesis of melanin. KA and its derivatives ae often used as antioxidants, anti-proliferatives, anti-inflammatory agents, radio protectives, and skin lightening agents in skin creams, lotions, soaps and dental care products.
Tranexamic acid, kojic acid, and niacinamide have been studied for the treatment of hyperpigmentation associated with melasma and post inflammatory hyperpigmentation (PIH).1-8
The efficacy of topical TA has been assessed by several studies. Five out of six studies, all of which had small sample sizes (n=13–50), demonstrated significant differences in Melasma Area and Severity Index (MASI) scores between before and after treatment.1-7 A variety of topical formulations and regimens were used, including 3% TA cream for 12 weeks, 5% TA gel for 12 weeks, 3% TA solution for 12 weeks, 5% TA liposome for 12 weeks, and 2% TA formulation for 12 weeks.1 A review of the studies reported supporting data of TA’s effectiveness in lightening dyschromia and decreasing MASI scores from baseline.1 Topical TA appears to be as effective as topical hydroquinone, combination topical hydroquinone and dexamethasone, and intradermal injections of TA.1
Twenty-seven melasma patients were randomized to receive for eight weeks either 4% niacinamide cream on one side of the face and 4% hydroquinone cream on the other. All patients showed pigment improvement with both treatments. Colorimetric measures did not show statistical difference between both sides. Good to excellent improvement was observed with 44% of niacinamide side versus 55% of hydroquinone side. Niacinamide also showed a reduction in mast cell infiltrate and improvement in solar elastosis in melasma skin.9
Sixty patients with facial melasma were randomized to receive either hydroquinone 4% cream or kojic acid 0.75% + vitamin C 2.5% cream over a 12-week period. Kojic acid and hydroquinone proved to be useful hypopigmentation agents, with hydroquinone performing with superior results in the Melasma Area Severity Index (MASI).10
Eight patients were randomized to receive Group A: kojic acid 1% cream, Group B: kojic acid 1% and hydroquinone 2% cream, Group C: KA 1% and betamethasone valerate (BV) 0.1% cream or Group D: KA 1%, HQ 2%, BV 0.1% cream for a 12-week period and compared every 12 weeks using MASI. The clinical efficacy of Group B was the highest followed closely by group D and group A, and that of group C being the lowest.11
In a 12-week clinical study, a novel, topical facial serum containing 3% TXA, 1% kojic acid, and 5% niacinamide was evaluated for its effectiveness in treating melasma, PIH, and hyperpigmentation in Brazilian female subjects with Fitzpatrick skin types I-IV.
Efficacy evaluations were performed at pre-treatment baseline, weeks 2, 4, 8, and 12, and included expert clinical grading, bio-instrumental measurements, and self-assessment questionnaires. Cutaneous tolerability was also evaluated by assessing subjective and objective irritation of the treatment area.
Researchers found that subjects’ melasma and hyperpigmentation improved an average 60%, while post-inflammatory hyperpigmentation decreased an average 81%. Researchers also noted a 54% improvement in skin tone and 59% improvement in skin homogeneity beginning at week 2 and continued after 12 weeks of daily serum application. Melanin index, as measured by Mexameter®, demonstrated a significant decrease by week 12 as compared to both pre-treatment baseline and control.8
- Apply serum over entire face or to affected areas twice daily (morning and evening) before applying morning sunscreen.
- Cosmetics may be applied after the application of tranexamic acid/kojic acid/niacinamide serum.
- Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy.
- Not for oral, ophthalmic, or intravaginal use.
- Over time, use of kojic acid may make skin more susceptible to sunburn. Sunscreen or protective clothing is recommended.
While topically applied tranexamic is usually considered to be safe, the following have occurred with oral use.
Gastrointestinal Disorders: Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur but disappear when the dose is reduced.
Nervous System Disorders: Isolated cases of dizziness or reduced blood pressure have been reported
Immune System Disorders: allergic dermatitis have been reported less commonly.
Eye Disorders: To be observed by reason of experimental findings in animals: In the dog, retina changes have been observed after long-term administration of large doses of tranexamic acid and CYKLOKAPRON® (tranexamic acid)
No retinal changes have been reported or observed at ophthalmic check-ups of patients treated with CYKLOKAPRON for several weeks or months.
Contact dermatitis may manifest as redness, irritation, itchiness, rash, or swollen skin. Contact dermatitis is most common in those with sensitive skin or in individuals using a product with a higher concentration that 1%.
The following patients should consult their doctor prior to initiating treatment with tranexamic acid: obese and diabetic, with polycystic ovary syndrome or a history of endometrial cancer in a first-degree relative, women receiving unopposed estrogen or tamoxifen.
While topically applied tranexamic is usually considered to be safe, the following precautions may still be considered:
Care should be taken in cases of renal insufficiency due to the risk of accumulation
Visual disturbances including visual impairment, vision blurred, impaired color vision have been reported with tranexamic acid. For patients who are to be treated for several weeks with tranexamic acid, an ophthalmic check-up is advisable (sharpness of vision, color vision, fundus, field of vision, etc.) if possible, before treatment is initiated and regularly during treatments.
Patients with irregular menstrual bleeding should not use CYKLOKAPRON until the cause of the irregularity has been established.
Venous and arterial thrombosis or thromboembolism has been reported in patients treated with oral tranexamic acid. Patients with a high risk for thrombosis a previous thromboembolic event and a family history of thromboembolic disease should not use this serum.
Cases of allergic reaction with use of intravenous tranexamic acid, including anaphylaxis or anaphylactoid reaction have been reported that are suggestive of a causal relationship.
Convulsions have been reported in association with oral tranexamic acid treatment.
Combination hormonal contraceptives are known to increase the risk of venous thromboembolism, as well as arterial thromboses such as stroke and myocardial infarction. Because tranexamic is an antifibrinolytic, concomitant use of hormonal contraception and oral tranexamic acid may further exacerbate this increased thrombotic risk.
Allergies
Niacinamide can make allergies more severe because they cause histamine, the chemical responsible for allergic symptoms, to be released.
Diabetes
Niacinamide might increase blood sugar. People with diabetes who take niacinamide should check their blood sugar carefully.
Gallbladder disease
Niacinamide, when taken orally, might make gallbladder disease worse.
Gout
Large amounts of niacinamide taken orally might bring on gout.
Kidney dialysis
Taking niacinamide orally seems to increase the risk of low blood-platelet levels in people with kidney failure who are on dialysis.
Liver disease
Niacinamide might increase liver damage when taken orally. Use with caution in patients with liver disease.
Stomach or intestinal ulcers
Niacinamide might make ulcers worse when taken orally. Use with caution in patients with liver disease.
Surgery
Niacinamide might interfere with blood sugar control during and after surgery. Stop taking niacinamide at least 2 weeks before a scheduled surgery.
Sunburn
Over time, use of kojic acid may make skin more susceptible to sunburn.
Discontinue use if the following symptoms occur: red dots, swollenness, itching. Do not apply to parts of the skin that have rashes, are cut, or are infected.
The safety of tranexamic acid/kojic acid/niacinamide during pregnancy has not yet been established. Therefore, this compound should not be used in pregnant women.
The safety of tranexamic acid/kojic acid/niacinamide during lactation has not yet been established. Therefore, this compound should not be used in lactating women who are breastfeeding.
The safety of tranexamic acid/kojic acid/niacinamide has not yet been established for children. Therefore, this compound should not be used in this population.
Patients with a history or risk of thrombosis should not be given tranexamic acid, unless at the same time it is possible to give treatment with anticoagulants. The preparation should not be given to patients with acquired disturbances of color vision. If disturbances of vision arise during the course of treatment the administration of the preparation should be discontinued. Patients with active thromboembolic disease, such as deep vein thrombosis, pulmonary embolism and cerebral thrombosis.
Known hypersensitity to niacinamide, tranexamic acid, kojic acid, or any of its components.
Potential drug-drug interactions leading to myocardial infarction after coadministration with hormonal contraceptives, hydrochlorothiazide, desmopressin, sulbactam-ampicillin, carbazochrome, ranitidine, or nitroglycerin.
Because tranexamic acid is an antifibrinolytic, concomitant use of hormonal contraception and tranexamic may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives.
- Keep out of reach from children.
- Store in a cool and dry place. Avoid exposure to direct sunlight.
- Taraz M, Niknam S, Ehsani AH. Tranexamic acid in treatment of melasma: a comprehensive review of clinical studies. Dermatol Ther. 2017.
- Steiner D, Feola C, Bialeski N et al. Study evaluating the efficacy of topical and injected tranexamic acid in treatment of melasma. Surgical and Cosmetic Dermatology. 2009;1:174–177.
- Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, Nakakes A. Topical 5% tranexamic acid for the treatment of melasma in Asians: a double-blind randomized controlled clinical trial. J Cosmet Laser Ther. 2012;14:150–154.
- Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014;19:753–757.
- Banihashemi M, Zabolinejad N, Jaafari MR, Salehi M, Jabari A. Comparison of therapeutic effects of liposomal tranexamic acid and conventional hydroquinone on melasma. J Cosmet Dermatol. 2015;14:174–177.
- Kim SJ, Park JY, Shibata T et al. Efficacy and possible mechanisms of topical tranexamic acid in melasma. Clin Exp Dermatol. 2016;41:480–485.
- Chung JY, Lee JH, Lee JH. Topical tranexamic acid as an adjuvant treatment in melasma: side-by-side comparison clinical study. J Dermatolog Treat. 2015;4:1–5.
- Desai S, Ayres E, Bak H, Manco M, Lynch S, Raab S, Du A, Green D, Skobowiat C, Wangari-Talbot J, Zheng Q. Effect of a Tranexamic Acid, Kojic Acid, and Niacinamide Containing Serum on Facial Dyschromia: A Clinical Evaluation. J Drugs Dermatol. 2019 May 1;18(5):454-459.
- Navarrete-Solís J, Castanedo-Cázares JP, Torres-Álvarez B, et al. A Double-Blind, Randomized Clinical Trial of Niacinamide 4% versus Hydroquinone 4% in the Treatment of Melasma. Dermatol Res Pract. 2011;2011:379173.
- Monteiro RC, Kishore BN, Bhat RM, Sukumar D, Martis J, Ganesh HK. A Comparative Study of the Efficacy of 4% Hydroquinone vs 0.75% Kojic Acid Cream in the Treatment of Facial Melasma. Indian J Dermatol. 2013 Mar;58(2):157
- Deo KS, Dash KN, Sharma YK, Virmani NC, Oberai C. Kojic Acid vis-a-vis its Combinations with Hydroquinone and Betamethasone Valerate in Melasma: A Randomized, Single Blind, Comparative Study of Efficacy and Safety. Indian J Dermatol. 2013 Jul;58(4):281-5
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