Drug Monograph

Tranexamic Acid/Kojic Acid/Niacinamide 3/1/5% Serum

DESCRIPTION

Tranexamic Acid/Kojic Acid/Niacinamide is a triple ingredient serum that targets and corrects the appearance of hyperpigmentation as found in melasma and acne scars.

INDICATIONS AND CLINICAL USE

Tranexamic Acid, kojic acid, and niacinamide have been studied for the treatment of hyperpigmentation associated with melasma.1-9

CLINICAL PHARMACOLOGY

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.

PHARMACODYNAMICS

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 photoimmunosuppression, photocarcinogeneiss, 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.

CLINICAL RESEARCH
Tranexamic Acid

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

Tranexamic Acid + Kojic Acid + Niacinamide

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

Niacinamide

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

DOSING AND ADMINISTRATION

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.

ADVERSE REACTIONS

While topically applied tranexamic is usually considered to be safe, the following have occurred with oral use.

Tranexamic Acid (Oral)

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.

WARNINGS

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.

While topically applied tranexamic is usually considered to be safe, the following are warnings for oral use.

Visual Disturbances

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.

Irregular Menstrual Bleeding

Patients with irregular menstrual bleeding should not use CYKLOKAPRON until the cause of the irregularity has been established.

Irrespective of the drug chosen to reverse the Naltrexone blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.

Venous and Arterial Thrombosis

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.

Allergic Reactions

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

Convulsions have been reported in association with oral tranexamic acid treatment.

Hormonal Contraceptives

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.

PRECAUTIONS
Tranexamic Acid

While topically applied tranexamic is usually considered to be safe, the following precautions may still be considered:

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.

Renal Insufficiency: Care should be taken in cases of renal insufficiency due to the risk of accumulation

Niacinamide

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.

PREGNANCY

The safety of tranexamic acid/kojic acid/niacinamide during pregnancy has not yet been established.

LACTATION

The safety of tranexamic acid/kojic acid/niacinamide during lactation has not yet been established.

CONTRAINDICATIONS

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.

DRUG INTERACTIONS
Tranexamic Acid

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.

STORAGE
  • Keep tightly closed after each use
  • Keep out of reach from children.
  • Store in a cool and dry place. Avoid exposure to direct sunlight.
REFERENCES
  1. Taraz M, Niknam S, Ehsani AH. Tranexamic acid in treatment of melasma: a comprehensive review of clinical studies. Dermatol Ther. 2017.
  2. 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.
  3. 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.
  4. Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014;19:753–757.
  5. 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.
  6. 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.
  1. 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.
  2. 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.
  3. 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.
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