Tranexamic acid (TA) is a synthetic derivative of the amino acid lysine, and is perhaps the most widely studied systemic agent for the treatment of melasma. The use of TA for melasma is off-label. TA has historically been employed as a hemostatic agent to treat conditions characterized by aberrant fibrinolysis, such as hemophilia and menorrhagia, at doses of around 3,000 g daily.34 There is no consensus for the optimal oral dosing of TA for melasma, though it typically ranges from 500–750 mg daily,35-37 which is around one-sixth of how it is dosed for its other indications. TA is thought to inhibit the UV-induced conversion of plasminogen to plasmin in keratinocytes, thereby causing a reduction in arachidonic acid and prostaglandins, which in turn decreases tyrosinase activity.38 TA has been shown to decrease angiogenesis and mast cells,34 thereby possibly functioning to counteract the vascular contribution to melasma’s pathogenesis. Due to structural similarities with tyrosinase, TA has also been postulated to competitively antagonize the enzyme, further impeding melanogenesis.39
A large retrospective study comprised of 561 Asian patients in Singapore who received oral TA 250 mg twice daily for melasma reported improvements in 89.7%, with a response usually seen within 2 months of treatment initiation. Additional noteworthy findings from this study included a relapse rate of 27.2% following cessation of therapy, and a superior response to treatment in those without a family history of melasma.36 Other studies have reported relapse rates as high as 72%, occurring within 2 months treatment cessation.40 A more recent US based prospective study comparing TA 250 mg twice daily with placebo showed a 49% reduction in the MASI score of the TA group versus an 18% reduction for the placebo group.41 One study that incorporated histologic evaluation of lesional and perilesional skin of patients treated with oral TA 125 mg twice daily in conjunction with topical 2% niacinamide for 8 weeks found significant decreases in melanin indices that were accompanied by a marked reduction in epidermal pigmentation, mast cell counts, and number of dermal blood vessels, the latter of which was thought to be attributable to the antiangiogenic effects of TA.35
Concern about potential thromboembolic events (TE) may limit a clinician’s willingness to treat melasma patients with oral TA, but these events are in reality exceedingly rare. In the aforementioned retrospective study out of Singapore (n=561), 1 patient developed a deep vein thrombosis and was later found to have familial protein S deficiency.36 In a meta-analysis comprised of 667 patients spanning 11 studies, no TEs were reported, though it should be noted that only 5 of the 11 studies examined the use oral TA in melasma patients.34 It is likelier for oral TA-associated side effects to be of a more mild, transient, and mundane variety, namely gastrointestinal upset, menstrual irregularities, and headache, at doses used to treat melasma.34,41,42
Patients who have experienced TEs with oral TA tend to not only be taking it at higher doses indicated for the management of hemorrhagic conditions, they also usually have one or more risk factors that predispose them to hypercoagulability, including prior history of TEs (including deep vein thrombosis, pulmonary embolism, arterial thrombosis, and cerebrovascular accidents), hormonal therapy, medication interactions, malignancy, surgery, and prolonged immobility.37 All melasma patients being considered for oral TA should be screened for other potential contraindications to therapy, which in addition to the aforementioned may also include renal dysfunction, cardiovascular disease, respiratory disease, smoking, and anticoagulant therapy.36,43 Oral TA is pregnancy category B, and is used in pregnant women with bleeding disorders such as von Willebrand disease.44 However, given the hypercoagulability induced by pregnancy, and the various treatment options that are available in the post-partum period, a clinician must carefully consider their own comfort level with managing oral TA in a pregnant patient who requests it for the treatment of melasma.
Topical formulations of TA have demonstrated varying degrees of efficacy in the treatment of melasma, though not necessarily superiority when compared with HQ. Two studies have found topical 5% TA to be as effective as HQ 3-4% cream in reducing MASI scores, while causing less erythema and irritation.45,46 A clinicohistologic study of lesional and perilesional skin in 23 Korean patients with mild melasma who were treated with 2% TA for 12 weeks exhibited significant improvements in MASI scores, as well as decreased epidermal melanin content, fewer CD-31 positive dermal vessels, and a notable decrease in the expression of vascular endothelial growth factor.47 These histologic findings echo results from previous studies that describe the antiangiogenic histologic changes TA is capable of inducing in the skin of melasma patients.
Microneedling and microinjections have also been successfully utilized to facilitate intradermal TA delivery, with microneedling found by some to deliver superior results, possibly as a consequence of deeper and more uniform drug delivery.48 There is one reported case of intradermal tranexamic acid administration that resulted in paradoxical hyperpigmentation at the treatment site, which was attributed to drug metabolite-protein-iron complexes akin to those observed in type II minocycline hyperpigmentation.49