Tranexamic Acid

Abstract

Tranexamic acid (Transamin®, Cyklokapron®, Exacyl®, Cyklo-f®) is a synthetic lysine derivative that exerts its antifibrinolytic effect by reversibly blocking lysine binding sites on plasminogen and thus preventing fibrin degradation. In a number of small clinical studies in women with idiopathic menorrhagia, tranexamic acid 2–4.5 g/day for 4–7 days reduced menstrual blood loss by 34–59% over 2–3 cycles, significantly more so than placebo, mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone at clinically relevant dosages. Intrauterine administration of levonorgestrel 20 μg/day, however, produced the greatest reduction (96% after 12 months) in blood loss; 44% of patients treated with levonorgestrel developed amenorrhoea. Tranexamic acid 1.5g three times daily for 5 days also significantly reduced menstrual blood loss in women with intrauterine contraceptive device-associated menorrhagia compared with diclofenac sodium (150mg in three divided doses on day 1 followed by 25mg three times daily on days 2–5) or placebo. Tranexamic acid, mefenamic acid, etamsylate, flurbiprofen or diclofenac sodium had no effect on the duration of menses in the studies that reported such data. In a large noncomparative, nonblind, quality-of-life study, 81% of women were satisfied with tranexamic acid 3–6 g/day for 3–4 days/cycle for three cycles, and 94% judged their menstrual blood loss to be ‘decreased’ or ‘strongly decreased’ compared with untreated menstruations. The most commonly reported drug-related adverse events are gastrointestinal in nature. The total incidence of nausea, vomiting, diarrhoea and dyspepsia in a double-blind study was 12% in patients who received tranexamic acid 1g four times daily for 4 days for two cycles (not significantly different to the incidence in placebo recipients). In conclusion, the oral antifibrinolytic drug tranexamic acid is an effective and well tolerated treatment for idiopathic menorrhagia. In clinical trials, tranexamic acid was more effective at reducing menstrual blood loss than mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone. Although it was not as effective as intrauterine administration of levonorgestrel, the high incidence of amenorrhoea and adverse events such as intermenstrual bleeding resulting from such treatment may be unacceptable to some patients. Comparative studies of tranexamic acid with e-aminocaproic acid, danazol and combined oral contraceptives, as well as long-term tolerability studies, would help to further define the place of the drug in the treatment of menorrhagia. Nevertheless, tranexamic acid may be considered as a first-line treatment for the initial management of idiopathic menorrhagia, especially for patients in whom hormonal treatment is either not recommended or not wanted. Tranexamic acid exerts its antifibrinolytic effect by reversibly blocking lysine binding sites on plasminogen, thus preventing plasmin (which is still formed via activation of plasminogen by a plasminogen activator) from interacting with lysine residues on the fibrin polymer and subsequent fibrin degradation. The reduction in plasminogen binding to fibrin appears to result in either a decrease in the production of tissue plasminogen activator (t-PA) by endothelial cells or an increase in the rate of its clearance from the endometrium. Endometrial t-PA levels were significantly lower after three treatment cycles than before treatment in 12 menorrhagic women who received tranexamic acid 500mg four times daily for 5 days. In women with menorrhagia, fibrinolytic activity in utero is higher than in women with normal menstrual blood loss; this increased fibrinolysis is most likely due to higher levels of endometrium-derived plasmin and plasminogen activators. Tranexamic acid 1g three times daily for 5 days significantly reduced tissue plasminogen activator and plasmin activity in the menstrual and peripheral blood of menorrhagic women, compared with pre-treatment values. Tranexamic acid has no effect on overall blood coagulation parameters (e.g. platelet counts, activated partial thromboplastin time and prothrombin times), as determined from studies in patients undergoing a variety of surgical procedures. The pharmacokinetics of tranexamic acid are unaffected by the presence of food in the gastrointestinal tract; the oral bioavailability is approximately 34%. After oral administration of a single 2g dose to ten fasting healthy male volunteers, the mean maximum plasma concentration of tranexamic acid was 14.4 mg/L and was achieved 2.8 hours postdose; the area under the concentration-time curve from 0–6 hours was 59.5 mg · h/L. Tranexamic acid is minimally bound to plasma proteins (≈3%) at therapeutic plasma concentrations (5–10 mg/L), and this appears to be fully accounted for by binding to plasminogen. The main route of elimination of tranexamic acid is via the kidneys. After oral administration of tranexamic acid 250 or 500mg to healthy adults, between 40 and 70% of the administered dose was excreted unchanged in the urine within 24 hours. The terminal elimination half-life is ≈2 hours. The efficacy of tranexamic acid in the treatment of idiopathic menorrhagia has been evaluated in several small (n = 15–76) studies of variable design. Compared with either placebo or control groups, oral tranexamic acid 2–4.5 g/day for 4–7 days (total doses of 10–21.5g) per cycle effectively reduced menstrual blood loss by 34–59% over 2–3 cycles in women with menorrhagia. Tranexamic acid was significantly more effective at reducing menstrual blood loss than mefenamic acid 1.5 g/day for 5 days, flurbiprofen 200 mg/day for 5 days, etamsylate 2 g/day for 5 days and oral luteal phase norethisterone 10 mg/day. However, intrauterine administration of levonorgestrel 20 μg/day...