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Erschienen in:
01.07.2003 | Adis Drug Evaluation
Tranexamic Acid
A Review of its Use in the Management of Menorrhagia
Erschienen in: Drugs | Ausgabe 13/2003
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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.
Overview of Pharmacodynamic Properties
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.
Pharmacokinetic Properties
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.
Therapeutic Efficacy
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 produced the greatest reduction in menstrual blood loss (96% reduction after 12 months; p < 0.01 vs tranexamic acid); 7 of the 16 patients treated with levonorgestrel developed amenorrhoea after up to 12 months’ treatment.
In two nonblind studies, all patients achieved blood loss of <80 mL/cycle during treatment with tranexamic acid; 56% of tranexamic acid recipients achieved blood loss of <80 mL/cycle in a double-blind study.
In a crossover study, tranexamic acid 1.5g three times daily for 5 days 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. At the end of two cycles each of tranexamic acid and diclofenac sodium and one cycle of placebo, 16, 10 and 5 of the 19 patients, respectively, had lost a mean of <80mL of blood per cycle.
Tranexamic acid, mefenamic acid, etamsylate, flurbiprofen or diclofenac sodium had no effect on the duration of menses in the studies that reported such data.
The quality of life (social activity, work performance, productivity, cleanliness, action radius, overall functioning and tiredness) of patients with menorrhagia was significantly improved after three cycles of tranexamic acid 3–6 g/day for 3–4 days/cycle in a large noncomparative, nonblind quality-of-life study. After the first and third treatment cycles, 58% and 81% of women were satisfied with tranexamic acid treatment, and 87% and 94% judged their menstrual blood loss to be ‘decreased’ or ‘strongly decreased’ compared with untreated menstruations.
Significantly more recipients of tranexamic acid 4 g/day for 4 days than recipients of luteal-phase norethisterone 10 mg/day experienced improved flooding/leakage (83% vs 45%) and improved sex life (46% vs 15%) in a double-blind study. However, there was no significant between-group difference in the effect of treatment on general health.
Tolerability
Oral tranexamic acid is well tolerated by most patients with menorrhagia. With the exception of dysmenorrhoea, 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; however, there were no statistically significant differences in the number or severity of adverse events experienced by patients during either the placebo run-in period or active treatment.
An improvement in symptoms of dysmenorrhoea was reported by 19%, 13% and 4% of patients who received tranexamic acid, mefenamic acid or etamsylate in a nonblind study, and 27%, 35% and 15% of patients rated their symptoms as worse than those before treatment. Nonetheless, 77%, 74% and 33% of patients expressed a desire to continue treatment at the end of the study. Tranexamic acid had no significant effect on symptoms of dysmenorrhoea compared with baseline or norethisterone in a double-blind study.
The percentage of patients who discontinued treatment because of adverse events while receiving tranexamic acid was 0–12% in six studies; in four of the studies there were no discontinuations due to adverse events.
There were no thromboembolic events in patients with menorrhagia in clinical studies. Furthermore, tranexamic acid has been widely used in Scandinavia as a first-line treatment for menorrhagia since the early 1970s and there has been no reported increase in the incidence of thromboembolic events.
Dosage and Administration
Tranexamic acid is approved for the treatment of menorrhagia. Underlying organic pathology as the cause of heavy menstrual bleeding (blood loss of >80mL per cycle) should be ruled out before initiating treatment. The recommended dosage differs from region to region. In Europe, however, the recommended oral dosage for the treatment of patients with menorrhagia is 1–1.5g three to four times daily for 3–4 days; the total daily oral dose should not exceed 4g, and treatment should be initiated once heavy menstrual bleeding has started.
In the UK, tranexamic acid is contraindicated in patients with a history of thromboembolic disease; in Japan and the rest of the EU, caution and supervision is recommended in these patients. Active thromboembolic disease, however, is a contraindication for tranexamic acid use in the EU, including the UK. The drug is also contraindicated in most of the EU in patients with severe renal failure because of the risk of accumulation. Dosage reductions are recommended in patients with mild to moderate renal insufficiency.