Long-Term Evaluation of Safety and Health-Related Quality of Life in Women with Heavy Menstrual Bleeding Treated with Oral Tranexamic Acid

Abstract

Aims: A multicenter, long-term, open-label study was conducted to assess the safety and health-related quality of life (HRQoL) of an oral tranexamic acid (TA) formulation in women with cyclic heavy menstrual bleeding (HMB). Materials & methods: Following a screening menstrual cycle, women with a history of cyclic HMB initiated 27 cycles of treatment with TA 1.3 g administered three-times daily for up to 5 days per menstrual cycle (maximum of 15 doses). Safety was assessed by treatment-emergent adverse event (TEAE) monitoring, physical examinations, laboratory results, ophthalmologic examinations and electrocardiography. HRQoL was evaluated using both generic and HMB-specific instruments. Results: Most of the TEAEs were mild to moderate in severity and were largely considered unrelated to study treatment. The most commonly reported TEAEs among women in the intent-to-treat population (n = 723) were headache, menstrual discomfort and back pain. Improvements in generic and disease-specific HRQoL measures were evident during the first treatment cycle and were maintained throughout the 15 cycles of measurement for most domains. Conclusion: Long-term TA treatment was well tolerated and improved measures of HRQoL in women with cyclic HMB.

Keywords

abnormal uterine bleeding competitive plasminogen inhibitor heavy menstrual bleeding Lysteda®menorrhagia tolerability tranexamic acid

Women who experience cyclic heavy menstrual bleeding (HMB), or menorrhagia, will often present to a healthcare professional because of the subsequent negative impact on their daily lives and activities [1,2]. HMB has been shown to adversely affect mood, energy/vitality, work productivity, social interactions, family life and sexual functioning [3 –5]. The impact on health-related quality of life (HRQoL) due to cyclic HMB derives from both the effort associated with managing menstrual bleeding and the consequences of excessive blood loss such as fatigue and iron deficiency anemia [5].

Previous HMB clinical trials have emphasized reduction in menstrual blood loss as the key efficacy end point, without measuring the effects of treatment on patient-reported outcomes. Thus, comparative data are lacking in this area and a standard HRQoL instrument has not been established [6]. Studies involving oral contraceptives, progestins and other pharmacological therapies for abnormal uterine bleeding have demonstrated some improvement in patient HRQoL using various instruments; however, these improvements were less than the HRQoL improvements noted with other treatments for HMB (i.e., ablation or hysterectomy) [5]. Recently, a study by Kouides et al. indicated that the treatment of women with menorrhagia and abnormal laboratory hemostasis with either tranexamic acid and intranasal desmopressin improved HRQoL, but that tranexamic acid proved more effective [7].

Tranexamic acid has been used for decades outside the USA to reduce bleeding in surgical applications [8] and to treat HMB [9]. Although generally well tolerated, the standard immediate-release formulation of tranexamic acid has been associated with nausea, vomiting, dyspepsia and diarrhea [8,9]. In Phase III trials of the novel, oral formulation of the competitive plasminogen inhibitor tranexamic acid (TA; Lysteda®, Ferring Pharmaceuticals, NJ, USA), women with cyclic HMB for three and six cycles experienced clinically significant improvements in menstrual blood loss and HRQoL, with a low incidence of treatment-related gastrointestinal (GI) adverse events (AEs) [10,11]. The current study was designed to assess long-term (up to 27 cycles) safety and evaluate HRQoL-based measures during treatment of cyclic HMB with TA.

Methods

Patients

Women (aged 18–49 years) with a history of cyclic HMB were enrolled in the study at 62 sites throughout the USA. Diagnosis of cyclic HMB was based on the medical judgment of each investigator. The diagnosis of HMB was made after review of the patient's medical history, a patient's self-report of the impact menstrual bleeding had on her normal activities, and then evaluation of a screening period, evaluation of results of a screening physical and gynecologic examination and laboratory results. Women with at least 6 months of regularly occurring menstrual cycles (21–35 days apart) with menstrual periods lasting no more than 10 days and normal findings on pelvic examination, normal cervical cytology results and no abnormal findings on transvaginal ultrasonography (fibroids or ovarian cysts were not considered abnormalities) were eligible to participate in the study. Women of childbearing potential were required to use an acceptable method of birth control other than hormonal contraception.

Women were excluded from study participation if they had a history or presence of clinically significant health problems (including thromboembolic disease or coagulopathy), endometrial abnormalities, cervical carcinoma, anovulatory dysfunctional uterine bleeding, metrorrhagia, menometrorrhagia, polymenorrhea, severe anemia (hemoglobin <8 g/dl), known acquired defective color vision, glaucoma, ocular hypertension, macular degeneration, retinopathy, or were pregnant or lactating.

Study design

Following one menstrual cycle screening phase, women who enrolled in this multicenter, open-label, long-term safety study received TA 1.3 g orally three-times daily for up to 5 days per menstrual cycle for a total of 27 menstrual cycles. Study visits were scheduled 1–7 days after the last day of the preceding menstrual period and occurred monthly through the third menstrual cycle, and thereafter at 3-month intervals.

Use of other medications or herbal remedies to relieve HMB were not allowed during the study. NSAIDs, vitamins and oral iron therapy were permitted.

The study received initial and annual Institutional Review Board approval at each site and was conducted in accordance with the Declaration of Helsinki and applicable regulatory requirements. All study participants provided written informed consent.

Measures

Safety was the primary end point of the study. Safety was assessed by the incidence of AEs; study discontinuation information; changes in physical examinations, vital sign measurements and laboratory test results (hematology, blood chemistry and urinalysis); ophthalmologic examinations (acuity, color blindness, intraocular pressure and dilated fundoscopic examination); and findings on 12-lead ECGs. AEs were coded using version 7.1 of the Medical Dictionary for Regulatory Activities and summarized for the number of subjects reporting the AE and the number of AEs reported. AEs were recorded from the time informed consent was signed until the participant completed the study.

Subjects' HRQoL was assessed via administration of the Ruta Menorrhagia Questionnaire (RMQ); the Short Form 36 Health Survey, Version 2.0 (SF-36v2®, Acute US Version 2.0, QualityMetrics Inc., RI, USA); and the Menorrhagia Impact Questionnaire (MIQ). The RMQ is disease specific and is scored from 0 to 100, with a higher score indicating more severe HMB symptoms [12]. The SF-36v2 is a generic HRQoL measure that provides two summary scores and eight individual concept scores, each measured on a scale from 0 (poor) to 100 (favorable). The MIQ is a disease-specific HRQoL measure that was completed by a subset of women following the pretreatment cycle and at treatment cycles 1, 2, 3 and 6. The RMQ and SF-36v2 were administered after the pretreatment cycle and at treatment cycles 1, 2, 3, 6, 9, 12 and 15. Change-from-baseline values were calculated for summary measures and individual domains, as appropriate.

Statistical analysis

A sample size of 865 women was determined to ensure that at least 200 women would receive study drug for 1 year or longer, with a minimum of 10,000 treatment cycles. Safety and efficacy analyses were conducted on the intent-to-treat population (all study participants who received at least one dose of study drug). The summaries for quantitative variables included appropriate descriptive statistics. Frequency counts were compiled for classification of qualitative variables. Normal–abnormal shift tables were generated for ophthalmologic examinations, with statistical significance determined using a Stuart–Maxwell test. All hypothesis testing and safety evaluations were two-sided with an α = 0.05 level of significance. Statistical analyses were conducted using statistical software (SAS®, Version 9.1.3, SAS Institute, NC, USA).

Results

A total of 1051 women were screened and 784 women were enrolled in the study ( Table 1 ). The first study visit was conducted on 9 June 2005, and the last study visit occurred on 13 May 2009. A total of 723 women were included in the intent-to-treat population. The mean age of patients was 38.3 years, the majority of women (75.5%) were white and the mean duration of HMB was 9.8 years ( Table 2 ).

Table 1.

Patient disposition of the women enrolled in the study.

Patient disposition	n (%) in category
Patients enrolled	784
ITT population†	723(92.2)
Patients†
Completed	239(30.5)
Withdrawn	545(69.5)
Primary reason for withdrawal‡
Failed to return	156(28.6)
Subject request unrelated to study	117(21.5)
Other event§	112(20.6)
Adverse event	97(17.8)
Protocol violation	32(5.9)
Unsatisfactory efficacy response	30(5.5)
Death	1 (0.2)

†

The number of patients enrolled was used as the denominator for calculated percentages.

‡

The number of patients withdrawn was used as the denominator for calculated percentages.

‘Other event’ category included noncompliance, withdrawal of consent, cessation of heavy menstrual bleeding, pregnancy or trying to conceive and surgical intervention or ablation, among other reasons for discontinuation.

ITT: Intent-to-treat.

Table 2.

Summary of demographic and baseline characteristics

Parameter	ITT population (n = 723)
Mean age, years (SD)	38.3(6.6)
Age range, years	18–50
Mean duration of HMB, years (SD)†	9.8(8.5)
Race, n (%)
White	546(75.5)
Black	148(20.5)
Asian	10(1.4)
Native American	1 (0.1)
Other	18(2.5)
History of alcohol use, n (%)
Yes	414(57.3)
No	309(42.7)
History of tobacco use, n (%)
Yes	254(35.1)
No	469(64.9)

†

Mean duration of HMB included data for 722 women.

HMB: Heavy menstrual bleeding; ITT: Intent-to-treat; SD: Standard deviation.

A total of 239 women remained in the study throughout all 27 on-treatment menstrual cycles ( Table 1 ). Failure to return was the predominant reason for study withdrawal (156 women [28.60025;]). The majority of AEs leading to discontinuation were considered ‘definitely not’, ‘probably not’ or ‘possibly related’ to study treatment.

Women enrolled in the study accumulated 29,767 days of TA exposure, with an average per patient exposure of 41 days. At least one dose of study drug was taken during 10,213 treatment cycles and 387 women received at least one dose of TA during 12 or more menstrual cycles. The mean daily dose was 3.81 g/day; the average period of drug taking was 2.91 days per menstrual cycle.

Safety

A total of 678 (93.8%) study participants experienced at least one treatment-emergent AE (TEAE; i.e., an AE that occurred after receipt of at least one dose of study drug, regardless of causality). The majority (94.6%) of TEAEs were mild or moderate in severity. Frequently reported TEAEs included headache, menstrual discomfort and back pain ( Table 3 ). The majority of TEAEs were not related to TA administration; however, approximately 11% of TEAEs were considered by the investigator to be at least possibly related to study drug treatment. The incidence of treatment-related GI TEAEs was low: three women had events that were considered definitely related; 12 women, probably related; and 87 women, possibly related to study treatment. Nausea was the most common GI TEAE that was at least possibly related to study treatment. Two GI-related serious AEs occurred (colitis and hiatus hernia); both were considered definitely not related to study treatment. No thrombotic or thromboembolic TEAEs occurred during the study.

Table 3.

Frequently occurring treatment-emergent adverse events†

Adverse event	ITT patients (n = 723), n (%)
Headache	437 (60.4)
Menstrual discomfort‡	360(49.8)
Back pain	227(31.4)
Viral upper respiratory tract infection	137(19.0)
Arthralgia	105(14.5)
Nausea	104(14.4)
Pain in extremity	100(13.8)
Throat irritation	100(13.8)
Musculoskeletal pain	98(13.6)
Sinusitis	94(13.0)
Diarrhea	88(12.2)
Abdominal discomfort	87(12.0)
Cough	80(11.1)
Dysmenorrhea	78(10.8)
Migraine	78(10.8)
Insomnia	74(10.2)

†

Events that occurred in ≥10% of patients.

‡

Menstrual discomfort includes but is not limited to menstrual cramps, breakthrough bleeding, menstrual pain and spotting.

ITT: Intent-to-treat.

A total of 28 women experienced a total of 42 serious TEAEs; none of these were considered by the investigator to be related to study treatment. The most common serious TEAEs were categorized as reproductive system and breast disorders (1.2% of patients), infections and infestations (1.1% of patients) or nervous system disorders (1.0% of patients). Two women had life-threatening TEAEs: one woman experienced cardiac arrest, pneumonia and pneumococcal sepsis (this woman later died of pneumonia and pneumococcal sepsis); and one woman experienced menorrhagia and was discontinued from the study. This patient was subsequently hospitalized and then underwent elective total abdominal hysterectomy.

A total of 14 pregnancies occurred during the study. There were no fetal abnormalities for those women who carried to full term.

Ophthalmologic examinations

A total of 82 women reported eye disorders during the study. Investigators considered these eye disorders definitely not related to study treatment in 51 women and probably not related to study treatment in 31 women. A few shifts in visual acuity, color vision and retinal/fundoscopic findings occurred during the study, although the majority of women remained within the normal range for these parameters throughout the study ( Table 4 ). One subject experienced severe blurred vision, which the investigator determined to be possibly related to study treatment. Subsequently, this eye disorder led to the subject's withdrawal. The severe blurred vision in this subject later resolved and was the only clinically significant ophthalmic impairment observed. At study termination for the overall study population, mean intraocular pressure for the right and left eyes was not significantly different from baseline. The mean change from baseline was 0.35 and 0.44 mmHg, which is a decrease from baseline for the right eye and left eye, respectively.

Table 4.

Shifts from baseline to last visit in ophthalmic parameters

Baseline	Study termination visit, n (%)
	Normal	Abnormal
Color vision
Normal	259(96.6)	2(0.8)
Abnormal	5(1.9)	2(0.8)
Retinal/fundoscopic examination
Normal	242(91.0)	7(2.6)
Abnormal	14(5.3)	3(1.1)

Laboratory parameters

Mean change from baseline and shifts from within the normal range for laboratory parameters were variable and not considered clinically significant. A nonsignificant trend toward a mean decrease in platelet count from baseline (298,791) was observed at visit five (296,237; change from baseline: 1660), visit six (294,000; 4933), visit 9 (288,177; 11,595) and study termination (282,689; 13,233).

Other safety parameters

Changes in blood pressure, pulse rate and weight, and minor changes noted at physical and gynecological examination and on ECGs were not considered to be clinically significant.

Quality of life

Significant improvements in HRQoL, as measured by the SF-36v2 and RMQ scales, were observed over the course of the study (p < 0.05) ( Figure 1 ). The greatest changes from baseline in SF-36v2 concept scores occurred for ‘Vitality’ (13.5% from baseline to cycle 15; p < 0.0001) and ‘Social Functioning’ (8.3% from baseline to cycle 15; p < 0.0001). Improvements in SF-36v2 scores were evident during the first on-treatment cycle and were maintained throughout the 15 cycles of HRQoL measurement for all domains except the ‘General Health’ concept score. Changes from baseline in RMQ global score were significant from treatment cycle 1 to cycle 15 (33.3–37.8% decrease; p < 0.0001).

Figure 1.

Improvements in health-related quality of life measures.

Data from the MIQ analysis were collected from 131 women who participated in the study and 131 age-matched controls. The RMQ global score highly correlated with each item of the MIQ (range: 0.757 to 0.809), whereas low-to-moderate correlation was observed between MIQ components and SF-36v2 domains (range: −0.303 to −0.118). The strongest correlations between SF-36v2 and MIQ occurred for the ‘Physical’ and ‘Role – Physical’ domains.

Discussion

A novel formulation of oral TA was found to be safe and was well tolerated during long-term administration. Long-term administration was up to 27 weeks with the dosing of TA only during heavy days of menstrual bleeding at 3.9 g/day for up to 5 days. The results of this study are consistent with the established safety profile of TA. As expected, in this study of nonhormonal TA treatment for women with HMB, the commonly reported TEAEs observed were different from the TEAEs reported in recent studies of hormonal treatments for HMB [13,14]. No serious AEs were reported that were considered related to study treatment. To our knowledge, this is the longest duration of tranexamic acid use within a clinical trial or research study.

In the current study, the number of subjects reporting treatment-related GI AEs is comparable to reports of treatment-related GI AEs in previous short-term studies of this novel oral formulation of TA [10]. The subject discontinuation rate due to AEs was 12.4% (97/784), which is comparable to discontinuation rates seen in other studies of tranexamic acid as reviewed by Wellington and Wagstaff (range: 0–12%) [9]. Serious AEs occurred in less than 4% of women, and none of the serious AEs were considered to be related to study treatment.

Ophthalmologic disorders were considered events of interest in this trial because of preclinical findings that indicated a potential for retinal degeneration with markedly high tranexamic acid doses using the immediate-release formulation, as well as in previous reports of color vision or visual acuity disturbances in patients treated with tranexamic acid [8,15]. Visual changes reported in the literature have typically been transient and resolved after drug cessation [15]. In the current study of a novel oral TA formulation, one subject experienced blurred vision that subsequently completely resolved, but resulted in this individual's withdrawal from the study. Otherwise, no significant ophthalmic impairment was evident in subjects.

Although speculation has been raised about the theoretical possibility of increased risk for thromboembolic events with antifibrinolytics such as tranexamic acid, the frequency of thrombosis over 19 years (238,000 patient years) in women treated with tranexamic acid for HMB was similar to the frequency of spontaneous thrombosis in women within the general population [16]. The lack of thromboembolic events in this study confirms data from prior studies demonstrating no increased risk with tranexamic acid treatment [9 –11,16]. A recent case–control study detected a nonsignificant increase in risk of venous thromboembolism among patients who had previously been exposed to tranexamic acid; however, significantly increased risk of venous thromboembolism was observed with other HMB therapies as well, including mefenamic acid and noretruster one [17]. In this study it was speculated that HMB may be a prothrombotic condition.

Unlike the pivotal TA efficacy and safety studies, NSAIDs were allowed during dosing in this study, thereby better reflecting a real-world treatment scenario. Certain NSAIDs, such as mefenamic acid, naproxen, ibuprofen and flurbiprofen, have been explored as treatment options for HMB, although their efficacy in reducing menstrual blood loss is generally low [18]. NSAIDs are among the most commonly used prescription or over-the-counter medications in the USA, and for women, they are often used for pain relief during menstruation [19]. Consequently, in the general population, there is a high likelihood that NSAIDs and TA would be used concomitantly. In our study, use of NSAIDs during TA dosing did not adversely affect the safety or tolerability of TA.

Women treated with TA in this study experienced significant improvements in HRQoL measures. In women with cyclic HMB, poorer performance in all eight concept scores of the SF-36v2 has been observed compared with population norms, with the largest deficits in ‘Role – Physical’, ‘Bodily Pain’ and ‘Role – Emotional’ concept scores [20]. Significant improvements from baseline with TA treatment were observed for all three of these domains, which, notably, include measures of interference with work, social or other activities. In an open, uncontrolled study of women with HMB, Winkler reported that subjects described improvements in social activity and work limitations, and increases in alertness, productivity, cleanliness, mood and overall well-being with TA treatment [4]. One of the strengths of the current study is the use of both generic (SF-36v2) and disease-specific (RMQ) HRQoL instruments. As might be predicted, findings from the disease-specific MIQ correlated more strongly with the RMQ than did findings from the SF-36v2.

Some of the observed HRQoL improvement may be linked to the improvements in hemoglobin concentrations observed during the study. In a recent study, de Souza et al. demonstrated that baseline and on-treatment hemoglobin concentrations correlated with SF-36v2 mental and physical composite scores in women with HMB [21]. However, menstrual blood loss poorly correlated with HRQoL, again suggesting that ameliorating the day-to-day functional problems associated with HMB is more important to patients than actually controlling the volume of menstrual blood lost.

One limitation of the current study is the lack of a placebo or control group. Without a placebo comparator, the true frequency of AEs associated with TA versus treatment-independent background events is not determinable. Interpretation of HRQoL is also hindered by the lack of a control arm, although baseline data and population norms aid in assessing the importance of observed changes in these parameters.

Conclusion

During a long-term treatment study, women received TA (Lysteda), which was well tolerated when used for up to 5 days during their menstrual cycles. Noticeable and sustained improvements in HRQoL as noted by study participants support TA as a beneficial addition to the current armamentarium available to treat cyclic HMB. TA should be considered as a first-line, nonhormonal treatment option for cyclic HMB.

Future perspective

Pharmacokinetic and clinical assessments of modified-release TA in an adolescent population with evidence of HMB would provide treating physicians with much-needed data regarding the treatment of HMB in this population. Also, studies of modified-release TA used in surgical procedures and dental procedures, and in the treatment of hemorrhages and hemophilia would allow for comparisons against immediate-release tranexamic acid currently being used for these purposes.

Prior presentations

Interim data from this clinical trial were presented at the American Congress of Obstetricians and Gynecologists (ACOG), LA, USA, 3–7 May 2008 and some of these data were presented at the American Society for Reproductive Medicine Annual Meeting, 23–27 October 2010. NIH clinical trials registry: NCT00113568.

Executive summary

The goal of this multicenter, long-term, open-label study was to assess the safety and health-related quality of life (HRQoL) of an oral tranexamic acid (TA; Lysteda®) formulation across 27 menstrual cycles in women with cyclic heavy menstrual bleeding (HMB).

Safety was assessed by treatment-emergent adverse event (TEAE) monitoring, physical examinations, laboratory results, ophthalmologic examinations and electrocardiography. HRQoL was evaluated using both generic and HMB-specific instruments.

Most of the TEAEs were mild to moderate in severity and were largely considered unrelated to study treatment.

The most frequently reported adverse events were consistent with those observed with the use of an immediate-release formulation of TA and included menstrual discomfort, headache and back pain.

The incidence of treatment-related gastrointestinal TEAEs was low, and no evidence of ocular toxicity or prothrombotic effects was observed.

Improvements in generic and disease-specific HRQoL measures were evident during the first treatment cycle and were maintained throughout the 15 cycles of measurement for most domains.

Long-term TA treatment was well tolerated and improved measures of HRQoL in women with cyclic HMB.

During a long-term treatment study, treatment with TA was well tolerated when used for up to 5 days during menstrual cycles and was consistent with the established safety profile.

This formulation of TA adds an oral, nonhormonal therapeutic option for the treatment of cyclic HMB.

Footnotes

Acknowledgements

The authors would like to thank Arkady Rubin for statistical consultation.

Financial support for data analysis and manuscript development was provided by Xanodyne Pharmaceuticals, Inc., and Ferring Pharmaceuticals Inc. K Muse has received research funding from Amgen, BioSante Pharmaceuticals, Wyeth, Xanodyne Pharmaceuticals, Inc. and Ferring Pharmaceuticals Inc. A Lukes receives or has received research support from Xanodyne Pharmaceuticals, Inc., Ethicon, Merck, Bayer, Luitpold, Hologic, National Improvement for Women's Healthcare, Duramed, the NIH, the Centers for Disease Control and Prevention/Association for Prevention Teaching and Research, Smith & Nephew, Trent Foundation and American Medical Systems. A Lukes consults with and/or has served on speakers' bureaus for Ferring Pharmaceuticals Inc., Xanodyne Pharmaceuticals, Inc., Hologic, American Medical Systems, Bayer, Interlace Medical, Ethicon, Boehringer Ingelheim, Myriad, Microsulis (5 years ago), AMAG (4 years ago) and Daichii. A Lukes has given expert testimony regarding US FDA approval. J Gersten has received research funding from Pfizer, Organon, Ortho-McNeil, Wyeth, Galen Holdings, Warner Chilcott, Lilly, Sepracor, TAP, Barrier Therapeutics, Xanodyne Pharmaceuticals, Inc., Roche, BioSante Pharmaceuticals, Duramed, Berlex, Johnson & Johnson, Amgen, Perrigo Pharmaceuticals, Boehringer Ingelheim, Bayer, Teva, Schering-Plough and Ferring Pharmaceuticals Inc. A Waldbaum has received research funding from Pfizer, Graceway, Boehringer Ingelheim, BioSante Pharmaceuticals, Third Wave, Wyeth, GlaxoSmithKline, Astellas, Depomed, Repros, Quatrx, Xanodyne Pharmaceuticals, Inc. and Ferring Pharmaceuticals Inc. E Trott is an employee of Ferring Pharmaceuticals Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript. Medical writing assistance was provided by Laura Miesle, PharmD, CMPP, of The JB Ashtin Group, Inc.

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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