ࡱ>  bjbj xx-`559994mmmhD" m%*Lq*p***mJn:nHJJJJJJ$uBn9JnlmJnJnn55**AsxxxJn 5*9*HxJnHxxJ(*0|MHmwN40z((\9JnJnxJnJnJnJnJnnnxJnJnJnJnJnJnJnJnJnJnJnJnJnJnJnJn : Tranexamic Acid Oral (Lysteda) National Drug Monograph June 2012 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Executive Summary: Lysteda is the first oral formulation of tranexamic acid (TXA), an antifibrinolytic agent, indicated for the treatment of cyclic heavy menstrual bleeding (HMB). The recommended dose is 3900 mg/day (two 650mg tablets three times a day) for a maximum of 5 days during monthly menstruation. Dose adjustment is required for women with renal dysfunction. The efficacy and safety of oral TXA for the treatment of HMB was evaluated in two pivotal, double-blind, randomized controlled trials, one of which is published. Both trials were similar in design, with the same 3-component primary endpoint that evaluated menstrual blood loss (MBL). The mean reduction in MBL had to be 1) significantly greater than placebo; 2) greater than 50mL improvement from baseline; and 3) greater than a pre-specified clinically meaningful threshold (36mL). In the 6-cycle, published trial, treatment with TXA 3900 mg per day was associated with significant improvements in MBL, as determined by all three components of the primary endpoint. Reduction in MBL of -69.6mL (40.4%) with TXA was superior to the -12.6mL (8.2%) reduction found in the placebo group (p<0.0001). More than half of the TXA-treated patients experienced a greater than 50 mL reduction in MBL, and the majority of cycles were associated with clinically meaningful reductions in MBL (pre-defined as 36 ml or greater). In the 3-cycle, unpublished study, TXA 3900 mg/day was found to significantly reduce menstrual blood loss (MBL) compared to placebo, with a 38.6% (65 mL) reduction from baseline with TXA vs. 2.9% (3 mL) with placebo (p <0.0001). A lower dose of 1950 mg/day failed to reach the primary endpoint. Both studies also found improvements in social or leisure and physical activities of daily living with TXA treatment. Of note, while TXA did decrease the severity of menorrhagia, the mean MBL remained >100 mL (menorrhagia defined as >80 mL), and less than half of the women in the 6-cycle study treated with TXA achieved MBL <80 mL. Six randomized, controlled, active comparator trials evaluated the efficacy of TXA and alternative treatments for menorrhagia including desmopressin, NSAIDs, progestins, and the levonorgestrel-bearing intrauterine device (IUD). In total, TXA appears to be at least as effective and possibly more effective than alternative agents including mefenamic acid , ethamsylate , norethisterone, flurbiprofen, intranasal desmopressin, and medroxyprogesterone in reducing MBL in women with menorrhagia. Similar to the results from placebo-controlled studies, TXA treatment significantly reduced MBL, with mean treatment-associated MBL measures above the threshold for menorrhagia in the majority of the active-control studies. TXA does not relieve dysmenorrhea. TXA was found to be less effective in reducing MBL compared to the levonorgestrel IUD. The majority of studies that evaluated laboratory parameters did not find an improvement in hemoglobin or ferritin concentrations with TXA. Some improvements in quality of life (QOL) measures with TXA were observed. Of note, 3 month post-treatment follow-up in the TXA vs. medroxyprogesterone study found that a significant portion of women in both groups experienced recurrence of menorrhagia to the same baseline severity, suggesting that effects do not persist once treatment is discontinued. The safety data for oral TXA were derived from the two short-term (3- and 6-cycle) RCTs and two long-term open label studies (up to 27-cycles). Supportive information is also available from the active comparator studies. Commonly reported adverse events with oral TXA include menstrual discomfort, headache, gastrointestinal upset and back pain. Drop-out rates due to adverse events in both placebo-controlled studies were low. The types and severity of adverse events in the long-term open-label studies were similar to those observed in the double-blind, randomized, placebo-controlled studies. Oral TXA is contraindicated in patients with active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism or cerebral thrombosis), history of thrombosis or thromboembolism (including retinal vein or artery occlusion), intrinsic risk of thrombosis (e.g., thrombogenic valvular disease, thrombogenic cardiac rhythm disease or hypercoagulopathy), and in patients with hypersensitivity to TXA or any of its components. Cases of venous and arterial thrombosis or thromboembolism and retinal artery and retinal vein occlusions have been reported with TXA. Thromboembolic risk: Review of US post-marketing reports of venous and arterial thrombotic events in women on oral TXA led to revised warnings and precautions in the product label in April 2011. In the majority of cases, women were using TXA concomitantly with combined hormonal contraceptives and/or were obese. Hormonal contraceptives: There are no clinical data on concomitant use of TXA and hormonal contraceptive agents, as women receiving hormonal contraceptive agents were excluded from clinical trials. Combination oral contraceptives are known to increase the risk of venous thromboembolism and arterial thrombosis (e.g., stroke, myocardial infarction). Co-administration of TXA, an antifibrinolytic agent, with hormonal contraceptives may further increase thromboembolic risk, which is a particular concern in patients over 35 years old and those who smoke. Women on hormonal contraception should not use TXA unless there are compelling needs. Do not use TXA in women who are taking more than the approved dose of a hormonal contraceptive. Other agents that may increase pro-coagulant effects: TXA should not be used in patients on Factor IX complex concentrates or anti-inhibitor coagulant concentrates. Caution should be used in prescribing TXA to patients on all trans retinoic acid. Ocular effects: Retinal venous and arterial occlusions have been reported in patients using TXA. Patients should be counseled to report any ocular or visual problems immediately. Oral TXA has been studied for the prevention of secondary hemorrhage in patients with traumatic hyphema and for its blood sparing effects in patients undergoing knee replacement surgery. These uses remain off label at this time. Introduction Normal menstrual periods last 3-6 days and involve blood loss of up to 80ml. Menorrhagia is defined as menstrual periods at regular cycle intervals lasting more than 7 days and/or involving blood loss greater than 80ml.1 TXA was initially approved in December 1986 as a solution for injection (Cyklokapron) for use in patients with hemophilia to reduce or prevent hemorrhage and to reduce the need for replacement therapy during and following tooth extraction.2 TXA solution for injection is also frequently used off-label for various conditions including: epistaxis, hereditary angioedema prophylaxis, trauma-associated hemorrhage, and blood loss reduction in patients undergoing major surgery (e.g., cardiac, orthopedic, spinal, etc.) or dental procedures.2,3 In November 2009, the FDA approved the first oral formulation of TXA for heavy menstrual bleeding. The FDA designated TXA as appropriate for Fast Track status and granted approval under the Priority Review process.4 Therapeutic options used in clinical practice for the treatment of HMB include non-steroidal anti-inflammatory drugs (NSAIDs), levonorgestrel-bearing intrauterine device (IUD), combination contraceptives (containing both estrogen and progestin), high-dose progestins (oral, injection), danazol, and gonadotropin-releasing hormones (GnRH agonists). Of these treatments, only the levonorgestrel IUD and one combination contraceptive product (estradiol valerate and dienogest) carry an FDA indication for HMB.5 The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating TXA for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics4 Mechanism of Action: TXA is a synthetic, lysine amino acid derivative that interferes with the interaction between fibrin and binding sites on plasminogen, ultimately diminishing the dissolution of hemostatic fibrin by plasmin. In the presence of TXA, the lysine-receptor binding sites of plasmin for fibrin are occupied, preventing binding to fibrin monomers, thus preserving and stabilizing fibrins matrix structure. The antifibrinolytic effects are mediated by competitive (immediate inhibition), rapidly reversible, dose-related, binding interactions at multiple distinguishable binding sites within plasminogen. Table 1. Pharmacokinetic Parameters (Oral Dose Administration)4 ParameterTXABioavailability (in women aged 18-49)45%Tmax ~3 hoursVolume of distributionInitial: 0.18L/kg Steady state: 0.39L/kgMetabolismA small fraction is metabolizedEliminationUrinary excretion via glomerular filtration with more than 95% of doses excreted unchanged.Half-life11 hoursProtein Binding3% bound to proteins, no binding to albumin Effect of food: TXA may be administered without regard to meals. A single dose administration (two 650 mg tablets) of TXA with food increased both Cmax and AUC (area under the concentration curve) by 7% and 16%, respectively. FDA Approved Indication(s)4 TXA is indicated for the treatment of cyclic HMB. Potential Off-label Uses: This section is not intended to promote any off-label uses. Off-label use should be evidence-based. See VA PBM-MAP and Center for Medication Safetys HYPERLINK "http://vaww.national.cmop.va.gov/PBM/Directives%20Policies%20and%20Information%20Letters/Guidance%20on%20Off%20Label%20Prescribing.pdf"Guidance on Off-label Prescribing (available on the VA PBM Intranet site only). Non-perforating traumatic hyphema: Oral TXA vs. oral prednisolone vs. placebo on the prevention of secondary hemorrhage This randomized, placebo-controlled study randomized 238 study participants into 3 groups: oral TXA 75mg/kg/d in 3 divided doses, oral prednisolone 0.75mg/kg/d in 2 divided doses or placebo for a duration of 5 days. The study population was exclusively white with the mean age of 14.9 years old in the TXA group. The primary outcome was secondary hemorrhage occurrence.6 Table 2. Incidence of secondary hemorrhage6 TreatmentTXA N=80Prednisolone N=78Placebo N=80P-value* Secondary hemorrhage10% (8/80)18% (14/78)26% (21/80)P=0.028 (Chi-square test of homogeneity) *Difference between the incidences of secondary bleeding of the three groups Comparator groupsPlacebo vs. TXAPrednisolone vs. TXAPlacebo vs. PrednisoloneOdds ratio3.2 99% CI = 1.1, 9.9 (p=0.008)2.0 99% CI = 0.6, 6.6 (p=0.15)1.6 99% CI = 0.6, 4.4 (p=0.21) Table 3. Odds ratio for secondary hemorrhage rate between two treatment groups6 Represents crude odds ratio; *CI=confidence interval Results showed that TXA was associated with a significantly reduced re-bleeding rate compared to placebo (10% vs. 26%; p=0.008). However, the difference in secondary hemorrhage rate between oral TXA and prednisolone was not statistically significant (p=0.15) (Table 3). Moreover, no difference was seen between placebo versus prednisolone (p=0.21). In the post-hoc analysis, the study was only 40% powered to detect the observed difference of 8% in re-bleeding among the prednisololone and TXA groups.6 Total knee replacement blood-sparing: oral TXA vs. variable TXA intravenous infusion7 This randomized, placebo-controlled, single-blinded study randomized 80 study participants into four different treatment groups: TXA-long infusion, TXA-short infusion, TXA-oral or control. The primary outcome was the measurement of blood loss in surgical drain measured at 12- and 24-hr after surgery. Results are as follows: Table 4. Comparison of blood accumulation in surgical drain post-operatively7 Blood accumulation in surgical drainControl N = 20 mL (SD)TXA-long N=20 mL (SD)TXA-short N=20 mL (SD)TXA- oral N=20 mL (SD)First 12-hrs post-op (SD)249 (130)121 (81)110(38) 231 (138)Next 12-hrs post-op (SD)195 (156)101 (57)95 (47)107 (52)SD=standard deviation The amount of blood in the surgical drain after administration of TXA-oral after the first 12-hours (231mL, SD 138mL) was similar to the results seen with control (249mL, SD 130mL). Blood accumulation in the drain was significantly more in the TXA-oral and control group when compared to the TXA-short and TXA-long (p <0.02). However, during the second 12-hour period, the extent of fibrinolysis decreased in a time-dependent manner (most-likely due to repeated oral drug administration). The amount of blood that accumulated in the surgical drain for patients taking TXA-oral in the next 12-hour post-op period was comparable to the results seen with intravenous infusion of TXA. Blood accumulation was significantly greater in the control group compared to all three-treatment arms (p <0.05) at the end of the subsequent 12 hours. Significantly more blood transfusions were administered to the control group compared with the three treatment groups (TXA-long, TXA-short, TXA-oral). Despite more blood transfusions given to the control group, post-operative hematocrit levels were lower in the control group compared to the three TXA treatment groups (statistically significant on post-operative days 1, 3 and 4). There were no post-operative thromboembolic events documented at the end of the 3-month follow-up period. Please see Appendix B for summary of clinical trials for potential off- label uses. Current VA National Formulary Alternatives Table 5. VA National Formulary Alternatives for the treatment of HMB* Combination Oral Contraceptives (with e" 35 mcg ethinyl estradiol)EE 35mcg/ norethindrone (Ortho Novum 1/35 and eqv, Ortho-Novum 7/7/7 and eqv) EE 35mcg/norgestimate (Ortho Tri-Cyclen and eqv)NSAIDsIbuprofen NaproxenProgestinsNorethindrone Medroxyprogesterone acetateEE=ethinyl estradiol *Note: Levonorgestrel IUD (Mirena) is readily available in VA and is obtained throughProsthetics. The product is not listed on VA National Formulary (since it is not a Pharmacy item). Dosage and Administration8 The FDA approved dosing of oral TXA for HMB is 1,300 mg (two 650 mg tablets) three times a day (3,900 mg/day) for a maximum of 5 days during monthly menstruation. Tablets may be administered without regards to meals and should be swallowed whole and not chewed or broken. Renal dosage adjustment is needed if serum creatinine concentration (SCr) is greater than 1.4 mg/dL: Table 6: Renal dosing for TXA for treatment of HMB8 Serum Creatinine (SCr) (mg/dL)Dose Adjustment*Total Daily Dose> 1.4 and d" 2.81,300 mg (two 650mg tabs) twice daily2600 mg> 2.8 mg/dL and d" 5.71,300 mg (650 mg tabs) daily 1300 mg> 5.7650mg (one 650mg tab) daily 650 mg*Max duration of 5 days during menstruation Efficacy Efficacy Measures Menstrual blood loss (MBL) is the primary efficacy measure in studies evaluating the use of TXA for the treatment of HMB. Accurate clinical diagnosis of menorrhagia (blood loss greater than 80mL) requires precise measurement of MBL.1 The gold standard for measuring MBL is the alkaline hematin technique.9 This method requires women to collect their used feminine hygiene products; consequently, it is rarely used outside of a research setting. The pictorial blood loss assessment chart (PBAC) uses a simple scoring system, which takes into account the number of feminine hygiene products used, and the degree of staining of each item.10 Secondary outcomes evaluated include quality of life (QOL) measures. Summary of Efficacy Findings Eight studies were identified that assessed the efficacy of oral TXA for heavy menstrual bleeding.4,12-18 In the two pivotal, double-blind, randomized, placebo-controlled, clinical trials, MBL was measured using a validated alkaline hematin method.4,12 One of these pivotal trials is published. In addition, six randomized controlled active comparator trials evaluated the efficacy of TXA and alternative treatments for menorrhagia, including desmopressin, NSAIDs, and progestins.13-18 Four of these studies used the validated alkaline hematin method, while the other two studies used the pictorial blood assessment chart (PBAC) to evaluate MBL. Oral TXA vs. Placebo4,12 There were two pivotal, multi-center, randomized, double-blind, placebo-controlled studies which assessed different doses of modified release TXA. The first 3-cycle unpublished study compared efficacy of TXA1950 mg per day (n=115) and 3900 mg per day (n=115) with placebo (n=67).4 Similarly, the second 6-cycle, published study assessed efficacy of TXA 3900 mg per day (n=115) compared to placebo (n=72).12 Both studies were similar in design in that both required participants to be initially enrolled in a two-cycle control phase, in which participants had to average at least 80 mL over both pretreatment cycles to be included. Additionally, women were included if they were between the ages of 18 to 49 years old with HMB including a history of 3 or more consecutive days of HMB for at least 4 out of their last 6 cycles. In addition, women had to have regularly occurring menstrual periods, a normal pelvic exam and no uterine abnormalities. Co-medication with acetaminophen, opioids and iron therapy were allowed during the study. NSAIDs were not allowed during menstrual periods, and oral contraceptives were not permitted at all.4,12 The primary endpoint for both studies evaluated the mean reduction of MBL according to three-components: Significantly greater mean reduction in blood loss than placebo Greater than 50mL mean reduction from baseline Mean reduction greater than a pre-determined meaningful threshold (36mL or higher, determined using primary receiver operating characteristic (ROC) curve analysis)11 Secondary outcome measures included the Menorrhagia Impact Questionnaire (MIQ), a validated instrument that assesses patient-reported outcomes such as limitation to leisure, work and physical activities, and patient assessment of blood loss.4,12 The MIQ is scored on a 1 to 5 point scale (1=not at all limiting, 5= extremely limiting). 3-cycle trial results: Mean reduction in MBL with treatment cycles vs. control cycles was 65mL for the 3900mg/d TXA group vs.3mL for placebo (p<0.0001). This was a 38.6% and 1.9% reduction in MBL from baseline in blood loss in the TXA and placebo groups, respectively (baseline and post-MBL values not given). TXA 1950mg/day did not meet efficacy requirements; however the 3900mg/d group met all three components of the primary outcome. Mean improvements in MIQ scores for limitations on social or leisure activities and limitation on physical activities were statistically greater in the TXA 3900 mg/d group compared with placebo (p<0.0001). There were no significant improvements noted in small or large stains, small or large clots, interruptions in sleep, or changes in ferritin or hemoglobin levels with TXA over placebo.4 6-cycle trial results: Baseline MBL for the TXA and placebo group was 172.3 95.6 and 153.0 66.6 mL, respectively. Women who received TXA 3900 mg per day met all three components of the primary efficacy end point: first, a significantly greater reduction in MBL of -69.6mL (40.4%) with TXA compared to a -12.6mL (8.2%) reduction in the placebo group (p<0.0001); reduction of MBL exceeding a pre-specified 50mL (56% of cycles with TXA vs. 19% of cycles with placebo; p <0.001) ; and lastly, reduction of MBL considered meaningful to women (69% of cycles with TXA vs. 29% of cycles with placebo; p <0.001).12 Treatment with TXA was associated with statistically significant improvements in components of the MIQ score related to limitation on social or leisure activities and physical activities. Scores generally improved from moderate impairment (score of 3) to slight impairment (score of 2).12 There was no statistically significant difference between the TXA and placebo groups in the number of large stains reported. TXA was not associated with improvements in hemoglobin or ferritin concentration.12 Oral TXA vs. intranasal desmopression13 This randomized, cross-over study randomized 116 women with menorrhagia and abnormal laboratory hemostasis (von Willebrand disease, platelet aggregation, or subnormal coagulation factor level) to either intranasal desmopression (300(g on days 2 and 3 of menstrual cycle; one spray in each nostril daily) or oral TXA (1g four times a day for the first 5 days of menstrual cycle) for two menstrual cycles. Without a washout period (due to the short half-lives of both agents), women were switched to the second drug for two cycles. Menorrhagia was defined as a pictorial blood assessment chart (PBAC) score >100. The primary outcome measures for this study were change in MBL and QOL. MBL was estimated by using the PBAC recorded at baseline and during a total of four menstrual cycles. QOL was assessed at baseline, after the second cycle of intranasal desmopression, and after the second cycle of TXA. QOL assessment included four different instruments: Health-Related Quality of life (HRQOL) instrument, Short Form- 36 (SF-36), The Center of Epidemiologic Studies Depression (CES-D) scale and the modified Ruta Menorrhagia Severity Scale. Results showed a statistically significant decrease in PBAC scores after both treatments (Table 7). Table 7. Mean PBAC and mean change in PBAC over time13 TreatmentPeriodNMean PBACMean ChangeGroup 1 (intranasal desmopression ( TXA x 2 cycles each)Baseline49280.1----IN-DDAVP1st cycle39244.5-48.0IN-DDAVP2nd cycle37220.1-76.7TXA3rd cycle28149.8-85.3TXA4th cycle28135.4-105.1Group 2 (TXA( intranasal desmopression) x 2 cycles each)Baseline67275----TXA1st cycle51189.3-100.8TXA2nd cycle49157.9-139.4IN-DDAVP3rd cycle45189.0-71.4IN-DDAVP4th cycle40221.1-52.4The estimated reduction in the PBAC score from baseline for intranasal desmopression was -64.1 (95% confidence interval (CI): -88.0, -40.3) and -105.7 (95% CI: -130.5, -81.0) for TXA. The magnitude of decrease in PBAC score was significantly larger for TXA versus intranasal desmopression (a difference of 41.6; p= 0.0002, 95% CI: 19.6, 63.6). Use of both intranasal desmopression and TXA generally improved QOL of women with menorrhagia and underlying hemostatic abnormality with all four measures of QOL; however, only mental health and the Ruta menorrhagia severity scale showed statistically significant improvement. Oral TXA vs. medroxyprogesterone acetate for dysfunctional uterine bleeding.14 This randomized controlled study compared the efficacy and safety of a lower dose of TXA in women with dysfunctional uterine bleeding (diagnosed with menorrhagia and PBAC score >100) to 21-day cyclical administration of medroxyprogesterone acetate. Subjects were randomized into two groups: TXA (n=49) 500mg four times daily x 5 days/cycle or medroxyprogesterone (n=45) 10 mg twice daily from day 5 to day 25 of the cycle for 3 months. Primary outcome measured MBL, based on PBAC scores. This is the only identified study that followed-up with patients 3 months after stopping therapy to assess recurrence of menorrhagia. Efficacy results are as follows: Table 8: PBAC percent reduction with TXA or medroxyprogesterone14 TreatmentTime PeriodMean PBACMean reduction* (%)TXA, n=49Baseline356.94------n=481st mo149.1758.2n=482nd mo138.9261.0n=473rd mo141.6460.3n=35FU, 3 mo after Tx------32.0Medroxyprogesterone, n=45Baseline370.24-------n=441st mo167.9354.6n=412nd mo179.5151.5n=333rd mo156.6757.7n=25FU, 3 mo after Tx-------35.3*p <0.005 for both drugs during the treatment period Treatment with either TXA or medroxyprogesterone was associated with significant and similar reductions in MBL as measured by PBAC scores. More patients in the medroxyprogesterone treatment group did not respond to therapy (28.9%, 13 of 45) compared to lack of response in TXA group (6.1%, 3 of 49), p =0.003. In both treatment groups, statistically significant increases in hemoglobin concentrations were noted (from 10.7 to 11.2 g/dL and from 10.9 to 11.4 g/dL in TXA and medroxyprogesterone groups, respectively). Furthermore, recurrence of menorrhagia of the same severity as before treatment within 3 months of last treatment dose was assessed: Table 9: Recurrence of menorrhagia 3 months after discontinuation of therapy14 TXA n=42Medroxyprogesterone N=30P-valueRecurrence rate, 3 months after treatment28/42 (66.7%)15/30 (50%)0.155 Although some carryover effect was seen after stopping treatment, a significant portion of women in both treatment groups experienced recurrence of menorrhagia to the same baseline severity, indicating that therapy did not result in a permanent decrease in menstrual blood loss. 4. Oral TXA vs. Ethamsylate and Mefenamic acid for dysfunctional uterine bleeding15 This randomized controlled trial randomized 76 women with dysfunctional uterine bleeding (MBL >80 mL/cycle) to compare the efficacy and acceptability of ethamsylate (hemostatic agent not available in the US), mefenamic acid and TXA for the treatment of menorrhagia. Patients were randomized into 3 groups: ethamsylate 500 mg every 6 hours (n=27), mefenamic acid 500mg every 8 hours (n=23) and TXA 1 g every 6 hours (n=26). Treatment length was from day 1 to day 5 of menses cycle for three consecutive menstrual cycles. Primary outcome measured MBL by the alkaline haematin method in three control menstrual periods and three treatment cycles. Table 10. Comparison of Average MBL between Ethamsylate, Mefenamic acid and TXA15 Control/Baseline MBL (mL)MBL after Treatment (mL)Reduction (%)P-valueEthamsylate (n= 27)1701750------Mefenamic acid (n= 23)18614820<0.001TXA (n=26)1647554<0.001 Ethamsylate had no effect on reducing MBL from baseline, while TXA reduced MBL by a significantly greater extent than mefenamic acid (p <0.05).15 Secondary outcomes included duration of bleeding, sanitary towel usage and patient assessment of blood loss and dysmenorrhea. There was no difference between the treatments in the duration of menstrual bleeding (mean 5.5 days). A significant reduction in the number of sanitary towels used was found in patients with mefenamic acid (p<0.05) and TXA (p<0.01), however there was no difference in patients using ethamsylate. Lastly, based on patient assessment on blood loss, 8 (30%) of patients taking ethamsylate believed that their MBL was greater during treatment, while 18 (69%) and 13(57%) taking TXA and mefenamic acid respectively, believed their MBL decreased during treatment. 5. Oral TXA vs. Norethisterone16 This small, randomized, double-blind, placebo controlled, single-center trial compared the efficacy of TXA and norethisterone (chemically identical to norethindrone) in the treatment of ovulatory menorrhagia. Forty-six patients were randomized to either receive norethisterone (n=21) 5 mg twice a day on days 19 to 26 of menstrual cycle or TXA (n=25) 1 g four times daily on days 1 to 4 of menstrual cycle. Primary outcome measured was MBL using the alkaline haematin method during two control and two treatment menstrual cycles. Table 11. Comparison of Average MBL Reduction between Norethisterone and TXA16 Control/ Baseline MBL (mL) (SD)MBL after Treatment (mL) (SD)Change (%)P-valueNorethisterone (n=21)173 (85)208 (135)+ 200.26TXA (n=25)175 (84)97 (89)- 45<0.0001 Treatment with TXA significantly reduced average MBL by 45% (p <0.0001), while the mean MBL increased by 20% (p= 0.26) in women receiving norethisterone. Fourteen of 25 (56%) women in TXA treated group and two out of 21 (9.5%) women in the norethisterone group achieved a mean MBL of <80 ml per cycle. 16 Secondary outcomes included a patient questionnaire to assess subjective endpoints. There was no significant difference in the two groups between the effect of treatment on general health or the amount of abdominal pain experienced. However, there was a significant benefit with TXA found in the amount of leakage reported and sex life. No significant improvements were seen with either treatment in laboratory parameters (iron or hemoglobin).16 6. Oral TXA vs. Flubiprofen17 This small, randomized, open-label, crossover, single-center study compared the effects of TXA and the NSAID flurbiprofen in 15 women for the treatment of idiopathic HMB. Women with HMB, defined as MBL > 80ml/cycle and women diagnosed with idiopathic menorrhagia were eligible, while women with HMB due to uterine myomata or an IUD were excluded. Women were randomized to two treatment groups: TXA 1500 mg per day divided in three doses on days 1 to 3 of the menstrual cycle, then 1000 mg twice daily on days 4 to 5 or flurbiprofen 100 mg twice daily on days 1 to 5. Each patient was followed for two control cycles, received each active treatment for 2 months and then crossed over to the other active treatment for another 2 months. The primary outcome measured MBL using the alkaline haematin method. Both TXA and flurbiprofen significantly reduced MBL from baseline. TXA was significantly more effective than flurbiprofen in reducing MBL, though the mean MBL in both groups remained >100 mL. There was no difference from baseline in duration of menses or hemoglobin concentrations with either treatment. Of note, more patients reported adverse effects when treated with TXA vs. flurbiprofen, though there were no discontinuations due to adverse events. Table 12. Comparison of Average MBL reduction between Flurbiprofen and TXA17 Baseline/Control MBL (mL)(SD)MBL after Treatment (mL) (SD)Reduction (%)P-valueTXA (n=15)295 (52)155 (33)53*<0.01Flurbiprofen (n=15)295 (52)223 (44)24*<0.01*p <0.05 between TXA and flurbiprofen treatment groups 7. Oral TXA vs. Flurbiprofen vs. Levonorgestrel IUD18 This small, open-label study appears to be a continuation of Andersch et al, 17 in which the efficacy of TXA, flurbiprofen and levonorgestrel IUD are compared in 35 women seeking medical care for the treatment of HMB. Women with confirmed idiopathic menorrhagia, MBL >80mL/cycle and no pelvic pathological conditions were included, while women with any abnormal gynecological exam (i.e. fibroids) were excluded. This study design can be described in two parts: 1) the first 20 consecutive women to seek medical assistance were assigned to receive the levonorgestrel IUD (releases 20g/day). MBL was measured during two control cycles before placement of the IUD and at 3, 6 and 12 months after placement. 2) The second part is the randomized, open-label, crossover study of Andersch et al, in which 15 women were treated with flurbiprofen and TXA during four consecutive menstrual cycles. In both cases, the primary outcome measured MBL using the alkaline haematin method. Table 13. Comparison of MBL between TXA, Flurbiprofen & Levonorgestrel-IUD18 Mean baseline MBL, mL (SD)Mean MBL after treatment, mL (SD)TXA (n=15)295 (52)155 (33), 53% reductionFlurbiprofen (n=15)295(52)223 (44), 24% reduction3 months6 months12 monthsLevonorgestrel- IUD (n=16)203 (25.2)34 (8.5) 82% reduction25 (7.3) 88% reduction9 (2.7) 96% reduction Both TXA and flurbiprofen reduced MBL, however neither treatment reduced MBL to <80mL. The greatest reduction in MBL was seen with levonorgestrel IUD, which resulted in reduced MBL that was statistically significant in comparison to both TXA (p<0.01) and flurbiprofen (p<0.001). Levonorgestrel reduced MBL to <80 mL at 3, 6 and 12 months respectively. Furthermore, use of levonorgestrel IUD resulted in a statistically significant increase in hemoglobin from baseline 12.7g/dL 2.6 to 13.8g/dL 2.1 at 6 months (p<0.05) to 13.9g/ dL 3.2 at12 months (p<0.01), while no significant changes in hemoglobin were seen with TXA or flurbiprofen. 8. Systematic reviews of TXA19,20 A Cochrane systematic review and meta-analysis reviewed the literature (up to April 2004) for treatment options for HMB. Treatment with antifibrinolytic therapy (TXA) resulted in a greater reduction in HMB when compared to placebo, NSAIDs, oral luteal phase progestagens and ethamsylate. When compared to these other treatment options, TXA reduced MBL 25 to 50% from baseline.19 In another review (literature up to May 2003) comparing TXA with other treatment options for menorrhagia, TXA was found to be more effective at reducing MBL in comparison to mefenamic acid, flurbiprofen, ethamsylate and oral luteal phase norethisterone. However TXA was significantly less effective than a levonorgestrel-releasing (20(g/day) IUD at 3 months, 6 months and 12 months.20 Summary of efficacy findings TXA vs. placebo Oral TXA 3900mg/d is more effective than placebo in reducing MBL, while the lower dose of 1950 mg/day did not meet the pre-specified primary endpoint. Reductions in MBL with TXA treatment were considered clinically meaningful according to a pre-defined standard. However, mean MBL in TXA-treated patients remained >100 mL, indicating that treatment did not cure menorrhagia (defined as MBL >80 mL) but only decreased its severity. In the 6-cycle trial, less than half of the women (43%) treated with TXA achieved MBL <80 ml. Compared to placebo, oral TXA has been shown to statistically significantly improve social or leisure and physical activities of daily living. TXA vs. active comparators Based on results from active comparator studies, TXA appears to be at least as effective and possibly more effective than alternative agents mefenamic acid , ethamsylate , norethisterone, flurbiprofen, intranasal desmopressin, and medroxyprogesterone in reducing MBL in women with menorrhagia. Similar to the results from placebo-controlled studies, TXA treatment significantly reduced MBL with mean MBL measures above the threshold for menorrhagia in the majority of the active-control studies. Compared to levonorgestrel- IUD, TXA appears to be less effective in reducing MBL. Of the active comparator studies that evaluated laboratory parameters including hemoglobin and iron concentrations, only two trials found a statistically significant improvement with any menorrhagia treatments. An increase of 0.5 g/dL from baseline in hemoglobin concentration was found with both TXA and medroxyprogesterone in one study, and an increase of over 1 g/dL in hemoglobin concentration from baseline was noted with levonorgestrel-IUD in another trial. In the two studies that investigated various QOL measures, some improvements were observed from baseline with menorrhagia treatment with TXA and IN-DDAVP (but not norethindrone). Of note, TXA does not relieve dysmenorrhea. For further details on the efficacy results of the clinical trials, refer to  REF _Ref80503441 \h \* MERGEFORMAT Appendix A: Clinical Trials. Adverse Events (Safety Data) The safety data for oral TXA were derived from the two short-term (3- and 6-cycle) RCTs and two long-term open label studies.4,12,21,22 Supportive information is also available from the active comparator studies. Table 14. Adverse Events Reported by e" 5% of Subjects Treated with Oral TXA in Short-Term Trials8 TXA 3900 mg/day n (%) N=232Placebo n (%) N=139Total Number of Adverse Events 1500923Patients with at Least One Adverse Event 208 (89.7%) 122 (87.8%)Headache117 (50.4%) 65 (46.8%) Nasal & Sinus Symptoms59 (25.4%) 24 (17.3%) Back Pain48 (20.7%) 21 (15.1%) Abdominal Pain 46 (19.8%) 25 (18.0%) Musculoskeletal Pain26 (11.2%) 4 (2.9%) Arthralgia 16 (6.9%) 7 (5.0%) Muscle Cramps and Spasms15 (6.5%) 8 (5.8%) Migraine14 (6.0%) 8 (5.8%) Anemia13 (5.6%) 5 (3.6%) Fatigue12 (5.2%) 6 (4.3%)  The multi-center, open-label, 27-cycle study assessed the long-term safety of oral TXA in the treatment of HMB.21 In addition, an extension trial (including women who completed the two pivotal placebo-controlled efficacy studies4,12) assessed the safety of TXA in an additional 9 cycles.22 The types and severity of adverse events in these two long-term open-label trials were similar to those observed in the double-blind, randomized, placebo-controlled studies. There was no evidence to suggest an increase in the frequency or severity of adverse events with continued TXA therapy. Based on the seven active comparator studies, six studies assessed the safety of TXA. The common adverse events reported with TXA were headache, gastrointestinal upset, nausea and dizziness. Furthermore, the majority of withdrawals reported were not due to adverse events, with the exception of participants (n=4) from Kouides et al13 and Bonnar et al15 (n=3). Additionally, a randomized, double-blind, placebo and positive-control, cross-over study assessed QTc interval conductance of oral TXA and confirmed the lack of QT interval impact of oral TXA acid at study doses.23 Deaths and Other Serious Adverse Events Five serious adverse events were reported in the 6-cycle RCT in the TXA group.12 One incident each of the following: tachycardia, acute bronchitis, hypoglycemia, posttraumatic stress disorder and urticaria. In comparison to the TXA group, one serious adverse event of deep vein thrombosis occurred in the placebo group. 12 Two women experienced a life-threatening adverse event in the long-term open-label safety trial.21 One women experienced cardiac arrest, pneumonia and pneumococcal sepsis, in which she later died of pneumococcal sepsis. The other women experienced severe menorrhagia. Additionally, five patients experienced a serious adverse event in the open-label extension study.22 These included a life-threatening decrease in blood glucose levels, a severe carcinoid tumor of the stomach, brainstem infarction, intracranial aneurysm and trigeminal neuralgia. In addition, two patients reported serious adverse events of menorrhagia. These events were considered to not be related to the treatment of TXA by the investigator. Common Adverse Events8 Commonly reported adverse events with oral TXA include menstrual discomfort, headache, gastrointestinal upset and back pain. For further details on the safety results of the clinical trials, refer to  REF _Ref80503441 \h \* MERGEFORMAT Appendix A: Clinical Trials. Tolerability Table 15. Tolerability of Oral TXA 3900 mg/d in the 3 and 6-Cycle RCT4,12 and the Two Long-Term, Open-Label studies21,22 Length of study (Months)Withdrawals due to adverse eventsAverage use of TXA per cycle (days)3- Cycle RCT (N= 297)31.0% (3/297)Not-stated6-Cycle RCT (N= 189)63.2% (6/189)3.4Long-Term OpenLabel Study (N= 723)2717.8% (97/723)2.9Long-Term Open Label Extension Study (N=260)96.5%(6/260)3.5 Contraindications8 1. Thromboembolic Risk: Cases of venous and arterial thrombosis or thromboembolism and retinal artery and retinal vein occlusions have been reported with TXA. Active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism or cerebral thrombosis) History of thrombosis or thromboembolism (including retinal vein or artery occlusion). Intrinsic risk of thrombosis (e.g., thrombogenic valvular disease, thrombogenic cardiac rhythm disease or hypercoagulopathy). 2. Hypersensitivity to TXA or any of its components Warnings and Precautions8 Thromboembolic Risk Combination hormonal contraceptives are known to increase the risk of venous thromboembolism as well as arterial thromboses (e.g., stroke and myocardial infarction). This risk may further increase when hormonal contraceptives are administered with TXA. Women using hormonal contraceptives were excluded from TXA clinical trials. There have been post-marketing reports of venous and arterial thrombotic events in women who have taken TXA concomitantly with hormonal contraceptives. Women on hormonal contraception should not use TXA unless there is a strong medical need and the benefit of treatment will outweigh the potential increased risk of a thrombotic event. Especially at risk patients may include those who are obese or smoke (particularly those over 35 years of age who smoke). Do not use TXA in women who are taking more than the approved dose of a hormonal contraceptive. TXA is not recommended in women taking either factor IX complex concentrates or anti-inhibitor coagulant concentrates, due to increased risk of thrombosis. Caution should be applied in women with acute promyelocytic leukemia taking all-trans retinoic acid (e.g., oral tretinoin) for remission induction, which may increase the risk of thrombosis. Ocular Effects: Patients should be instructed to report any visual or ocular symptoms, because retinal venous and arterial occlusions have been reported. TXA should be discontinued immediately and an ophthalmic evaluation should be performed. Severe Allergic reaction: One case of severe allergic reaction to TXA has been reported in clinical trials. Subarachnoid hemorrhage: Cerebral edema and cerebral infarction may be caused by use of TXA in women with subarachnoid hemorrhage. Ligneous conjunctivitis: Ligneous conjunctivitis has been reported in patients taking TXA. The conjunctivitis resolved following cessation of the drug. Pregnancy (Category B) and Lactation8 TXA is not indicated for use in pregnant women. There are no adequate or well-controlled studies in pregnant women. There have been reproduction studies in mice, rats and rabbits, which have revealed no evidence of impaired fertility or harm to the fetus due to TXA. However, TXA is known to cross the placenta and appears in cord blood at concentrations approximately equal to the maternal concentration. In the long-term open-label safety study, 14 pregnancies occurred, in which no fetal abnormalities were reported in the women who carried to full term.21 In addition, TXA should be used during lactation only if clearly needed, as it has been found to be present in the mothers milk at a concentration of about one hundredth of the corresponding serum concentration. Post-marketing Safety Experience8,24 Review of US post-marketing reports of venous and arterial thrombotic events in women on oral TXA led to revised warnings and precautions in the product label in April 2011. In the majority of cases, women were using TXA concomitantly with combined hormonal contraceptives and/or were obese.24 In addition, the following reactions have been reported based on US and worldwide post-marketing reports in patients receiving TXA for various indications: nausea, vomiting, diarrhea, allergic skin reactions, anaphylactic shock and anaphylactoid reactions, thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction, impaired color vision and other visual disturbances, dizziness, ligneous conjunctivitis. Sentinel Events No Data Look-alike / Sound-alike (LA / SA) Error Risk Potential NME Drug NameLexi-CompFirst Data BankUSPISMPClinical JudgmentTranexamic acid 650 mg tabNoneNoneNoneNoneTranxeneLystedaNoneNone NoneNoneLunesta Lyrica Lutera Lusedra Drug Interactions8 Drug-Drug Interactions No drug-drug interaction studies were conducted with TXA. Hormonal contraceptives: The concomitant use of hormonal contraceptives and TXA, an antifibrinolytic, may further increase the thrombotic risk of venous thromboembolism, as well as arterial thromboses such as stroke. Concurrent use should only be considered if there is a strong medical need and the potential benefits will outweigh the risks. (See Warnings and Precautions) Factor IX complex concentrates or anti-inhibitor coagulant concentrates: Not recommended due to increased risk of thrombosis. Tissue plasminogen activators (t-PA): Concomitant use may decrease the efficacy of both TXA and tissue plasminogen activators. All-trans retinoic acids (oral tretinoin): Exercise caution due to increased risk of thrombosis. Acquisition Costs Please refer to the last page for VA acquisition costs for oral TXA and comparators. Prices shown in this internal, draft document may include additional discounts available to VA. This information is considered strictly confidential and must not be shared outside of VA. All cost information will be removed from the document when posted to the PBM website. References: Marret H, Fauconnier N, Chabbert-Buffer L, Golfier C, et al. Clinical practice guidelines on menorrhagia:management of abnormal uterine bleeding before menopause. Eur J Obstet Gynecol Reprod Biol.2010 Oct; 152(2):133-7. Lexi-Comp Online"!, Lexi-Drugs OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; accessed October 27, 2011. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc,2011.Available at http://www.clinicalpharmacology.com. Accessed: October 27,2011. Lysteda( tranexamic acid) Product Dossier. Ferring Pharmaceuticals, Inc. September 2010. Zacur HA. Chronic Menorrhagia or anovulatory uterine bleeding. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012. Rahmani B, Jahadi HR. Comparison of tranexamic acid and prednisolone in the treatment of traumatic hyphema. A randomized clinical trial.Opthalmology 1999:Feb;106 (2):375-9. Zohar E, Ellis M, Ifrach N, et al. The Postoperative Blood-Sparing Efficacy of Oral Versus Intravenous Tranexamic Acid After Total Knee Replacement. Anesth Analg 2004; 99: 1679-83. 10. Rahamani B, Jahadi, Hamid R. Comparison of Tranexamic Acid and Prednisolone in the Treatment of Traumatic Hyphema. Opthamology 1999; 106: 375-379. Lysteda Prescribing Information. Ferring Pharmaceuticals, Inc. Parsippany, NJ. August 2011. L Hallberg and L Nilsson, Determination of menstrual blood loss. Scand J Clin Lab Invest.1964;16:244248. J.M Higham, P.M.S OBrien and R.W Shaw, Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol.1990;97:734739. Lukes AS, Muse K, Richter HE, Moore KA, Patrick DL. Estimating a meaningful reduction in menstrual blood loss for women with heavy menstrual bleeding. Current Medical Research & Opinion.2010; 26 (11): 2673-2678. Lukes, Andrea S, Moore, Keith A, Muse, Ken N, et al. Tranexamic Acid Treatment for Heavy Menstrual Bleeding: A Randomized Controlled Trial. Journal of Ob & Gyn 2010; 116(4): 865-75 Kouides, Peter A, Byams, Vanessa R, Phillipp, Claire S, et al. Multisite Management study of Menorrhagia with abnormal laboratory haemostasis: a prospective crossover study of intranasal desmopressin and oral tranexamic acid. British Journal of Haematol 2009; 145:212-220. Kriplani A, Kulshrestha V, Agarwal N, Diwakar S.Role of tranexamic acid in management of dysfunctional uterine bleeding in comparison with medroxyprogesterone acetate.J Obset Gynaecol 2006 Oct;26(7):673-8. Bonnar J, Sheppard BL.Treatment of menorrhagia during menstruation: randomized controlled trial of ethamsylate, mefenamic acid and tranexamic acid. BMJ 1996;313:579-82. Preston JT, Cameron IT, Adams EJ, Smith SK. Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia. British J Obset &Gynecol 1995;102:401-406 Andersch B, Milsom I, Rybo G. An objective evaluation of flurbiprofen and tranexamic acid in the treatment of idiopathic menorrhagia. Acta Obstet Gynecol Scand 1988;67:645-64. Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel- releasing intrauterine contraceptive device in the treatment if idiopathic menorrhagia. Am J Obstet Gynecol 1991;164;879-83. LethabyA, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2000, Issue 4. Art.No.:CD000249.DOI:10.1002/14651858.CD000249. Wellington K, Wagstaff AJ, Drugs.2003;63(13):1417-1433. Muse K, Lukes A, Gertsen J, et al. Long-term evaluation of safety and health-related quality of life in women with heavy menstrual bleeding treated with oral tranexamic acid.Women;s Health 2011; 7(6). Lukes, Andrea S, Freeman, Ellen W, Van Drie D, et al. Safety of tranexamic acid in women witrh heavy menstrual bleeding: an open-label extension study. Womens Health 2011; 7(5): 591-598. 23. Moore, Keith A, Callahan, Timothy S, Maison-Blanche, Pierre, et al. Thorough Cardiac QTc interval conductance assessment of a novel oral tranexamic acid treatment for heavy menstrual bleeding. Expert Opinion Pharmacother 2010; 11(14): 2281-2290. 24. Tranexamic acid (Lysteda) FDA Clinical Review Memo Labeling Supplement. March 2011. Accessed at:  HYPERLINK "http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist" http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist on April 18, 2012. Prepared by Nermeen Madkour, PharmD. PGY1 Managed Care Resident, VA San Diego Reviewed by Mark Bounthavong, PharmD VA San Diego and Lisa Longo, PharmD, BCPS, VA Pharmacy Benefits Management Services Appendix A: Clinical Trials A literature search was performed on Pubmed/Medline (1950 to August 2011) using the search terms and (n=29). A second search was done using the search terms tranexamic acid and heavy menstrual bleeding on 02/01/2012 (n=25). Both searches were limited to studies performed in humans, published in the English language and RCTs. Reference lists of review articles and the manufacturers AMCP dossier were searched for relevant clinical trials. All relevant RCTs published in peer-reviewed journals were included. My Search: (("mouth"[MeSH Terms] OR "mouth"[All Fields] OR "oral"[All Fields]) AND ("tranexamic acid"[MeSH Terms] OR ("tranexamic"[All Fields] AND "acid"[All Fields]) OR "tranexamic acid"[All Fields])) AND #5 AND ("humans"[MeSH Terms] AND Randomized Controlled Trial [ptyp] AND English[lang])       Appendix A: Efficacy Trials Citation Design Analysis type SettingPopulationInterventions/ Endpoints Baseline/Efficacy Results  Safety Results/ ConclusionsLukes et al.12 (2010) MC, DB, PC, ITT mITT, RE, WE, BE N=189 US Industry sponsoredInclusion Women 18-49 yr with HMB; h/o e" 3 consecutive days of HMB for e"4 of last 6 cycles; blood loss of 60ml during 2-cycle pre-tx and avg. of 80mL for both pre-tx cycles; normal pelvic exam, no cervical/uterine abnormalities; regularly occurring periods (21-35d between cycles) of no more than 10 d duration; nonhormonal contraception. Exclusion h/o TE disease; coagulopathy; SAH; endocrinopathy; ocular disease; Hgb <8g/dL; preg or nursing; h/o endometrial abnormality or cervical cancer; anovulatory DUB; metorrhagia; menometrorrhagia; polymenorrheaInterventions: 1. TXA1.3g (2 tabs, 650mg) PO TID for up to 5 d per cycle x6 2. PBO (2 control cycles) Co-meds: permitted - APAP, opioids, oral iron therapy, vitamins; NSAIDs permitted only during intermenstrual phase; OCs not permitted 1 End Point: Mean reduction in MBL measured by: 1.Greater reduction in MBL than PBO from baseline 2.Greater than 50mL mean reduction from baseline 3. Mean reduction greater than a pre-determined meaningful threshold (36mL or higher) 2 End Points: -QoL from MIQ -Occurrence of large blood stains -Hgb/ ferritin conc -MBL was objectively measured using a validated alkaline hematin method.Baseline Characteristics: Mean age 39yr; duration of HMB 10 yr; uterine leiomyomas 36%; MBL 172 ml (TXA), 153 ml (PBO) -Mean number of tx days per cycle was 3.4 d (TXA) and 3.3 d (PBO) Primary Outcomes: TXA n=117 PBO n=72 Mean reduction in MBL* -69.6mL (40.4%) -12.6mL (8.2%) % cycles w/ e"50 mL reduction* 56% 19% %cycles w/ MBL reduction e"36 mL* 69% 29% *p <0.001 Secondary Outcomes: -MIQ scores improved from moderate impairment (score of 3) to slight impairment (score of 2) with TXA vs. PBO -No significant differences in large stain responders -Hgb and ferritin changes from baseline were not significant between TXA and PBO. Reported AE >10% in ITT AE TXA N=117 (%) PBO N=72 (%) P-value Menstrual cramps 62 50 .120 Headache 56 50 .457 Back pain 24 19 .471 Nausea 15 15 .888 Anemia 10 6 .260 Withdrawals due to AE: TXA: 3 pts; PBO: 3 pts Withdrawals due to unsatisfactory efficacy: TXA: none; PBO: 2 pts Conclusions: Use of TXA significantly reduced MBL from baseline and improved QoL while maintaining safety and tolerability. Limitations: -Pts were not permitted to use NSAIDs for menstrual discomfort -Cannot determine safety of women who remain on OCs while on taking TXA. Citation Design Analysis type SettingPopulationInterventions/ EndpointsBaseline/ Efficacy Results Safety Results/ ConclusionsStudy XP12B-MR-3014 Unpublished MC, PC mITT N=304 U.S Industry Sponsored Inclusion Women 18-49 yr with HMB; h/o e" 3 consecutive days of HMB for e"4 of last 6 cycles; blood loss of 60ml during 2-cycle pre-tx and avg. of 80mL for both pre-tx cycles; normal pelvic exam, no cervical/uterine abnormalities; regularly occurring periods (21-35d between cycles) of no more than 10 d duration; nonhormonal contraception Exclusion: Anovulatory DUB; metorrhagia; menometorrhagia; polymenorrheaInterventions: 1. TXA 1300mg TID (3900mg/d) 2. TXA 650mg TID (1950mg/d) 3. PBO Administered during menstruation for up to 5 days over 3 cycles after 2 control cycles. Co-meds: APAP, opioids and iron therapy allowed 1 End Point: Mean reduction in MBL measured by: 1.Greater reduction in MBL than PBO from baseline 2.Greater than 50mL mean reduction from baseline 3. Mean reduction greater than a pre-determined meaningful threshold (36mL or higher) 2 End Points: -HRQoL, social and physical activities -Occurrence of large blood stains -Hgb/ ferritin conc -Number and type of sanitary products -Sleep interruptionsBaseline Characteristics: Mean Age 39.5yrs; duration of HMB 11yrs; % fibroids 44 (TXA 3.9g), 38 (TXA 1.9g), 36 (PBO); 66% Caucasian; MBL not stated Primary Outcomes: TXA 3.9g/d N= 115 TXA 1.95g/d N=115 PBO N=67 MBL -65.5mL* (38.6% reduction) -47mL* (26.1% reduction) -3mL (1.9% reduction) %cycles blood loss e"36mL 71% 58% 23% P <0.05 vs. placebo TXA 1950mg/d failed to meet pre-specified efficacy criteria of reduction in menstrual losses >50mL/cycle Mean exposure to active tx: 3.4 days per cycle Secondary Outcomes: -1950mg/d and 3900mg/day both improved all components of HRQoL: Social leisure, physical activity, work -No significant difference in stain size or sleep interruption -No significant difference in ferritin/Hgb levelsAEs Reported in >5% patients TXA 3.9g/d N=115 TXA 1.95g/d N=115 PBO N=67 Fatigue 3.5% 11.3% 4.5% VURI 7.0% 10.4% 4.5% Musculoskeletal pain 5.2% 8.7% 3.0% Nasal Congestion 2.6% 7.0% 0% Withdrawals, any: 32/304 (10.5%) Withdrawals due to AEs: 5/32 (15.6%) Conclusions: TXA3900mg/d reduces mean MBL in patients with HMB, while maintaining tolerability. TXA1950mg/d did not meet pre-specified efficacy requirements Kriplani et al14 RE, WE, RCT N=94 India Objective: To determine efficacy and safety of TXA vs. MPA in women with DUB Inclusion: Women diagnosed with menorrhagia (PBAC >100) with confirmed DUB. Exclusion: Fibroids Adenomyosis Endometrioisis Thyroid disease Hx of hormone therapy within 3 months. Interventions: Two groups: 1. TXA 500mg QID x 5 days of cycle 2. MPA 10mg BID from day 5 to day 25 of cycle. Duration: 3 months Iron supplementation if Hemoglobin <8% Follow-up 3 months after stopping therapy to assess recurrence 1 End Point: MBL, measured using PBAC scores 2 End Points: Lack of response, recurrence of menorrhagia after stopping therapy. Treatment Period Mean PBAC mL Mean reduction (%) TXA, n=49 Baseline 356.94 ____ n=48 1st mo 149.17 58.2 n=48 2nd mo 138.92 61.0 n=47 3rd mo 141.64 60.3 n=35 FU, 3 mo after Tx ____ 32.0 MPA, n=45 Baseline 370.24 _____ n=44 1st mo 167.93 54.6 n=41 2nd mo 179.51 51.5 n=33 3rd mo 156.67 57.7 n=25 FU, 3 mo after Tx ____ 35.3 Baseline: Mean Age 36yr;Duration of HMB 26mo (TXA), 24 mo (MPA); Hgb 10.7(TXA), 10.9(MPA) Primary Outcome: Percentage reduction of PBAC Score PBAC score reduced considerably by both the drugs during the treatment period (p<0.005) Secondary Outcomes: TXA n=49 MPA n=45 P-value Lack of response 3/49 (6.1%) 13/45 (28.9%) 0.003 TXA n=42 MPA N=30 P-value Recurrence Rate, 3 mo after treatment 28/42 (67%) 15/30 (50%) 0.155 Hgb levels increased significantly at end of 3 mo Tx TXA 10.7( 11.3 ( p=0.003) MPA 10.9( 11.4 (p=0.019) TXA MPA P-value AE 16.3% (8/49) 33.3% (15/45) P=0.09 Major Side effects seen with TXA: Headache: 6.1% (3/49) GI upset: 6.1% (3/49) Giddiness: 2% (1/49) Major Side effects seen with MPA: Intermenstrual bleeding: 11.1% (5/45) Giddiness: 6.7% (3/45) Headaches: 4.4% (2/45) Breast Tenderness: 4.4%(2/45) GI Upset: 4.4% (2/45) Mood Changes: 2.2% (1/45) TXA Discontinuation: 4.1% (2/49) due to allergic reaction and no relief MPA Discontinuation: 26.7% (12/45) N=10- Tx failure (continuous bleeding (n=6), or heavy bleeding (n=4) N=2- due to AEs ( intermentstrual bleeding, diarrhea) Discontinuation rate significantly greater in the MPA group (p=0.002) Conclusions: No clear difference stated between menorrhagia and DUB. -MBL increased after stopping treatment, suggesting a non-permanent decrease in blood loss. Citation Design Analysis type SettingPopulationInterventions/ EndpointsBaseline/Efficacy Results  Safety Results/ConclusionsKouides et al13 Prospective, multi-site Cross-over N=116 USInclusion: -Women 18-50 y.o w/ confirmed menorrhagia (PBAC ( 100)with abnormal coagulation or platelet function - Negative pelvic exam, PAP -Regular periods every 39days -Discontinue OCs** NSAIDS Exclusion: Abnormal TSH Interventions: Phase 1: Lab testing to confirm abnormal coagulation or platelet function. Phase 2: Optional OC treatment arm Phase 3: Cross over treatment arm -IN-DDVAP 300 (g on day 2 &3 of menstrual cycle, one spray in each nostril daily -TXA 1 g QID for the 1st 5d of menstrual cycle 2 groups: 1.IN-DDAVP x 2 cycles, then TXA x 2 cycles 2. TXA x 2 cycles, then IN-DDAVP x 2 cycles No washout period due to short half-life 1 End Point: Change in MBL and QOL MBL estimated by PBAC measured at baseline and during 4 menstrual cycles. 2 End Points: QOL- assessed at baseline, after 2nd cycle of IN-DDAVP and after 2nd cycle of TXA 4 QOL measures: 1. (HRQoL) 2. (SF-36) 3. CESD-D 4. Ruta***Baseline: Mean age 36yr; Mean PBAC 275 mL (TXA), 280 mL (IN-DDAVP); Race- Majority White PBAC decrease from baseline (Average) 95% CI TXA N=67 -105.7mL -130.5, -81.0 IN-DDAVP N=49 -64.1,L -88.0, -40.3 * Difference of 41.6 in PBAC score between TXA & IN-DDAVP; p=0.0002 95%CI 19.6, 63.6 Dropout rate: IN-DDAVP( TXA 43% TXA(IN-DDAVP 33% QOL Measures: The Ruta menorrhagia severity scale showed the most SS improvement. -Changes from baseline for the 1st treatment medication had larger improvement in QOL than after 2nd treatment medication, regardless of sequence.Most commonly reported side effect in taking both IN-DDAVP and TXA was headaches. Withdrawals due to AEs: IN-DDAVP n=6 TXA n=4 Conclusions: Both IN-DDAVP and TXA reduced MBL and improved QOL among females with menorrhagia and abnormal lab haemostasis, but TXA proved more effective. Note- Neither treatment controlled menorrhagia in terms of a PBAC <100. Limitations: 1. High dropout rate 2. Gold standard to measure MBL is alkaline haematin spectrophotometric method VS. PBAC 3.Small population size Citation Design Analysis type SettingPopulationInterventions/ EndpointsBaseline/Efficacy Results  Safety Results/ConclusionsBonnar et al15 ITT, WE, RE N=76 UK Objective: To compare efficacy of ETA, MEF and TXA for treating menorrhagia. Inclusion: -Women with DUB -Normal cervical smear Exclusion: -Hx of renal or hepatic dysfunction -Hx of thromboembolic dx -Inflammatory bowel dx -Peptic ulcer dx -Firbrinolytic dx Interventions: 1.ETA 500mg q 6hrs 2. MEF 500mg q 8hrs 3. TXA 1 g q 6hrs Duration: 5 days from day 1 of menses x 3 consecutive pretreatment (control) cycles followed by 3 treatment cycles MBL measured by alkaline haematin method 1 End Point: Change in MBL 2 End Point: Duration of bleeding, sanitary towel usage and patient assessment of blood loss Baseline: Mean Age 39yrs; Height 162cm; Weight 65kg; MBL 170mL (ETA), 186mL(MEF), 164mL (TXA) Primary Outcomes: Average MBL (mL) over 3 control and 3 treatment cycles Control (mL) Treatment (mL) Reduction (%) P value ETA (n=27) 170 175 0 MEF (n=23) 186 148 20 <0.001 TXA (n=26) 164 75 54 <0.001 Secondary Outcomes: -No difference between treatments in duration of menstrual bleeding. -Significant reduction in the number of sanitary towels in patients treated w/ MEF (p<0.05) and TXA (p<0.01). -30% of patients taking ETA believed their menstrual loss was greater during treatment. Safety Not assessed Withdrawals due to AEs (nausea, headache, dizziness) ETA: n= 4 MEF: n=1 TXA: n=3 Withdrawals due to poor efficacy: ETA: n=5 MEF: n=1 TXA: n=0 Conclusion: A significant reduction of MBL was seen in women treated with MEF (20%) and TXA (54%) with menorrhagia. ETA had no effect on MBL. Note: MEF treated women still met definition for menorrhagia (MBL > 80mL), despite a 20% reduction.  Citation Design Analysis type SettingPopulationInterventions/ EndpointsBaseline/Efficacy Results  Safety Results/ConclusionsPreston et al16 ITT, RE, WE N= 46 UK Objective: To compare the efficacy and safety of TXA and NET in the treatment of ovulatory menorrhagia. Inclusion: -Women 18 e" y.o -Confimed ovulatory menorrhagia -MBL > 80mL/cycle -No hormone therapy within 3 months -Not on any meds that may affect MBL -Normal renal function, pelvic exam and negative cervical cytology -Confirmed to be ovulating (mid-luteal phase serum progesterone > 9nmol/l) Exclusion: None statedInterventions: 1. NET 5 mg BID on days 19-26 of cycle 2. TXA 1 g QID on days 1-4 of cycle Duration: 4 cycles (2 control cycles, 2 treatment cycles) MBL measured by alkaline haematin method Hgb, serum ferritin, transferrin and creatinine measured. 1 End Point: Change in MBL 2 End Point: Patient questionnaire Baseline: Mean Age: 40yrs; Weight 71kg (TXA), 63.5 kg (NET); MBL 175ml(TXA), 173 (NET) * Significant difference in weight between groups ( p<0.048) Primary Outcome: Average MBL (ml) over 2 control and 2 treatment cycles Control (mL) (SD) Treatment (mL)(SD) Average MBL reduction, p-value NET (n=21) 173 (85) 208 (135) + 20%, p =0.26 TXA (n=25) 175 (84) 97 (89) - 45%, p <0.0001 56% (14/25) women in TXA group achieved MBL <80ml/cycle compared to 9.5% (2/21) women who received NET. No significant difference in Hgb/serum ferritin/transferrin levels between groups. Creatinine levels within normal ranges (<125umol/l) Secondary Outcome: -Significant difference in the amount of leakage and limitation of social activities and sex life, with beneficial effects seen in both with TXA compared to NET. -No significant difference between the 2 groups on general health or abdominal pain.  Common Adverse Events TXA (%) NET (%) Dysmenorrhea 80 85 Headache 32 48 GI (d/n/v) 12 33 Withdrawals due to AEs: none Withdrawals, other: n=4 (n=1) duodenal ulcer requiring hospitalization (TXA) (n=2) failure to collect MBL (TXA, NET) (n=1) incorrect administration (NET) Conclusion: TXA 1 g QID is safe and effective in the treatment of menorrhagia. Norethistrone at the dose used (5 mg BID) is not an effective therapy in the treatment of menorrhagia. Citation Design Analysis type SettingPopulationInterventions/ EndpointsBaseline/Efficacy Results  Safety Results/ConclusionsAndersch et al17 Open-label, cross-over, single-center N=15 Sweden Objective: To compare the effects of TXA and FLB in the treatment of idiopathic HMBInclusion: -MBL > 80mL/cycle -Idiopathic menorrhagia -Regular cycle Exclusion: -HMB due to uterine myomata -Use of IUDInterventions: 1. TXA 1.5gmTID on day 1 to 3 of menstrual cycle, then 1000mg on days 4 to 5 2. FLB 100 mg BID on days 1 to 5 Duration: 2 control cycles prior to 2 months of each active treatment, then crossover to other active treatment x 2 months. MBL measured via alkaline hematin method. No additional medications or iron supplements allowed during study. 1 End Point: Change in MBL Baseline: Mean Age: 40.5yrs; Avg. H/o 1.7 pregnancies; Mean MBL 295mL; Mean Hgb: 127.4 g/l Primary Outcome: Comparison of MBL between TXA and FLB Mean baseline MBL (mL) (SD) Mean MBL (mL) after treatment (SD) P-value TXA n=15 295 (52) 155 (33) <0.01 FLB n=15 295 (52) 223 (44) <0.01 No significant difference in Hgb levels Adverse events: 46% (7/15) included: -Nausea/ vomiting -Difficulty swallowing -Dizziness -Numbness -Restless legs -Headache No withdrawals due to AEs Conclusion: TXA was well tolerated and significantly reduced MBL compared to flubiprofen. Important to note: Patients treated with both FLB and TXA maintained a MBL > 80ml/cycle, and still met definition of menorrhagia Limitation: -Small population size (n=15) -Open-label Citation Design Analysis type SettingPopulationInterventions/ EndpointsBaseline/Efficacy Results  Safety Results/ConclusionsMilsom et al18 WE N=35 Sweden Objective: To compare the effects of TXA, FLB and LNG-IUD in the treatment of idiopathic HMBInclusion: -MBL > 80mL/cycle during two control cycles -Idiopathic menorrhagia -Regular cycle -No use of OCs or IUD within two months prior Exclusion: -Pregnancy -Pelvic pathologic conditions (i.e. fibroids)Interventions: 1.Insertion of LNG-IUD (20ug/d) 2. TXA 1.5gmTID on day 1 to 3 of menstrual cycle, then 1g on days 4 to 5 3. FLB 100 mg BID on days 1 to 5 (Note: Pts on interventions 2 or 3 were crossed over after 2 cycles) Duration: MBL measured during 2 control cycles before insertion of LNG-IUD, then at 3mo, 6mo and 12mo OR 2 control cycles prior to 2 months of each oral active treatment, then crossover to other oral active treatment x 2 months. MBL measured via alkaline hematin method. No additional medications or iron supplements allowed during study. 1 End Point: Change in MBL Baseline: Mean Age: 38yrs (LNG-IUD), 41yrs (FLB & TXA); Avg. H/o pregnancies 2.2 (LNG-IUD), 1.7 (FLB & TXA); Mean MBL 295mL (FLB), 203mL (TXA); 203mL (LNG-IUD); Mean Hgb: 127.4 g/l Primary Outcome: Comparison of MBL between TXA, FLB & LNG-IUD Mean baseline MBL (mL)(SD) Mean MBL after treatment (mL) (SD) TXA n=15 295 (52) 155 (33) FLB n=15 295(52) 223 (44) 3mo 6mo 12mo LNG-IUD n=16 203 (25.2) 34 (8.5) 25 (7.3) 9 (2.7) MBL reduction was significantly greater with use of LNG-IUD in comparison to both TXA (p<0.01) and FLB (p<0.001) MBL reduction was significantly greater with TXA when compared to FLB (p<0.05) No significant difference in Hgb levels with FLB or TXA treatment Use of LNG-IUD resulted in a statistically significant increase in Hgb at 6 mo (p<0.05) and 12 mo (p<0.01)AEs: TXA- 46% (7/15); dizziness, numbness (restless legs), headache FLB- (4/15); tiredness, stomach pains, nausea No withdrawals due to AEs with TXA or FLB Withdrawals with LNG-IUD due to AEs (n=3) n=2: Inter-menstrual bleeding n=1: Acne, weight gain (2.5kg), mood changes and inter-menstrual bleeding Conclusion: -Both TXA and FLB reduced MBL, however, neither treatment reduced MBL to <80ml. -TXA significantly reduced MBL when compared to FLB -The use of LNG-IUD significantly reduced MBL, resulting in MBL <80ml at 3,6,& 12 months -LNG-IUD resulted in an increase in Hgb levels Limitation: -Small population size -Open-label -Study Design Appendix B: Potential Off-Label Uses Citation Design Analysis type SettingPopulationInterventions/ EndpointsBaseline/Efficacy Results  Safety/ConclusionsRahmani et. al6 WE, RE, RCT Iran N=238 Objective: Compare effects of oral TXA and oral PR on the prevention of 2 hemorrhage in pts with nonperforating traumatic hyphemaInclusion: Pts admitted with traumatic hyphema Exclusion: -black ball hyphema -penetrating eye injury -need for intraocular surgery -h/o bleeding disorder -recent use of ASA or anticoagulants -topical steroid use after eye trauma -renal insufficiency -acid peptic dx -definite re-bleeding before admissionInterventions: Oral TXA 75mg/kg/d in 3 divided doses Or Placebo Or Oral PR 0.75mg/kg/d in 2 divided doses. Duration: 5 days & if no re-bleeding occurred med was D/C Prohibited: ASA, topical steroids 1 End Point: Secondary hemorrhage occurrence Baseline: 79% male (187/238); Mean Age: 14.6 years (range 1-65); white population TXA N=80 PR N=78 PBO N=80 Secondary Hemorrhage 10% (8/80) 18% (14/78) 26% (21/80) Comparator groups PBOvs. TXA PR vs. TXA PBO vs. PR Odds ratio 3.2 99% CI = 1.1, 9.9 (p=0.008) 2.0 99% CI = 0.6, 6.6 (p=0.15) 1.6 99% CI = 0.6, 4.4 (p=0.21) crude odds ratioSafety not assessed Conclusion: In a population with a high rate of secondary bleeding, TXA is more effective than no oral treatment in preventing re-bleeding among patients with traumatic hyphema. No significant differences were found between TXA and PR, though there was a favorable trend with TXA. Limitations: -All pts were white, no diversity -Small study; 40% power to detect differencesZohar et. al7 RCT Single-blinded RE N=80 Israel Objective: To assess the blood-sparing efficacy of TXA when administered orally or via a variable IV infusion after TKR.Inclusion: Pts undergoing elective TKR Exclusion: -Pts with a h/o severe ischemic heart disease, renal failure, cirrhosis, bleeding disorders, current anticoagulant therapy.Interventions: 1. TXA-long: IV bolus TXA 15mg/kg over 30 min, then IV infuse. 10mg/kg/h x12h 2. TXA- short: IV bolus TXA 15mg/kg over 30 min, then IV infuse. 10mg/kg/h x 2h, then oral TXA 1 g x 2 doses 3. TXA-oral: TXA 1g 1h before surgery, then 1g x 3 doses post surgery 4. Control: no TXA; std of care 1 End Point: Blood loss in surgical drain measured at 12 & 24h post surgery 2 End Point: Allogenic blood transfusions Baseline: Age 69-73yr; Weight 75-78kg; Majority females Blood accumulation in sgx drain Control n=20 TXA-long n=20 TXA-short n=20 TXA- oral n=20 1st 12 hrs post-op 249130 (mL) 12181 (mL) 11038 (mL) 231138 (mL) Next 12 hrs post-op 195156 (mL) 10157 (mL) 9547 (mL) 10752 (mL) Primary Outcome: Secondary Outcome: Post-op allogenic blood administration Control N=20 TXA-long N=20 TXA-short N=20 TXA- oral N=20 No. patients 12 3 2 4 Total No. of units 12 3 4 5 Safety not assessed Conclusions: Following the 2nd dose 12 hours post-op, oral TXA was more effective than control at preventing blood loss. No difference was found between oral TXA vs. TXA infusion after the 2nd oral dose was given. KEY AE: adverse events APAP: acetominophen BE: blinding explained DB: double blind D/N/V: diarrhea, nausea, vomitting DUB: dysfunctional uterine bleeding ETA: ethamsylate FLB: flurbiprofen Hgb: hemoglobin HRQoL: health related quality of life- consists of 36 questions covering 8 health domains IN-DDAVP: intranasal desmopressin ITT: intention to treat IUD: intrauterine device LNG-IUD: levonorgestrel intrauterine device MBL: menstrual blood loss MC: multicenter MEF: mefenamic acid MI: myocardial infarction MIQ: menorrhagia impact questionnaire mITT-: modified intention to treat MOX: moxifloxacin MPA: medroxyprogesterone acetate NET: norethisterone OC: oral contraceptive OR: odds ratio PBAC: pictorial blood assessment chart PBO: placebo PC: placebo-controlled PE: physical exam PP : per protocol PR: prednisolone QoL: quality of life RE: randomization explained RMQ: disease-specific QoL measure consisting of 15 questions assessing cycle duration, regularity, extent of bleeding, days of heavy bleeding/cycle, degree of pain, impact on daily leisure and sexual activity and sanitary product use SAH: subarachnoid hemorrhage SH: secondary hemorrhage SS: statistically significant TE: thromboembolic disease TEAE: treatment emergent adverse events TIA: transient ischemic attack TKR: total knee replacement TXA: tranexamic acid US: United States UK: United Kingdom VURI: viral upper respiratory tract infection WE: withdrawals explained *HMB defined as menstrual blood loss of 80mL or more per menstrual cycle Change in MBL was calculated by subtracting the MBL during the   7;@ABbiklmF O  3 6 7 9 U _ ſ˿˿ݱ݇~uluf]~uhuqh42CJ h3CJhuqhMCJhuqhrCJhuqh/+qCJhuqhMCJh&{h&{CJaJh3C<6CJ]aJh#6CJ]aJh&{h&{6CJ]aJ h#CJ h&`CJ h~SCJh3h42h`!h~Sh_h_^J h_^JhXmmH sH h:h_$7B [ \ }q}  & F$^gduq & F^`gduq^gduqgd&{(($d&d-DM NP(($d&d-DM NP"(($d&d-DM NPgd_ Z [ \ b ( 1 w ? 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