Tranexamic Acid 650 mg Tablet, 30-count — NDC 69918-301-30 (Billing 69918-0301-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tranexamic acid is a synthetic lysine amino acid derivative, which diminishes the dissolution of hemostatic fibrin by plasmin. In the presence of tranexamic acid, the lysine receptor binding sites of plasmin for fibrin are occupied, preventing binding to fibrin monomers, thus preserving and stabilizing fibrin’s matrix structure. The antifibrinolytic effects of tranexamic acid are mediated by reversible interactions at multiple binding sites within plasminogen.

Native human plasminogen contains 4 to 5 lysine binding sites with low affinity for tranexamic acid (K d = 750 μmol/L) and 1 with high affinity (K d = 1.1 μmol/L). The high affinity lysine site of plasminogen is involved in its binding to fibrin. Saturation of the high affinity binding site with tranexamic acid displaces plasminogen from the surface of fibrin.

Although plasmin may be formed by conformational changes in plasminogen, binding to and dissolution of the fibrin matrix is inhibited.

12.2Pharmacodynamics Tranexamic acid, at in vitro concentrations of 25–100 μM, reduces by 20–60% the maximal rate of plasmin lysis of fibrin catalyzed by tissue plasminogen activator (tPA). Elevated concentrations of endometrial, uterine, and menstrual blood tPA are observed in women with heavy menstrual bleeding (HMB) compared to women with normal menstrual blood loss. The effect of tranexamic acid on lowering endometrial tPA activity and menstrual fluid fibrinolysis is observed in women with HMB receiving tranexamic acid total oral doses of 2–3 g/day for 5 days.

In healthy subjects, tranexamic acid at blood concentrations less than 10 mg/mL has no effect on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood. Tranexamic acid, however, at blood concentrations of 1 and 10 mg/mL prolongs the thrombin time. Cardiac Electrophysiology The effect of tranexamic acid USP tablets on QT interval was evaluated in a randomized, single-dose, 4-way crossover study in 48 healthy females aged 18 to 49 years.

Subjects received (1) tranexamic acid USP tablets 1300 mg (2) tranexamic acid USP tablets 3900 mg (three times the maximum recommended single dose), (3) moxifloxacin 400 mg, and (4) placebo. There was no significant increase in the corrected QT interval at any time up to 24 hours after the administration of either dose of tranexamic acid USP tablets. Moxifloxacin, the active control, was associated with a maximum 14.1 msec mean increase in corrected QT interval (moxifloxacin – placebo) at 3 hours after administration.

12.3Pharmacokinetics Absorption After a single oral administration of 1300 mg of tranexamic acid USP tablets, the peak plasma concentration (C max ) occurred at approximately 3 hours (T max ). The absolute bioavailability of tranexamic acid USP tablets in women aged 18–49 is approximately 45%. Following multiple oral doses (1300 mg tablets three times daily) administration of tranexamic acid USP tablets for 5 days, the mean C max increased by approximately 19% and the mean area under the plasma concentration-time curve (AUC) remained unchanged, compared to a single oral dose administration (1300 mg ).

Plasma concentrations reached steady state at the 5th dose of tranexamic acid USP tablets on Day 2. The mean plasma pharmacokinetic parameters of tranexamic acid determined in 19 healthy women following a single (1300 mg ) and multiple (1300 mg tablets three times daily for 5 days) oral dose of tranexamic acid USP tablets are shown in Table 3. Table 3.

Mean (CV%) Pharmacokinetic Parameters Following a Single (1300 mg) and Multiple Dose (1300 mg three times daily for 5 days) Oral Administration of tranexamic acid USP tablets in 19 Healthy Women under Fasting Conditions Parameter Arithmetic Mean (CV%) Single dose Multiple dose C max = maximum concentration AUC tldc = area under the drug concentration curve from time 0 to time of last determinable concentration AUC inf = area under… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Tranexamic acid is a synthetic lysine amino acid derivative, which diminishes the dissolution of hemostatic fibrin by plasmin. In the presence of tranexamic acid, the lysine receptor binding sites of plasmin for fibrin are occupied, preventing binding to fibrin monomers, thus preserving and stabilizing fibrin’s matrix structure. The antifibrinolytic effects of tranexamic acid are mediated by reversible interactions at multiple binding sites within plasminogen.

Native human plasminogen contains 4 to 5 lysine binding sites with low affinity for tranexamic acid (K d = 750 μmol/L) and 1 with high affinity (K d = 1.1 μmol/L). The high affinity lysine site of plasminogen is involved in its binding to fibrin. Saturation of the high affinity binding site with tranexamic acid displaces plasminogen from the surface of fibrin.

Although plasmin may be formed by conformational changes in plasminogen, binding to and dissolution of the fibrin matrix is inhibited.

12.3Pharmacokinetics Absorption After a single oral administration of 1300 mg of tranexamic acid USP tablets, the peak plasma concentration (C max ) occurred at approximately 3 hours (T max ). The absolute bioavailability of tranexamic acid USP tablets in women aged 18–49 is approximately 45%. Following multiple oral doses (1300 mg tablets three times daily) administration of tranexamic acid USP tablets for 5 days, the mean C max increased by approximately 19% and the mean area under the plasma concentration-time curve (AUC) remained unchanged, compared to a single oral dose administration (1300 mg ).

Plasma concentrations reached steady state at the 5th dose of tranexamic acid USP tablets on Day 2. The mean plasma pharmacokinetic parameters of tranexamic acid determined in 19 healthy women following a single (1300 mg ) and multiple (1300 mg tablets three times daily for 5 days) oral dose of tranexamic acid USP tablets are shown in Table 3. Table 3.

Mean (CV%) Pharmacokinetic Parameters Following a Single (1300 mg) and Multiple Dose (1300 mg three times daily for 5 days) Oral Administration of tranexamic acid USP tablets in 19 Healthy Women under Fasting Conditions Parameter Arithmetic Mean (CV%) Single dose Multiple dose C max = maximum concentration AUC tldc = area under the drug concentration curve from time 0 to time of last determinable concentration AUC inf = area under the drug concentration curve from time 0 to infinity T max = time to maximum concentration t 1/2 = terminal elimination half-life C max (mcg/mL) 13.83 (32.14) 16.41 (26.19) AUC tldc (mcg∙h/mL) 77.96 (31.14)

77.67AUC 0-tau (mcg·h/mL) = area under the drug concentration curve from time 0 to 8 hours (29.39) AUC inf (mcg∙h/mL) 80.19 (30.43) - T max (h) Data presented as median (range) 2.5 (1 – 5) 2.5 (2 – 3.5) t 1/2 (h) 11.08 (16.94) - Effect of food: Tranexamic acid USP tablets may be administered with or without food. A single dose administration (1300 mg ) of tranexamic acid USP tablets with food increased both C max and AUC by 7% and 16%, respectively. Distribution Tranexamic acid is 3% bound to plasma proteins with no apparent binding to albumin.

Tranexamic acid is distributed with an initial volume of distribution of

0.18 L/kg and steady-state apparent volume of distribution of

0.39L/kg. Tranexamic acid crosses the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood.

Tranexamic acid concentration in cerebrospinal fluid is about one tenth of the plasma concentration. The drug passes into the aqueous humor of the eye achieving a concentration of approximately one tenth of plasma concentrations. Elimination Most elimination post intravenous administration occurred during the first 10 hours, giving an apparent elimination half-life of approximately 2 hours.

The mean terminal half-life of tranexamic acid is approximately 11 hours. Plasma clearance of tranexamic acid is 110–116 mL/min. Metabolism A small fraction of the tranexamic acid is metabolized.

Excretion Tranexamic acid is eliminated by urinary excretion primarily via glomerular filtration with more than 95% of the dose excreted unchanged. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10 mg/kg. Specific Populations Pediatric Patients Tranexamic acid USP tablets are indicated for females of reproductive age (not approved for use in premenarcheal girls).

In a randomized, single dose, two-way crossover study of two dose levels (650 mg and 1,300 mg), pharmacokinetics of tranexamic acid was evaluated in 20 female adolescents (12 to 16 years of age) with heavy menstrual bleeding. The C max and AUC values after a single oral dose of 650 mg in the adolescent females were 32–36% less than those after a single oral dose of 1,300 mg in the adolescent females. The C max and AUC values after a single oral dose of 1300 mg in the adolescent females were 20–25% less than… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Tranexamic acid, at in vitro concentrations of 25–100 μM, reduces by 20–60% the maximal rate of plasmin lysis of fibrin catalyzed by tissue plasminogen activator (tPA). Elevated concentrations of endometrial, uterine, and menstrual blood tPA are observed in women with heavy menstrual bleeding (HMB) compared to women with normal menstrual blood loss. The effect of tranexamic acid on lowering endometrial tPA activity and menstrual fluid fibrinolysis is observed in women with HMB receiving tranexamic acid total oral doses of 2–3 g/day for 5 days.

In healthy subjects, tranexamic acid at blood concentrations less than 10 mg/mL has no effect on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood. Tranexamic acid, however, at blood concentrations of 1 and 10 mg/mL prolongs the thrombin time. Cardiac Electrophysiology The effect of tranexamic acid USP tablets on QT interval was evaluated in a randomized, single-dose, 4-way crossover study in 48 healthy females aged 18 to 49 years.

Subjects received (1) tranexamic acid USP tablets 1300 mg (2) tranexamic acid USP tablets 3900 mg (three times the maximum recommended single dose), (3) moxifloxacin 400 mg, and (4) placebo. There was no significant increase in the corrected QT interval at any time up to 24 hours after the administration of either dose of tranexamic acid USP tablets. Moxifloxacin, the active control, was associated with a maximum 14.1 msec mean increase in corrected QT interval (moxifloxacin – placebo) at 3 hours after administration.

14 CLINICAL STUDIES

14.1Overview of the Clinical Studies The efficacy of tranexamic acid USP tablets in the treatment of heavy menstrual bleeding (HMB) in women of reproductive potential was demonstrated in two randomized, double-blind, placebo-controlled studies: one 3-cycle treatment study (Study 1) and one 6-cycle treatment study (Study 2) [see Adverse Reactions (6.1) ]. In these studies, HMB was defined as an average menstrual blood loss of ≥ 80 mL as assessed by alkaline hematin analysis of collected sanitary products over two baseline menstrual cycles.

Subjects were 18 to 49 years of age with a mean age of approximately 40 years, had cyclic menses every 21–35 days, and a BMI of approximately 32 kg/m 2 . On average, subjects had an HMB history of approximately 10 years and 40% had fibroids as determined by transvaginal ultrasound. Approximately 70% were Caucasian, 25% were Black, and 5% were Asian, Native American, Pacific Islander, or Other.

Seven percent (7%) of all subjects were of Hispanic origin. In these studies, the primary outcome measure was menstrual blood loss (MBL), measured using the alkaline hematin method. The endpoint was change from baseline in MBL, calculated by subtracting the mean MBL during treatment from the mean pretreatment MBL.

The key secondary outcome measures were based on specific questions concerning limitations in social or leisure activities (LSLA) and limitations in physical activities (LPA). Large stains (soiling beyond the undergarment) were also included as a key secondary outcome measure.

14.2Heavy Menstrual Bleeding in the Three-Cycle Treatment Study Study 1 compared the effects of two doses of tranexamic acid USP tablets (1950 mg and 3900 mg per day for up to 5 days during each menstrual period) versus placebo on MBL over a 3-cycle treatment duration. Of the 294 evaluable subjects, 115 subjects received tranexamic acid USP tablets 1950 mg/day, 112 subjects received tranexamic acid USP tablets 3900 mg/day and 67 subjects received placebo (subjects took at least one dose of study drug and had post-treatment data available).

Results are shown in Table 4. Menstrual blood loss (MBL) was statistically significantly reduced in patients treated with 3900 mg/day tranexamic acid USP tablets compared to placebo. Study success also required achieving a reduction in MBL that was determined to be clinically meaningful to the subjects.

The 1950 mg/day tranexamic acid USP tablets dose did not meet the criteria for success. Table 4. Mean Reduction from Baseline in Menstrual Blood Loss in Women with Heavy Menstrual Bleeding (Study 1) Treatment Arm N Baseline Mean MBL (mL) Least Squares Mean Reduction in MBL (mL) Percent Reduction in MBL Tranexamic acid USP tablets 3900 mg/day 112 169 65 p<0.001 versus placebo 39% Tranexamic acid USP tablets 1950 mg/day 115 178 44 25% Placebo 67 154 7 5% Tranexamic acid USP tablets also statistically significantly reduced limitations on social, leisure, and physical activities in the 3900 mg/day dose group compared to the placebo group (see Table 5 ).

No statistically significant treatment difference was observed in response rates on the number of large stains. Table 5: Secondary Outcomes in 3-Cycle Study in Women with Heavy Menstrual Bleeding (Study 1) Outcome Measure N Baseline Mean Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited Least Squares Mean Reduction Positive means reflect an improvement from baseline. Social and Leisure Activities 3900 mg/day tranexamic acid USP tablets 112 3.00 0.98 p-value <0.05 versus placebo Placebo 66 2.85

0.39Physical Activities 3900 mg/day tranexamic acid USP tablets 112 3.07

0.94Placebo 66 2.96

0.34N Responders Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains. Reduction in Large Stains 3900 mg/day tranexamic acid USP tablets 111 64% Non-significant difference versus placebo Placebo 67 52% 14.3… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies with tranexamic acid in male mice at doses as high as 6 times the recommended human dose of 3900 mg/day showed an increased incidence of leukemia which may have been related to treatment. Female mice were not included in this experiment. The dose multiple referenced above is based on body surface area (mg/m 2 ).

Actual daily dose in mice was up to 5000 mg/kg/day in food. Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses.

Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver. Mutagenesis Tranexamic acid was neither mutagenic nor clastogenic in the in vitro Bacterial Reverse Mutation Assay (Ames test), in vitro chromosome aberration test in Chinese hamster cells, and in in vivo chromosome aberration tests in mice and rats. Impairment of Fertility Reproductive studies performed in mice, rats and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid.

13.2Animal Toxicology and/or Pharmacology Ocular Effects In a 9-month toxicology study, dogs were administered tranexamic acid in food at doses of 0, 200, 600, or 1200 mg/kg/day. These doses are approximately 2, 5, and 6 times, respectively, the recommended human oral dose of 3900 mg/day based on AUC. At 6 times the human dose, some dogs developed reversible reddening and gelatinous discharge from the eyes.

Ophthalmologic examination revealed reversible changes in the nictitating membrane/conjunctiva. In some female dogs, the presence of inflammatory exudate over the bulbar conjunctival mucosa was observed. Histopathological examinations did not reveal any retinal alteration.

No adverse effects were observed at 5 times the human dose. In other studies, focal areas of retinal degeneration were observed in cats, dogs and rats following oral or intravenous tranexamic acid doses at 6–40 times the recommended usual human dose based on mg/m 2 (actual animal doses between 250–1600 mg/kg/day).