Tranexamic Acid: Package Insert and Label Information (Page 3 of 4)

Drug Interactions

No drug-drug interaction studies were conducted with Tranexamic acid tablets.

Hormonal Contraceptives

Because Tranexamic acid tablets are antifibrinolytic, concomitant use of hormonal contraception and Tranexamic acid tablets may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. Women using hormonal contraception should use Tranexamic acid tablets only if there is a strong medical need and the benefit of treatment will outweigh the potential increased risk of a thrombotic event [see Warnings and Precautions ( 5.1) and Drug Interactions ( 7.1) ].

Factor IX Complex Concentrates or Anti-inhibitor Coagulant Concentrates

Tranexamic acid tablets are not recommended in patients taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Warnings and Precautions ( 5.4) and Drug Interactions(7.3)].

Tissue Plasminogen Activators

Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both Tranexamic acid tablets and tissue plasminogen activators. Therefore, exercise caution if a patient taking Tranexamic acid tablets therapy requires tissue plasminogen activators [see Drug Interactions(7.2)].

All-Trans Retinoic Acid (Oral Tretinoin)

In a study involving 28 patients with acute promyelocytic leukemia who were given either orally administered all-trans retinoic acid plus intravenously administered tranexamic acid, all-trans retinoic acid plus chemotherapy, or all-trans retinoic acid plus tranexamic acid plus chemotherapy, all 4 patients who were given all-trans retinoic acid plus tranexamic acid died, with 3 of the 4 deaths due to thrombotic complications. It appears that the procoagulant effect of all-trans retinoic acid may be exacerbated by concomitant use of tranexamic acid. Therefore, exercise caution when prescribing Tranexamic acid tablets to patients with acute promyelocytic leukemia taking all-trans retinoic acid [see Warnings and Precautions ( 5.5) and Drug Interactions ( 7.4) ].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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/m2). 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.

In a rat embryo-fetal developmental toxicity study, tranexamic acid had no adverse effects on embryo-fetal development when administered during the period of organogenesis (from gestation days 6 through 17) at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day. In a perinatal-postnatal study in rats, tranexamic acid had no adverse effects on pup viability, growth or development when administered from gestation day 6 through postnatal day 20 at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day.

The dose multiples referenced above are based on body surface area (mg/m2). Actual daily doses in rats were 300, 750 or 1500 mg/kg/day.

13.2 Animal 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/m2 (actual animal doses between 250-1600 mg/kg/day).

14 CLINICAL STUDIES

The efficacy and safety of Tranexamic acid tablets in the treatment of heavy menstrual bleeding (HMB) was demonstrated in one 3-cycle treatment and one 6-cycle treatment, randomized, double-blind, placebo-controlled study [see Adverse Reactions ( 6) ]. 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/m2. 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.

14.1 Three-Cycle Treatment Study

This study compared the effects of two doses of Tranexamic acid tablets (1950 mg and 3900 mg given daily 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 Tranexamic acid tablets 1950 mg/day subjects, 112 Tranexamic acid tablets 3900 mg/day subjects and 67 placebo subjects took at least one dose of study drug and had post-treatment data available.

Results are shown in Table 4. MBL was statistically significantly reduced in patients treated with 3900 mg/day Tranexamic acid 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 tablets dose did not meet the criteria for success.

Table 4. Mean Reduction from Baseline in MBL
Treatment Arm N Baseline Mean MBL (mL) Least Squares Mean Reduction in MBL (mL) Percent Reduction in MBL
Tranexamic acid tablets 3900 mg/day 112 169 65* 39%
Tranexamic acid tablets 1950 mg/day 115 178 44 25%
Placebo 67 154 7 5%

* p<0.001 versus placebo

Tranexamic acid tablets also statistically significantly reduced limitations on social, leisure, and physical activities in the 3900 mg/day dose group compared to placebo (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
Outcome Measure N Baseline Mean a Least Squares Mean Reduction b
Social and Leisure Activities
3900 mg/day Tranexamic acid tablets 112 3.00 0.98c
Placebo 66 2.85 0.39
Physical Activities
3900 mg/day Tranexamic acid tablets 112 3.07 0.94c
Placebo 66 2.96 0.34
N Responders d
Reduction in Large Stains
3900 mg/day Tranexamic acid tablets 111 64%e
Placebo 67 52%

a Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited

b Positive means reflect an improvement from baseline.

c p-value <0.05 versus placebo

d Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains.

e Non-significant difference versus placebo

14.2 Six-Cycle Treatment Study

This study compared the effects of Tranexamic acid tablets 3900 mg/day given daily for up to 5 days during each menstrual period versus placebo on MBL over a 6-cycle treatment duration. Of the 187 evaluable subjects, 115 Tranexamic acid tablets subjects and 72 placebo subjects took at least one dose of study drug and had post-treatment data available.

Results are shown in Table 6. MBL was statistically significantly reduced in patients treated with 3900 mg/day Tranexamic acid tablets compared to placebo. Study success also required achieving a reduction in MBL that was determined to be clinically meaningful to the subjects.

Table 6. Mean Reduction from Baseline in MBL
Treatment Arm N Baseline Mean MBL (mL) Least Squares Mean Reduction in MBL (mL) Percent Reduction in MBL
Tranexamic acid tablets 3900 mg/day 115 172 66* 38%
Placebo 72 153 18 12%

* p<0.001 versus placebo

Limitations on social, leisure, and physical activities were also statistically significantly reduced in the Tranexamic acid tablets group compared to placebo (see Table 7). No statistically significant treatment difference was observed in response rates on the number of large stains.

Table 7. Secondary Outcomes in 6-Cycle Study
Outcome Measure N Baseline Mean a Least Squares Mean Reduction b
Social and Leisure Activities
3900 mg/day Tranexamic acid tablets 115 2.92 0.85c
Placebo 72 2.74 0.44
Physical Activities
3900 mg/day Tranexamic acid tablets 115 3.05 0.87c
Placebo 72 2.90 0.40
N Responders d
Reduction in Large Stains
3900 mg/day Tranexamic acid tablets 115 57%e
Placebo 72 51%

a Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited

b Positive means reflect an improvement from baseline

c p-value <0.05 versus placebo

d Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains

e Non-significant difference versus placebo

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