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

13.2 Animal Toxicology and/or Pharmacology

Ocular EffectsIn 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

14.1 Overview of the Clinical Studies

The efficacy of tranexamic acid 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/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.

14.2 Heavy Menstrual Bleeding in the Three-Cycle Treatment Study

Study 1 compared the effects of two doses of tranexamic acid 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 tablets 1950 mg/day, 112 subjects received tranexamic acid 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 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 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 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 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 a

Least Squares Mean Reduction b

Social and Leisure Activities 3900 mg/day tranexamic acid tablets Placebo

Physical Activities 3900 mg/day tranexamic acid tablets Placebo

11266 11266

3.002.85 3.072.96

0.98c 0.39 0.94c 0.34

N

Responders d

Reduction in Large Stains 3900 mg/day tranexamic acid tablets Placebo

11167

64%e 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

14.3 Heavy Menstrual Bleeding in the Six-Cycle Treatment Study

Study 2 compared the effects of tranexamic acid tablets 3900 mg/day given daily for up to 5 days during each menstrual period versus placebo on menstrual blood loss (MBL) over a 6-cycle treatment duration. Of the 187 evaluable subjects, 115 subjects received tranexamic acid tablets and 72 subjects received 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 Menstrual Blood Loss in Women with Heavy Menstrual Bleeding (Study 2)

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 in Women with Heavy Menstrual Bleeding (Study 2)

Outcome Measure

N

Baseline Mean a

Least Squares Mean Reduction b

Social and Leisure Activities 3900 mg/day tranexamic acid tablets PlaceboPhysical Activities 3900 mg/day tranexamic acid tablets Placebo

11572 11572

2.922.74 3.052.90

0.85c 0.44 0.87c 0.40

N

Responders d

Reduction in Large Stains 3900 mg/day tranexamic acid tablets Placebo

11572

57%e 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

14.4 Heavy Menstrual Bleeding Results over Time

The efficacy of tranexamic acid tablets 3900 mg/day over 3 menstrual cycles and over 6 menstrual cycles was demonstrated versus placebo in Studies 1 and 2 (see Figure 1). The change in menstrual bleeding loss from baseline was similar across all post-baseline treatment cycles.

Figure 1: Menstrual Bleeding Loss Levels over Duration of Therapy in Women with Heavy Menstrual Bleeding (Studies 1 and 2)

Figure 1
(click image for full-size original)
Figure 1

16 HOW SUPPLIED/STORAGE AND HANDLING

Tranexamic acid tablets USP 650 mg are provided as white to off-white, oval, unscored tablets debossed with “AMG229” on one side with the other side blank and are supplied in bottles of 30 (NDC 62559-265-30).

StorageStore at 20° to 25°C (68° to 77°F); excursions permitted at 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Thromboembolic Risk

Inform patients that tranexamic acid tablets may increase the risk of venous and arterial thrombosis or thromboembolism and to contact their healthcare provider for any signs or symptoms suggestive of thromboembolism [see Warnings and Precautions (5.1)].

Advise patients to discontinue use of tranexamic acid tablets and promptly report visual and ocular symptoms to their health care provider as retinal venous and arterial occlusion have been reported in patients using tranexamic acid tablets [see Warnings and Precautions (5.1)].

Severe Allergic Reactions

Inform patients that they should stop tranexamic acid tablets and seek immediate medical attention if they notice symptoms of a severe allergic reaction (e.g., shortness of breath or throat tightening) [see Warnings and Precautions (5.2)].

Administration Instructions

Instruct patients to take tranexamic acid tablets only during menstruation and for a maximum of 5 days each month [see Recommended Dosage (2.1)].

Manufactured by:

Suzhou Amerigen Pharmaceutical Co. Ltd.

Jiangsu, China 215006

Distributed by:

ANI Pharmaceuticals, Inc.

10405 Rev 01/21

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