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/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.

13.2 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/m 2 (actual animal doses between 250-1600 mg/kg/day).

14 CLINICAL STUDIES

14.1 Overview 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/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 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.

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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.

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14.3 Heavy Menstrual Bleeding in the Six-Cycle Treatment Study

Study 2 compared the effects of tranexamic acid USP 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 USP 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 USP 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
*
p<0.001 versus placebo
Tranexamic acid USP tablets 3900 mg/day 115 172 66 * 38%
Placebo 72 153 18 12%

Limitations on social, leisure, and physical activities were also statistically significantly reduced in the tranexamic acid USP 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
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
Social and Leisure Activities
3900 mg/day tranexamic acid USP tablets 115 2.92 0.85 c
Placebo 72 2.74 0.44
Physical Activities
3900 mg/day tranexamic acid USP tablets 115 3.05 0.87 c
Placebo 72 2.90 0.40
N Responders d
Reduction in Large Stains
3900 mg/day tranexamic acid USP tablets 115 57% e
Placebo 72 51%

14.4 Heavy Menstrual Bleeding Results over Time

The efficacy of tranexamic acid USP 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
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16 HOW SUPPLIED/STORAGE AND HANDLING

Tranexamic acid USP tablets are provided as white oval-shaped 650 mg tablets. Each tablet is debossed with the marking “FP650”and are supplied as:

NDC 50268-772-13 (10 tablets per card, 3 cards per carton).

Dispensed in Unit Dose Package. For Institutional Use Only.

Storage

Store at room temperature 25° C (77° F); excursions permitted to 15-30° C (59-86° 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 USP 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 USP 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 USP tablets [see Warnings and Precautions (5.1)].

Severe Allergic Reactions
Inform patients that they should stop tranexamic acid USP 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 USP tablets only during menstruation and for a maximum of 5 days each month [see Recommended Dosage (2.1)].

Manufactured for:
AvKARE
Pulaski, TN 38478

Mfg. Rev. 12/20
AV 09/22 (W)
AvPAK

PATIENT INFORMATION

TRANEXAMIC ACID (TRAN-ex-AM-ik AS-id), USP TABLETS, for oral use

Read the Patient Information that comes with tranexamic acid USP tablets before you start using the drug and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is tranexamic acid USP tablets?

Tranexamic acid USP tablets is a prescription medicine used to treat your heavy monthly period (menstruation) when your bleeding gets in the way of social, leisure and physical activities. Tranexamic acid USP tablets does not contain any hormones. On average, tranexamic acid USP tablets has been shown to lower the amount of blood lost during your monthly period by about one-third, but it is not meant to stop your period.

Tranexamic acid USP tablets is taken only during your period and is not meant to treat pre-menstrual symptoms (symptoms that occur before your bleeding starts). Tranexamic acid USP tablets does not affect your fertility and cannot be used as birth control. Tranexamic acid USP tablets does not protect you against diseases that you may get if you have unprotected sex.

Tranexamic acid USP tablets has not been studied in adolescents younger than 18 years of age.

Tranexamic acid is not for women who have already gone through menopause (post-menopausal).

Who should not take tranexamic acid USP tablets?

Do not take tranexamic acid USP tablets if you:

  • Are using a form of birth control that contains estrogen and a progestin (like a birth control pill, patch, or vaginal ring). Ask your healthcare provider before taking tranexamic acid USP tablets if you are not sure if your birth control method contains estrogen and a progestin.
  • Currently have a blood clot
  • Have ever had a blood clot
  • Have been told that you are at risk of having a blood clot
  • Are allergic to tranexamic acid

What should I tell my healthcare provider before taking tranexamic acid USP tablets?

Before taking tranexamic acid USP tablets, tell your healthcare provider about all of your medical conditions, including whether:

  • You have ever had a blood clot or been told that you are at risk of having a blood clot
  • You are using a form of birth control that contains estrogen and a progestin (like a birth control pill, patch, or vaginal ring). Using hormonal birth control along with tranexamic acid USP tablets may increase your chance of having a serious blood clot, stroke, or heart attack. For this reason, do not use tranexamic acid USP tablets if you use a form of birth control that contains estrogen and a progestin.
  • You are pregnant or think you may be pregnant
  • You are breastfeeding or plan to breast-feed. Tranexamic acid USP tablets can pass into your milk. Talk to your healthcare provider about the best way to feed your baby if you take tranexamic acid USP tablets.
  • The time between the start of your periods is less than 21 days or more than 35 days
  • You have any other medical conditions

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tranexamic acid USP tablets and other medicines can affect each other, causing side effects. Tranexamic acid USP tablets can affect the way other medicines work and other medicines can affect how tranexamic acid USP tablets works.

Especially tell your healthcare provider if you take:

  • Birth control pills or other hormonal birth control
  • Medicines used to help your blood form clots
  • Medicines used to break up blood clots
  • Any medicines to treat leukemia

Ask your healthcare provider if you are not sure if your medicine is one that is described above.

How should I take tranexamic acid USP tablets?

  • Take tranexamic acid USP tablets exactly as your healthcare provider tells you.
  • Do not take tranexamic acid USP tablets until your period has started.
  • Do not take tranexamic acid USP tablets for more than 5 days in a row.
  • Do not take tranexamic acid USP tablets when you do not have your period.
  • Once your period has started, take 2 tablets of tranexamic acid USP tablets three times per day (e.g., in the morning, afternoon, and evening).
  • Tranexamic acid USP tablets should be swallowed whole and not chewed or broken apart.
  • Tranexamic acid USP tablets may be taken with or without food.
  • Do not take more than 6 tablets of tranexamic acid USP tablets in a day. If you take more than 6 tablets, call your healthcare provider.
  • If you miss a dose, take it when you remember, and then take your next dose at least six hours later. Do not take more than two tablets at a time to make up for missed doses.
  • If tranexamic acid USP tablets does not help to lessen bleeding with your periods after 2 cycles or seems to stop working, talk to your healthcare provider.

What are the possible side effects of tranexamic acid USP tablets?

Tranexamic acid USP tablets can cause serious side effects, including:

  • Blood clots. You may have a higher risk of having serious blood clots if you take tranexamic acid USP tablets with:
    • medicines used to help your blood form clots
    • some medicines used to treat leukemia
  • Eye changes. Stop taking tranexamic acid USP tablets and promptly report any eye problems you have while taking tranexamic acid USP tablets. Your doctor will refer you to an eye doctor who will examine your eyes.
  • Allergic reaction. If you have severe shortness of breath and your throat feels tight, stop taking tranexamic acid USP tablets and get medical care right away.

The most common side effects of tranexamic acid USP tablets include:

  • Headaches
  • Sinus and nasal problems
  • Back pain
  • Pain in your abdomen
  • Pain in your muscles or joints
  • Anemia
  • Fatigue

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects of tranexamic acid USP tablets. For more information, ask your healthcare provider or pharmacist.

If you notice a change in your usual bleeding pattern that worries you, or your heavy bleeding continues, contact your healthcare provider right away. This may be a sign of a more serious condition.

Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects to Amring Pharmaceuticals Inc. at 1-844-Amring1 (1-844-267-4641).

How should I store tranexamic acid USP tablets?

Store tranexamic acid USP tablets at room temperature between 59°F to 86°F (15°C to 30°C).

Keep tranexamic acid USP tablets and all medicines out of the reach of children.

General information about tranexamic acid USP tablets

Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information Leaflets. Do not use tranexamic acid USP tablets for a condition for which it was not prescribed. Do not give tranexamic acid USP tablets to other people, even if they have the same symptoms that you have. It may harm them.

This patient information leaflet summarizes the most important information about tranexamic acid USP tablets. If you would like more information about tranexamic acid USP tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about tranexamic acid USP tablets that is written for healthcare professionals. For more information, call AvKARE at 1-855-361-3993.

What are the ingredients of tranexamic acid USP tablets?

Active ingredient: tranexamic acid

Inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, pregelatinized corn starch, povidone, hypromellose, stearic acid, and magnesium stearate.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for:
AvKARE
Pulaski, TN 38478

Mfg. Rev. 12/20
AV 09/22 (W) AvPAK

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