Tranexamic Acid: Package Insert and Label Information

TRANEXAMIC ACID- tranexamic acid tablet
ANI Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Tranexamic Acid Tablets are indicated for the treatment of cyclic heavy menstrual bleeding in females of reproductive potential [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Testing Prior to Tranexamic Acid Tablets Administration

Prior to prescribing tranexamic acid tablets, exclude endometrial pathology that can be associated with heavy menstrual bleeding.

2.2 Recommended Dosage

The recommended dosage of tranexamic acid tablets for patients with normal renal function is 1300 mg orally three times daily (3900 mg/day) for a maximum of 5 days during monthly menstruation. Tranexamic acid tablets may be administered with or without food. Swallow tablets whole; do not chew or break apart.

2.3 Dosage Recommendations in Patients with Renal Impairment

The recommended dosage (for a maximum of 5 days during monthly menstruation) in patients with renal impairment with serum creatinine concentration higher than 1.4 mg/dL is described in Table 1.

Table 1. Recommended Dosage of Tranexamic Acid Tablets in Patients with Renal Impairment

Serum Creatinine (mg/dL)

Recommended Dosage(maximum of 5 days during menstruation)

Total Daily Dose

Above 1.4 and ≤ 2.8

1300 mg two times a day

2600 mg

Above 2.8 and ≤ 5.7

1300 mg once a day

1300 mg

Above 5.7

650 mg once a day

650 mg

3 DOSAGE FORMS AND STRENGTHS

Tablets: 650 mg white to off-white, oval, unscored tablets debossed with “AMG229” on one side with the other side blank.

4 CONTRAINDICATIONS

4.1 Thromboembolic Risk

Tranexamic acid tablets are contraindicated in females of reproductive potential who are [see Warnings and Precautions (5.1)]:

Using combined hormonal contraception
Known to have any of the following conditions:
o
Active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, or cerebral thrombosis)
o
A history of thrombosis or thromboembolism, including retinal vein or artery occlusion
o
An intrinsic risk of thrombosis or thromboembolism (e.g., thrombogenic valvular disease, thrombogenic cardiac rhythm disease, or hypercoagulopathy)

4.2 Hypersensitivity to Tranexamic Acid

Tranexamic acid tablets are contraindicated in females with reproductive potential with known hypersensitivity to tranexamic acid [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Risk

Venous and arterial thrombosis or thromboembolism, as well as cases of retinal artery and retinal vein occlusions, have been reported with tranexamic acid.

Retinal venous and arterial occlusion have been reported in patients using tranexamic acid. Patients should be instructed to report visual and ocular symptoms promptly. In the event of such symptoms, patients should be instructed to discontinue tranexamic acid tablets immediately and should be referred to an ophthalmologist for a complete ophthalmic evaluation, including dilated retinal examination, to exclude the possibility of retinal venous or arterial occlusion.

Concomitant Use of Hormonal Contraceptives
Combined hormonal contraceptives are known to increase the risk of venous thromboembolism, as well as arterial thromboses such as stroke and myocardial infarction. Because tranexamic acid is antifibrinolytic, the risk of venous thromboembolism, as well as arterial thromboses such as stroke, may increase further when combined hormonal contraceptives are administered with tranexamic acid tablets. This is of particular concern in women who are obese or smoke cigarettes, especially smokers over 35 years of age.

Women using combined hormonal contraception were excluded from the clinical trials supporting the safety and efficacy of tranexamic acid, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of tranexamic acid tablets with combined hormonal contraceptives. However, there have been US postmarketing reports of venous and arterial thrombotic events in women who have used tranexamic acid tablets concomitantly with combined hormonal contraceptives. For this reason, concomitant use of tranexamic acid tablets with combined hormonal contraceptives is contraindicated [see Contraindications (4.1) and Drug Interactions (7.1)].

Concomitant Use with 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 Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

Patients with Acute Promyelocytic Leukemia Taking Concomitant All-Trans Retinoic Acid (Oral Tretinoin)
Tranexamic acid tablets are not recommended in patients with acute promyelocytic leukemia taking all-trans retinoic acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

5.2 Severe Allergic Reactions

A case of severe allergic reaction to tranexamic acid was reported in the clinical trials, involving a subject who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment. A case of anaphylactic shock has also been reported in the literature, involving a patient who received an intravenous bolus of tranexamic acid. Tranexamic acid tablets are contraindicated in females of reproductive potential with known hypersensitivity to tranexamic acid.

5.3 Subarachnoid Hemorrhage

Cerebral edema and cerebral infarction may be caused by use of tranexamic acid in patients with subarachnoid hemorrhage.

5.4 Ligneous Conjunctivitis

Ligneous conjunctivitis has been reported in patients taking tranexamic acid. The conjunctivitis resolved following cessation of tranexamic acid tablets.

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions in Short-term StudiesThe safety of tranexamic acid in the treatment of heavy menstrual bleeding in females of reproductive potential was studied in two randomized, double-blind, placebo-controlled studies [see Clinical Studies (14)].

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 over a 3-cycle treatment duration. A total of 304 women were randomized to this study, with 115 receiving at least one dose of 3900 mg/day of tranexamic acid tablets.
Study 2 compared the effects of tranexamic acid tablets (3900 mg/day) versus placebo over a 6-cycle treatment duration. A total of 196 women were randomized to this study, with 117 receiving at least one dose of tranexamic acid tablets.

Across the studies, the combined exposure to 3900 mg/day tranexamic acid tablets was 947 cycles and the average duration of use was 3.4 days per cycle. In both studies, subjects were generally healthy women who had menstrual blood loss of ≥ 80 mL. In these studies, 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 body mass index (BMI) of approximately 32 kg/m2. On average, subjects had a history of heavy menstrual bleeding for 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. Women using hormonal contraception were excluded from the trials.

A list of adverse reactions occurring in ≥ 5% of subjects and more frequently in tranexamic acid-treated subjects receiving 3900 mg/day compared to placebo-treated subjects is provided in Table 2.

Table 2. Adverse Reactions* Reported in Women with Heavy Menstrual Bleeding (Studies 1 and 2)

Tranexamic Acid Tablets3900 mg/dayn (%) (N=232)

Placebon (%)(N=139)

Number of Subjects with at Least One Adverse Reaction

208 (89.7%)

122 (87.8%)

Headache a

117 (50.4%)

65 (46.8%)

Nasal & sinus symptoms b

59 (25.4%)

24 (17.3%)

Back pain

48 (20.7%)

21 (15.1%)

Abdominal pain c

46 (19.8%)

25 (18.0%)

Musculoskeletal pain d

26 (11.2%)

4 (2.9%)

Arthralgia e

16 (6.9%)

7 (5.0%)

Muscle cramps & spasms

15 (6.5%)

8 (5.8%)

Migraine

14 (6.0%)

8 (5.8%)

Anemia

13 (5.6%)

5 (3.6%)

Fatigue

12 (5.2%)

6 (4.3%)

* Adverse reactions that were reported by ≥ 5% of tranexamic acid-treated subjects and more frequently in tranexamic acid-treated subjects compared to placebo-treated subjects
a Includes headache and tension headache
b Nasal and sinus symptoms include nasal, respiratory tract and sinus congestion, sinusitis, acute sinusitis, sinus headache, allergic sinusitis and sinus pain, and multiple allergies and seasonal allergies
c Abdominal pain includes abdominal tenderness and discomfort
d Musculoskeletal pain includes musculoskeletal discomfort and myalgia
e Arthralgia includes joint stiffness and swelling

Adverse Reactions in Long-term Studies
Long-term safety of tranexamic acid was studied in two open-label studies. In one study, subjects with physician-diagnosed heavy menstrual bleeding (not using the alkaline hematin methodology) were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 27 menstrual cycles. A total of 781 subjects were enrolled and 239 completed the study through 27 menstrual cycles. A total of 12.4% of the subjects withdrew due to adverse reactions. Women using hormonal contraception were excluded from the study. The total exposure in this study to 3900 mg/day tranexamic acid tablets was 10,213 cycles. The average duration of tranexamic acid tablet use was 2.9 days per cycle.

A long-term open-label extension study of subjects from the two short-term efficacy studies was also conducted in which subjects were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 9 menstrual cycles. A total of 288 subjects were enrolled and 196 subjects completed the study through 9 menstrual cycles. A total of 2.1% of the subjects withdrew due to adverse reactions. The total exposure to 3900 mg/day tranexamic acid tablets in this study was 1,956 cycles. The average duration of tranexamic acid tablet use was 3.5 days per cycle.

The types and severity of adverse reactions in these two long-term open-label trials were similar to those observed in the double-blind, placebo-controlled studies although the percentage of subjects reporting them was greater in the 27-month study, most likely because of the longer study duration.

A case of severe allergic reaction to tranexamic acid was reported in the extension trial, involving a subject on her fourth cycle of treatment, who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment.

6.2 Postmarketing Experience

The following adverse reactions have been identified from postmarketing experience with tranexamic acid tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye disorders: Impaired color vision and other visual disturbances
Gastrointestinal disorders: Nausea, vomiting, and diarrhea
Immune system disorders: Anaphylactic shock and anaphylactoid reactions
Nervous system disorders: Dizziness
Skin and subcutaneous tissue disorders: Allergic skin reactions
Vascular disorders: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction); cases have been
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