TRANEXAMIC ACID

Tranexamic Acid Tablets USP are an antifibrinolytic drug administered orally. The chemical name is trans-4-aminomethyl‑cyclohexanecarboxylic acid. The structural formula is: Tranexamic acid USP is a white crystalline powder. It is freely soluble in water and in glacial acetic acid and is very slightly soluble in ethanol and practically insoluble in ether. The molecular formula is C 8 H 15 NO 2 and the molecular weight is 157.2. Tranexamic Acid Tablets USP are provided as white to off-white, oval, unscored tablets debossed with “AMG229” on one side with the other side blank. The active ingredient in each tablet is 650 mg tranexamic acid USP. The inactive ingredients contained in each tablet are: hypromellose, microcrystalline cellulose, povidone, colloidal silicon dioxide, stearic acid, and magnesium stearate. Tranexamic Acid Tablets USP meet USP Dissolution Test 3 .

Tranexamic Acid Tablets are indicated for the treatment of cyclic heavy menstrual bleeding in females of reproductive potential [see Clinical Studies ( 14 )]. Tranexamic Acid Tablets are an antifibrinolytic indicated for the treatment of cyclic heavy menstrual bleeding in females of reproductive potential. ( 1 )

• 1,300 mg three times a day (3,900 mg/day) for a maximum of 5 days during monthly menstruation ( 2.1 ) • Renal impairment : Lower dosage is needed (for a maximum of 5 days during menstruation) if serum creatinine concentration (Cr) is higher than 1.4 mg/dL ( 2.2 ) o Cr above 1.4 mg/dL and ≤ 2.8 mg/dL: 1,300 mg two times a day (2,600 mg/day) o Cr above 2.8 mg/dL and ≤ 5.7 mg/dL: 1,300 mg once a day (1,300 mg/day) o Cr above 5.7 mg/dL: 650 mg once a day (650 mg/day) 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

• Concomitant use of combined hormonal contraceptives ( 4.1 ) • Active thromboembolic disease or a history or intrinsic risk of thrombosis or thromboembolism, including retinal vein or artery occlusion ( 4.1 ) • Hypersensitivity to tranexamic acid ( 4.2 ) 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 )].

Most common adverse reactions in clinical trials (≥ 5%, and more frequent in tranexamic acid-treated subjects compared to placebo-treated subjects) are headache, sinus and nasal symptoms, back pain, abdominal pain, musculoskeletal pain, joint pain, muscle cramps, migraine, anemia and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Studies The 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/m 2 . 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 Tablets 3900 mg/day n (%) (N=232) Placebo n (%) (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

No drug-drug interaction studies were conducted with tranexamic acid tablets. Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both tranexamic acid and tissue plasminogen activators. ( 7.2 ) 7.1 Combined Hormonal Contraceptives Because tranexamic acid is antifibrinolytic, concomitant use of combined hormonal contraception and tranexamic acid may increase the thrombotic risk associated with combined hormonal contraceptives. For this reason, concomitant use of tranexamic acid tablets with combined hormonal contraceptives is contraindicated [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. 7.2 Tissue Plasminogen Activators Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both tranexamic acid and tissue plasminogen activators. Discontinue tranexamic acid tablets if a patient requires tissue plasminogen activators. 7.3 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 ( 5.1 )]. 7.4 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 Warnings and Precautions ( 5.1 )].