Tranexamic Acid

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 )]. Tranexamic acid tablets are an antifibrinolytic indicated for the treatment of cyclic heavy menstrual bleeding in females of reproductive potential. ( 1 )

2 DOSAGE AND ADMINISTRATION 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 ) Cr above 1.4 mg/dL and ≤ 2.8 mg/dL: 1,300 mg two times a day (2,600 mg/day) Cr above 2.8 mg/dL and ≤ 5.7 mg/dL: 1,300 mg once a day (1,300 mg/day) 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

3 DOSAGE FORMS AND STRENGTHS Tranexamic acid tablets are provided as follows: 650 mg: White to off-white, oval-shaped, film-coated tablets debossed with “ WPI 3720 ” on one side of the tablet. Tablets: 650 mg ( 3 )

4 CONTRAINDICATIONS 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: Active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, or cerebral thrombosis) A history of thrombosis or thromboembolism, including retinal vein or artery occlusion 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 )].

6 ADVERSE REACTIONS Most common adverse reactions in clinical trials (≥ 5%, and more frequent in tranexamic acid tablets-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 Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 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 tablets 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 to 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 tablets-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 tablets-treated subjects and more frequently in tranexamic acid tablets-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 tablets was studied in two open-label studies. In one study …

7 DRUG INTERACTIONS 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 tablets and tissue plasminogen activators. ( 7.2 ) 7.1 Combined Hormonal Contraceptives Because tranexamic acid tablets are antifibrinolytic, concomitant use of combined hormonal contraception and tranexamic acid tablets 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 tablets 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 )] .

8 USE IN SPECIFIC POPULATIONS Geriatric use: Tranexamic acid tablets are not indicated for use in postmenopausal women ( 8.5 ) Renal impairment: A lower dosage is needed. ( 2.2 , 8.6 ) Hepatic impairment: No dosage adjustment is needed. ( 8.7 ) 8.1 Pregnancy Risk Summary Tranexamic acid tablets are not indicated for use in pregnant women . There are no available data on tranexamic acid tablets use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Tranexamic acid crosses the placenta. Animal reproduction studies have not identified adverse developmental outcomes with oral administration of tranexamic acid to pregnant rats at doses up to 4 times the recommended human dose (see Data) . In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data 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 twice daily doses of 0, 150, 375, and 750 mg/kg (1, 2 and 4 times the recommended human oral dosage of 3900 mg/day based on body surface area (mg/m 2 )). In a perinatal-postnatal developmental toxicity study in rats administered tranexamic acid from gestation day 6 through postnatal day 20 at twice daily doses of 0, 150, 375, and 750 mg/kg, no significant adverse effects on maternal behavior or body weight were observed, and no significant effects on pup viability, body weight, developmental milestones or adult fertility were observed. It was concluded that the no-observed-effect-level (NOEL) for this study was 1500 mg/kg/day in both F 0 and F 1 generations, which is equivalent to 4 times the recommended human oral dose of 3900 mg/day based on body surface area (mg/m 2 ). 8.2 Lactation Risk Summary Tranexamic acid is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentration (see Data). The amount of tranexamic acid a nursing infant would absorb is unknown. There are no adequate data on the effects of tranexamic acid on the breastfed infant or the effects of tranexamic acid on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tranexamic acid tablets and any potential adverse effects on the breast-fed child from tranexamic acid tablets or from the underlying maternal condition. Data Human Data One hour after the last dose following a 2-day treatment course in lactating women, the milk concentration of the tranexamic acid was 1% of the peak serum concentration. 8.4 Pediatric Use The safety and effectiveness of tranexamic acid tablets have been established in females of reproductive potential. Efficacy is expected to be the same for post-menarchal females under the age of 17 as for those 17 years and older. Tranexamic acid tablets are not indicated before menarche. 8.5 Geriatric Use Tranexamic acid tablets are indicated for females of reproductive potential and are not intended for use by postmenopausal women. 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of tranexamic acid tablets has not been studied. Because tranexamic acid is primarily eliminated via the kidneys by glomerular filtration with more than 95% excreted as unchanged in urine, the recommended dosage in patients with renal impairment is lower than the recommended dosage in patients with normal renal function [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of tranexamic acid tablets has not been studied. Because only a small fraction of the drug is metabolized, the recommended dosage in patients with hepatic impairment is the same as in pat …

12.1 Mechanism of Action Tranexamic acid is a synthetic lysine amino acid derivative, which diminishes the dissolution of hemostatic fibrin by plasmin. In the presence of tranexamic acid, the lysine receptor binding sites of plasmin for fibrin are occupied, preventing binding to fibrin monomers, thus preserving and stabilizing fibrin’s matrix structure. The antifibrinolytic effects of tranexamic acid are mediated by reversible interactions at multiple binding sites within plasminogen. Native human plasminogen contains 4 to 5 lysine binding sites with low affinity for tranexamic acid (K d = 750 μmol/L) and 1 with high affinity (K d = 1.1 μmol/L). The high affinity lysine site of plasminogen is involved in its binding to fibrin. Saturation of the high affinity binding site with tranexamic acid displaces plasminogen from the surface of fibrin. Although plasmin may be formed by conformational changes in plasminogen, binding to and dissolution of the fibrin matrix is inhibited.

11 DESCRIPTION Tranexamic acid tablets 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 N0 2 and the molecular weight is 157.2. Tranexamic acid tablets are provided as white to off-white, oval-shaped, film-coated tablets, debossed with “ WPI 3720 ” on one side of the tablet. The active ingredient in each tablet is 650 mg tranexamic acid, USP. The inactive ingredients contained in each tablet are: colloidal silicon dioxide, copovidone, crospovidone, dimethylaminoethyl methacrylate - butyl methacrylate - methyl methacrylate copolymer, glyceryl dibehenate, lactose monohydrate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polyethylene glycol 8000, talc, and triethyl citrate. Structural Formula for Tranexamic Acid

10 OVERDOSAGE There are no known cases of intentional overdose with tranexamic acid tablets and no subjects in the clinical program took more than 2 times the prescribed amount of tranexamic acid tablets in a 24-hour period (>7800 mg/day). However, cases of overdose of tranexamic acid have been reported. Based on these reports, symptoms of overdose may include gastrointestinal (nausea, vomiting, diarrhea); hypotensive (e.g., orthostatic symptoms); thromboembolic (arterial, venous, embolic); visual impairment; mental status changes; myoclonus; or rash. No specific information is available on the treatment of overdose with tranexamic acid tablets. In the event of overdose, employ the usual supportive measures (e.g., clinical monitoring and supportive therapy) as dictated by the patient's clinical status.

HOW SUPPLIED Tranexamic acid tablets are provided as white to off-white, oval-shaped, unscored, film coated 650 mg tablets. Each tablet is debossed with WPI 3720 on one side of the tablet and are supplied as: Quantity Pacakage Type NDC Number 30 tablets HDPE Bottle 63629-8838-1 Storage Store at 20o to 25o C (68o to 77o F). [See USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504