Tranexamic Acid

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

Tablets: 650 mg white oval-shaped debossed with the marking “FP650” Tablets: 650 mg ( 3 )

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 USP 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 USP 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) ] .

Thromboembolism, including retinal occlusion, has been reported with tranexamic acid USP tablets use. Concomitant use of tranexamic acid USP tablets with combined hormonal contraceptives, Factor I X complex concentrates, anti-inhibitor coagulant concentrates or all-trans retinoic acid (oral tretinoin) may increase the risk of thrombosis. ( 5.1 ) Visual or ocular adverse reactions may occur with tranexamic acid USP tablets. Immediately discontinue use if visual or ocular symptoms occur. ( 5.1 ) In case of severe allergic reaction, discontinue tranexamic acid USP tablets and seek immediate medical attention. ( 5.2 ) Cerebral edema and cerebral infarction may be caused by use of tranexamic acid USP tablets in patients with subarachnoid hemorrhage. ( 5.3 ) Ligneous conjunctivitis has been reported in patients taking tranexamic acid. ( 5.4 )

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 USP tablets. 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 USP 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 USP tablets are 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 USP 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 USP tablets, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of tranexamic acid USP 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 USP tablets concomitantly with combined hormonal contraceptives. For this reason, concomitant use of tranexamic acid with combined hormonal contraceptives is contraindicated [see Contraindications (4.1) and Drug Interactions (7.1) ]. Concomitant Use with Factor I X Complex Concentrates or Anti-Inhibitor Coagulant Concentrates Tranexamic acid USP tablets are not recommended in patients taking either Factor I X 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 USP 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 USP tablets 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 USP 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 USP tablets 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 USP tablets.

Most common adverse reactions in clinical trials (≥ 5%, and more frequent in tranexamic acid USP 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 Nordic Pharma, Inc. at 1-844-267-4641 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 USP 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 USP 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 USP tablets. Study 2 compared the effects of tranexamic acid USP 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 USP tablets. Across the studies, the combined exposure to 3900 mg/day tranexamic acid USP 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 USP 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 USP tablets 3900 mg/day n (%) (N=232) Placebo n (%) (N=139) * Adverse reactions that were reported by ≥ 5% of tranexamic acid USP tablets-treated subjects and more frequently in tranexamic acid USP 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 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 in Long-term Studies Long-term safety of tranexamic acid USP tablets 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 USP tablets was 10,213 cycles. The average duration of tranexamic acid USP tablets 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 USP tablets in this study was 1,956 cycles. The average duration of tranexamic acid USP tablets 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 USP tablets 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 USP 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 associated with concomitant use of combined hormonal contraceptives

No drug-drug interaction studies were conducted with tranexamic acid USP tablets. Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both tranexamic acid USP tablets and tissue plasminogen activators. ( 7.2 )

7.1 Combined Hormonal Contraceptives Because tranexamic acid USP tablets are antifibrinolytic, concomitant use of combined hormonal contraception and tranexamic acid USP tablets may increase the thrombotic risk associated with combined hormonal contraceptives. For this reason, concomitant use of tranexamic acid USP 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 USP tablets and tissue plasminogen activators. Discontinue tranexamic acid USP tablets if a patient requires tissue plasminogen activators.

7.3 Factor I X Complex Concentrates or Anti-Inhibitor Coagulant Concentrates Tranexamic acid USP tablets are not recommended in patients taking either Factor I X 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 USP 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) ].

Geriatric use: Tranexamic acid USP tablets is 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 USP tablets are not indicated for use in pregnant women. There is no available data on tranexamic acid USP 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 USP tablets and any potential adverse effects on the breast-fed child from tranexamic acid USP 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 USP 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 USP tablets are not indicated before menarche.

8.5 Geriatric Use Tranexamic acid USP tablets are indicated for females of reproductive potential and is not intended for use by postmenopausal women.

8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of tranexamic acid USP 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 patient 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 USP 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 patients with normal hepatic function [see Clinical Pharmacology (12.3) ].

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.