FDA label 98f71f3f-db32-5cc2-e053-2995a90aaba9

5 WARNINGS AND PRECAUTIONS Concomitant use of tranexamic acid tablets with Factor IX 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 effects may occur with tranexamic acid tablets. Immediately discontinue use if visual or ocular symptoms occur. ( 5.1 ) In case of severe allergic reaction, discontinue tranexamic acid tablets and seek immediate medical attention. ( 5.2 ) Cerebral edema and cerebral infarction may be caused by use of tranexamic acid tablets in women with subarachnoid hemorrhage. ( 5.3 ) Ligneous conjunctivitis has been reported in patients taking tranexamic acid. ( 5.4 ) 5.1 Thromboembolic Risk Concomitant Use of Hormonal Contraceptives Combination 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 tablets are antifibrinolytic, the risk of venous thromboembolism, as well as arterial thromboses such as stroke, may increase further when 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 hormonal contraception were excluded from the clinical trials supporting the safety and efficacy of tranexamic acid tablets, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of tranexamic acid tablets with 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 combination hormonal contraceptives. For this reason, concomitant use of tranexamic acid tablets with combination hormonal contraceptives is contraindicated. [see Contraindications ( 4.1 ) and Drug Interactions ( 7.1 )] . Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates Tranexamic acid tablets is not recommended for women 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 )] . All-Trans Retinoic Acid (Oral Tretinoin) Exercise caution when prescribing tranexamic acid tablets to women 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 )]. Ocular Effects Retinal venous and arterial occlusion has 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. 5.2 Severe Allergic Reaction A case of severe allergic reaction to tranexamic acid 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. 5.3 Subarachnoid Hemorrhage Cerebral edema and cerebral infarction may be caused by use of tranexamic acid tablets in women with subarachnoid hemorrhage. 5.4 Ligneous Conjunctivitis Ligneous conjunctivitis has been reported in patients taking tranexamic acid. The conjunctivitis resolved following cessation of the drug.

6 ADVERSE REACTIONS Most common adverse reactions in clinical trials (≥ 5%, and more frequent in tranexamic acid tablets subjects compared to placebo 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 Actavis at 1-800-272-5525 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. Short-term Studies The safety of tranexamic acid tablets in the treatment of heavy menstrual bleeding (HMB) was studied in two randomized, double-blind, placebo-controlled studies [see Clinical Studies ( 14 )] . One study compared the effects of two doses of tranexamic acid tablets (1950 mg and 3900 mg given daily 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. A second study 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. 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 BMI of approximately 32 kg/m 2 . On average, subjects had a history of HMB 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. The rates of discontinuation due to adverse events during the two clinical trials were comparable between tranexamic acid tablets and placebo. In the 3-cycle study, the rate in the 3900 mg tranexamic Acid tablets dose group was 0.8% as compared to 1.4% in the placebo group. In the 6-cycle study, the rate in the tranexamic acid tablets group was 2.4% as compared to 4.1% in the placebo group. 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. A list of adverse events occurring in ≥ 5% of subjects and more frequently in tranexamic acid tablets treated subjects receiving 3900 mg/day compared to placebo is provided in Table 2 . Table 2. Adverse Events Reported by ≥ 5% of Subjects Treated with Tranexamic Acid Tablets and More Frequently in Tranexamic Acid Tablets-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 Tranexamic Acid Tablets 3900 mg/day n (%) (N=232) Placebo n (%) (N=139) Total Number of Adverse Events 1500 923 Number of Subjects with at Least One Adverse Event 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%) Long-term Studies Long-term safety of tranexamic acid 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 events. 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 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 events. The total exposure to 3900 mg/day tranexamic acid tablets in this study was 1,956 cycles. The average duration of tranexamic acid tablets use was 3.5 days per cycle. The types and severity of adverse events 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 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. 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. Based on US and worldwide postmarketing reports, the following have been reported in patients receiving tranexamic acid for various indications: Nausea, vomiting, and diarrhea Allergic skin reactions Anaphylactic shock and anaphylactoid reactions 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 combination hormonal contraceptives Impaired color vision and other visual disturbances Dizziness

<table width="100%" ID="_Ref414963444"> <caption>Table 2. Adverse Events Reported by &#x2265; 5% of Subjects Treated with Tranexamic Acid Tablets and More Frequently in Tranexamic Acid Tablets-treated Subjects</caption> <colgroup> <col width="50%"/> <col width="29%"/> <col width="21%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="3" styleCode="Botrule" valign="top"> ^aIncludes headache and tension headache ^bNasal 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 ^cAbdominal pain includes abdominal tenderness and discomfort ^dMusculoskeletal pain includes musculoskeletal discomfort and myalgia ^eArthralgia includes joint stiffness and swelling </td> </tr> </tfoot> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph/> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Tranexamic </content> <content styleCode="bold">Acid Tablets</content> <content styleCode="bold">3900 mg/day </content> <content styleCode="bold">n (%)</content> <content styleCode="bold">(N=232)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">n (%)</content> <content styleCode="bold">(N=139)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Total Number of Adverse Events</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1500</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>923</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Number of Subjects with at Least One Adverse Event</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>208 (89.7%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>122 (87.8%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>HEADACHE ^a </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>117 (50.4%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>65 (46.8%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>NASAL &amp; SINUS SYMPTOMS ^b </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>59 (25.4%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>24 (17.3%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>BACK PAIN</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>48 (20.7%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>21 (15.1%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>ABDOMINAL PAIN ^c </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>46 (19.8%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>25 (18.0%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>MUSCULOSKELETAL PAIN ^d </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>26 (11.2%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>4 (2.9%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>ARTHRALGIA ^e </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>16 (6.9%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>7 (5.0%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>MUSCLE CRAMPS &amp; SPASMS</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>15 (6.5%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>8 (5.8%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>MIGRAINE</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>14 (6.0%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>8 (5.8%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>ANEMIA</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>13 (5.6%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>5 (3.6%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>FATIGUE</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>12 (5.2%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>6 (4.3%)</paragraph> </td> </tr> </tbody> </table>