TRANEXAMIC ACID IN SODIUM CHLORIDE

1 INDICATIONS AND USAGE Tranexamic acid in 0.7% sodium chloride injection is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. Tranexamic acid in 0.7% sodium chloride injection is an antifibrinolytic indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. ( 1 )

2 DOSAGE AND ADMINISTRATION Before Extraction: Administer 10 mg/kg actual body weight of tranexamic acid in 0.7% sodium chloride injection intravenously with replacement therapy. After Extraction: Administer 10 mg/kg actual body weight 3 to 4 times daily for 2 to 8 days. Infuse no more than 10 mL/minute to avoid hypotension. ( 2.1 ) Reduce the dosage for patients with renal impairment. ( 2.2 , 8.6 ) 2.1 Recommended Dosage The recommended dose of tranexamic acid in 0.7% sodium chloride injection is 10 mg/kg actual body weight intravenously administered as a single-dose, immediately before tooth extractions. Infuse no more than 10 mL/minute to avoid hypotension [see Warnings and Precautions (5.1) ] . Following tooth extraction, tranexamic acid in 0.7% sodium chloride injection may be administered for 2 to 8 days at a dose of 10 mg/kg actual body weight three to four times daily, intravenously. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use tranexamic acid in 0.7% sodium chloride injection if particulate matter or coloration is seen. Tranexamic acid in 0.7% sodium chloride injection should NOT be mixed with blood. The drug is a synthetic amino acid and should NOT be mixed with solutions containing penicillin. The premix non-PVC bag contains no preservative; discard any unused portion. 2.2 Recommended Dosage for Patients with Varying Degrees of Renal Impairment * For patients with moderate to severe impaired renal function, the following dosages are recommended: Table 1: Recommended Dosage in Patients with Varying Degrees of Renal Impairment Serum Creatinine (mg/dL) Tranexamic Acid in 0.7% Sodium Chloride Injection Intravenous Dosage 1.36 to 2.83 (120 to 250 micromol/L) 10 mg/kg twice daily 2.83 to 5.66 (250 to 500 micromol/L) 10 mg/kg daily > 5.66 (> 500 micromol/L) 10 mg/kg every 48 hours or 5 mg/kg every 24 hours * Dose reduction is recommended for all doses, both before and after tooth extraction.

5 WARNINGS AND PRECAUTIONS Risk of thrombosis with concomitant use of Factor IX: Avoid concomitant use. ( 5.1 ) Seizures: Inadvertent injection into neuraxial system may result in seizures. ( 5.2 ) Hypersensitivity Reactions: In case of severe reaction, discontinue use and seek immediate medical attention. ( 5.3 ) Visual Disturbances: Visual or ocular adverse effects may occur. Discontinue use if visual or ocular symptoms occur. ( 5.4 ) Dizziness. Advise patients not to drive if dizziness occurs. ( 5.5 ) 5.1 Thromboembolic Risk Tranexamic acid in 0.7% sodium chloride injection is contraindicated in patients with active intravascular clotting. Tranexamic acid is an antifibrinolytic and may increase the risk of thromboembolic events. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid. Avoid concomitant use of tranexamic acid in 0.7% sodium chloride injection and medical products that are pro-thrombotic, as the risk of thrombosis may be increased. These medications include but are not limited to, Factor IX Complex concentrates, Anti-inhibitor coagulant concentrates and hormonal contraceptives [see Drug Interactions (7.1) , Use in Specific Populations (8.3) ] . 5.2 Seizures Tranexamic acid may cause seizures, including focal and generalized seizures. The most common setting for tranexamic acid-induced seizures has been during cardiovascular surgery (a setting in which tranexamic acid in 0.7% sodium chloride injection is not FDA approved and which uses doses of up to ten-fold higher than the recommended human dose and in patients inadvertently given tranexamic acid into the neuraxial system). Tranexamic acid in 0.7% sodium chloride injection is not approved and not recommended for neuraxial administration. Consider dose reduction during surgery and dose adjustments for patients with clinical conditions such as renal dysfunction. Closely monitor the patient during surgery. Consider electroencephalogram (EEG) monitoring for patients with history of seizures or who experience myoclonic movements, twitching, or show evidence of focal seizures. Discontinue tranexamic acid in 0.7% sodium chloride injection if seizures occur. 5.3 Hypersensitivity Reactions Cases of hypersensitivity reactions, including anaphylactic reactions, have occurred with use of intravenous tranexamic acid. Discontinue treatment with tranexamic acid in 0.7% sodium chloride injection if serious reaction occurs, provide appropriate medical management and do not restart treatment. Tranexamic acid in 0.7% sodium chloride injection is contraindicated in patients with a history of hypersensitivity to tranexamic acid. 5.4 Visual Disturbances Although not seen in humans, focal areas of retinal degeneration have been observed in cats and dogs following oral or intravenous tranexamic acid at doses between 250 to 1,600 mg/kg/day (1.6 to 22 times the recommended usual human dose based on body surface area) from 6 days to 1 year. No retinal changes have been observed in eye examinations of patients treated with tranexamic acid for up to 8 years. Patients expected to be treated for greater than 3 months may consider ophthalmic monitoring including visual acuity and optical coherence tomography at regular intervals. Discontinue tranexamic acid in 0.7% sodium chloride injection if changes in ophthalmological examination occurs. 5.5 Dizziness Tranexamic acid may cause dizziness. Concomitant use of other drugs that may also cause dizziness may worsen this effect. Advise patients to avoid driving or using machines until they know how tranexamic acid in 0.7% sodium chloride injection affects them.

4 CONTRAINDICATIONS Tranexamic acid in 0.7% sodium chloride injection is contraindicated: In patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid in such patients. In patients with active intravascular clotting [see Warnings and Precautions (5.1) ] . In patients with hypersensitivity to tranexamic acid or any of the ingredients [see Warnings and Precautions (5.3) ] . In patients with subarachnoid hemorrhage, due to risk of cerebral edema and cerebral infarction. ( 4 ) In patients with active intravascular clotting. ( 4 ) In patients with severe hypersensitivity reactions to tranexamic acid or any of the ingredients. ( 4 )

7 DRUG INTERACTIONS Prothrombotic Medical Products: Avoid concomitant use, can further increase the risk of thromboembolic adverse reactions associated with tranexamic acid. ( 5.1 , 7.1 , 8.3 ) 7.1 Prothrombotic Medical Products Avoid concomitant use of tranexamic acid in 0.7% sodium chloride injection with medical products that are prothrombotic because concomitant use can further increase the risk of thromboembolic adverse reactions associated with tranexamic acid [see Warnings and Precautions (5.1) , Use in Specific Populations (8.3) ].

8.1 Pregnancy Risk Summary Available data from published studies, case series and case reports with tranexamic acid use in pregnant women in the second and third trimester and at the time of delivery have not clarified whether there is a drug-associated risk of miscarriage or adverse maternal or fetal outcomes. There are 2 (0.02%) infant cases with structural abnormalities that resulted in death when tranexamic acid was used during conception or the first trimester of pregnancy; however, due to other confounding factors the risk of major birth defects with use of tranexamic acid during pregnancy is not clear. Tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration (see Data) . Reproduction studies performed in mice, rats and rabbits have not revealed any adverse effects on the fetus due to tranexamic acid administered during organogenesis. Doses examined were multiples of up to 3 times (mouse), 6 times (rat) and 3 times (rabbit) the maximum human dose based on body surface area in the mouse, rat and rabbit, respectively (see Data) . The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. It is not known whether tranexamic acid use in pregnant women may cause a drug-associated risk of miscarriage or adverse maternal or fetal outcomes. For decisions regarding the use of tranexamic acid in 0.7% sodium chloride injection during pregnancy, the potential risk of tranexamic acid in 0.7% sodium chloride injection administration on the fetus should always be considered along with the mother’s clinical need for tranexamic acid in 0.7% sodium chloride injection; an accurate risk-benefit evaluation should drive the treating physician’s decision. Data Human Data Tranexamic acid passes through the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood. There were 13 clinical studies that described fetal and/or neonatal functional issues such as low Apgar score, neonatal sepsis, cephalohematoma and 9 clinical studies that discussed alterations to growth including low birth weight and preterm birth at 22 to 36 weeks of gestation in fetuses and infants exposed to tranexamic acid in-utero . Animal Data In embryo-fetal development studies, tranexamic acid was administered to pregnant mice from Gestation day (GD) 6 through GD 12 and rats from GD 9 through GD 14 at daily doses of 0.3 g/kg or 1.5 g/kg. There was no evidence of adverse developmental outcomes in mice and rats at multiple of 3 and 6 times the maximum recommended human dose based on body surface area in the mouse and rat, respectively. In rabbits, tranexamic acid was administered intravenously at doses of 50, 100, or 200 mg/kg/day or orally at doses of 100, 200, or 400 mg/kg/day from GD 6 through GD 18. There was no evidence of adverse developmental outcomes at dose multiples of 2 or 3 times, respectively, the maximum recommended human dose based on body surface area. Intravenous doses of 200 mg/kg/day showed slightly retarded weight gain in pregnant rabbits.

8.3 Females and Males of Reproductive Potential Contraception Concomitant use of tranexamic acid in 0.7% sodium chloride injection, which is an antifibrinolytic, with hormonal contraceptives may increase the risk for thromboembolic adverse reactions. Advise patients to use an effective alternative (nonhormonal) contraceptive method [see Warnings and Precautions (5.5) , Drug Interactions (7.1) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Thromboembolic Risk [see Warnings and Precautions (5.1) ] Seizures [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Visual Disturbances [see Warnings and Precautions (5.4) ] Dizziness [see Warnings and Precautions (5.5) ] Most common adverse reactions are nausea, vomiting, diarrhea, allergic dermatitis, giddiness, hypotension and thromboembolic events. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of 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. Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur and may resolve with dose-reduction. Allergic dermatitis and giddiness have been reported. Hypotension has been reported when intravenous injection is too rapid. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis and central retinal artery, vein obstruction and cases associated with concomitant use of combination hormonal contraceptives) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, cromatopsia and visual impairment have also been reported. Anaphylaxis or anaphylactoid reactions have been reported that are suggestive of a causal relationship.