Tranexamic Acid

RECENT MAJOR CHANGES Boxed Warning 08/2025 Dosage and Administration (2) 08/2025 Contraindications (4) 08/2025 Warnings and Precautions (5) 08/2025

1 INDICATIONS AND USAGE Tranexamic Acid in 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 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 injection intravenously with replacement therapy as a single-dose. ( 2.1 ) • After Extraction: Administer 10 mg/kg actual body weight of tranexamic acid injection intravenously 3 to 4 times daily for 2 to 8 days. ( 2.1 ) • Infuse undiluted solution no more than 1 mL/minute to avoid hypotension. ( 2.3 ) • Reduce the dosage for patients with renal impairment. ( 2.2 , 8.6 ) 2.1 Recommended Dosage The recommended dose of tranexamic acid injection is 10 mg/kg actual body weight administered as a single intravenous dose immediately before tooth extractions. Following tooth extraction, tranexamic acid injection may be administered at a dose of 10 mg/kg actual body weight intravenously 3 to 4 times daily for 2 to 8 days . 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 Dose reduction is recommended for all doses, both before and after tooth extraction . Serum Creatinine (mg/dL) Tranexamic Acid Injection Dosage 1.36 mg/dL to 2.83 mg/dL 10 mg/kg intravenously twice daily 2.83 mg/dL to 5.66 mg/dL 10 mg/kg intravenously daily > 5.66 mg/dL 10 mg/kg intravenously every 48 hours or 5 mg/kg intravenously every 24 hours 2.3 Preparation and Administration Tranexamic acid injection is for intravenous administration only. Tranexamic acid injection can be administered undiluted or as a diluted solution. • Use aseptic technique to prepare tranexamic acid injection. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Tranexamic acid injection is a clear and colorless solution. Discard the vial if particulate matter is observed. • Calculate the dose (mg) based on the patient’s actual body weight and the total volume (mL) of tranexamic acid injection solution required. If diluting tranexamic acid injection , follow the instructions below: • From the diluent infusion bag, withdraw a volume equal to the volume of the tranexamic acid injection solution required for the patient’s dose. • Withdraw the required volume of tranexamic acid injection solution from the vial and dilute with a compatible diluent (see below) to make a final concentration of 10 mg/mL or 20 mg/mL. Discard any unused portion left in the vial. o For intravenous infusion, tranexamic acid injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and Dextran solutions. o Heparin may be added to tranexamic acid injection. o Tranexamic acid injection should NOT be mixed with blood. o The drug is a synthetic amino acid and should NOT be mixed with solutions containing penicillin. • Gently invert the infusion bag to mix the diluted solution. DO NOT SHAKE. • If not used immediately, store the diluted tranexamic acid injection infusion solution at room temperature 20oC to 25°C (68oF to 77°F) for up to 4 hours . Administration Infuse undiluted solution no more than 1 mL/minute to avoid hypotension [see Adverse Reactions (6.2) ] . Administer the undiluted and diluted solutions intravenously according to Table 2. Table 2. Administration Rates for Undiluted and Diluted Solutions Undiluted solution Diluted solution Final concentration 100 mg/mL 10 mg/mL 20 mg/mL Administration rate 0.5 mL/minute (no more than 1 mL/minute) 5 mL/minute 2.5 mL/minute

3 DOSAGE FORMS AND STRENGTHS Injection: 1,000 mg of tranexamic acid in 100 mL (10 mg per mL), colorless solution in a single-dose bag for intravenous use Injection: 1,000 mg of tranexamic acid in 100 mL (10 mg per mL) sterile, unpreserved, colorless solution in a single-dose bag for intravenous use ( 3 ).

4 CONTRAINDICATIONS Tranexamic acid injection is contraindicated: • As a neuraxial (i.e., intrathecal, epidural) injection [see Warnings and Precautions (5.1) ] . • In patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid injection in such patients. • In patients with active intravascular clotting [see Warnings and Precautions (5.2) ] . • In patients with hypersensitivity to tranexamic acid or any of the ingredients [see Warnings and Precautions (5.4) ] . • As a neuraxial (i.e., intrathecal, epidural) injection. ( 4 ) • 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 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Risk of Medication Errors Due to Incorrect Route of Administration [see Warnings and Precautions (5.1) ] • Thromboembolic Risk [see Warnings and Precautions (5.2) ] • Seizures [see Warnings and Precautions (5.3) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] • Visual Disturbances [see Warnings and Precautions (5.5) ] • Dizziness [see Warnings and Precautions (5.6) ] Most common adverse reactions are nausea, vomiting, diarrhea, allergic dermatitis, giddiness, hypotension, and thromboembolic events. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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, chromatopsia, and visual impairment have also been reported. Anaphylaxis or anaphylactoid reactions have been reported that are suggestive of a causal relationship.

7 DRUG INTERACTIONS Prothrombotic Medical Products: Avoid concomitant use, can further increase the risk of thromboembolic adverse reactions associated with tranexamic acid. ( 5.2 , 7.1 , 8.3 ) See 17 for PATIENT COUNSELING INFORMATION. 7.1 Prothrombotic Medical Products Avoid concomitant use of tranexamic acid 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 (5.2) , Use in Specific Populations (8.3) ].

8 USE IN SPECIFIC POPULATIONS 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 Sodium Chloride Injection during pregnancy, the potential risk of Tranexamic Acid in Sodium Chloride Injection administration on the fetus should always be considered along with the mother's clinical need for Tranexamic Acid in 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 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. 8.2 Lactation Risk Summary Published literature reports the presence of tranexamic acid in human milk. There are no data on the effects of tranexamic acid on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Tranexamic Acid in Sodium Chloride Injection and any potential adverse effects on the breastfed child from Tranexamic Acid in Sodium Chloride Injection or from the underlying maternal condition. 8.3 …

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 (Kd = 750 micromol/L) and 1 with high affinity (Kd = 1.1 micromol/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 is trans-4-(aminomethyl)cyclohexanecarboxylic acid, an antifibrinolytic agent. Tranexamic acid is a white crystalline powder. The structural formula is Empirical Formula: C 8 H 15 NO 2 Molecular Weight: 157.2 Tranexamic Acid in Sodium Chloride Injection is a clear to colorless sterile, nonpyrogenic injectable solution for intravenous administration. Each IV bag contains 1,000 mg tranexamic acid, USP, 700 mg of sodium chloride, USP and Water for Injection, USP. The aqueous solution has a pH of 6.5 to 8.0. Structural Formula

10 OVERDOSAGE Cases of overdosage of tranexamic acid have been reported. Based on these reports, symptoms of overdosage may be gastrointestinal, e.g., nausea, vomiting, diarrhea; hypotensive, e.g., orthostatic symptoms; thromboembolic; e.g., arterial, venous, embolic; neurologic, e.g., visual impairment, convulsions, headache, mental status changes; myoclonus; and rash. Tranexamic acid is not dialyzable.

16 HOW SUPPLIED/STORAGE AND HANDLING Tranexamic Acid in Sodium Chloride Injection is supplied as a colorless solution in a single-dose polymeric bag containing 1,000 mg tranexamic acid in 100 mL of solution (10 mg per mL) sealed with a Twist Off port and oversealed in an aluminum pouch. NDC Tranexamic Acid in Sodium Chloride Injection (10 mg per mL) Package Factor 25021-418-82 1,000 mg per 100 mL Single-Dose Bag 10 bags per carton Discard any unused portion. Sterile, Nonpyrogenic, Preservative-free, PVC-free, DEHP-free. The container closure is not made with natural rubber latex. Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]