2.1 Recommended Dosage

The recommended dose of Tranexamic Acid in 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 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 Sodium Chloride Injection if particulate matter or coloration is seen.

Tranexamic Acid in 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 flexible plastic container 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:

INSTRUCTIONS FOR USE:

Check solution container composition, lot number, and expiry date.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not admix with other drugs.

Do not use solution containers in series connections.

Do not remove solution container from its overwrap until immediately before use.

The intact port cap provides visual tamper evidence. Do not use if a port cap is prematurely removed.

Maintain strict aseptic technique during handling.

To Open:

1.

Always inspect the solution container before and after removal from the overwrap.

2.

Place the solution container on a clean, flat surface. Remove the solution container from the overwrap.

3.

Check the solution container for leaks by squeezing firmly. If leaks are found discard.

4.

Do not use if the solution is cloudy or a precipitate is present.

To Prepare for Administration:

1.

Immediately before inserting the infusion set, break off BLUE Infusion Port Cap with the arrow pointing away from the solution container.

2.

Use a non-vented infusion set or close the air-inlet on a vented set.

3.

Close the roller clamp of the infusion set.

4.

Hold the base of the BLUE Infusion Port., twist and push spike until fully inserted.

5.

The BLUE Infusion Port contains a self-sealing septum that helps prevent leakage after removing the spike. The infusion port is not intended to be spiked more than once.

6.

Suspend solution container from hanger hole.

7.

For Single Use Only. Discard unused portion.

5.1 Thromboembolic Risk

Tranexamic Acid in 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 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 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 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 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 Sodium Chloride Injection if serious reaction occurs, provide appropriate medical management, and do not restart treatment. Tranexamic Acid in 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 1600 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 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 Sodium Chloride Injection affects them.

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, cromatopsia, and visual impairment have also been reported.

Anaphylaxis or anaphylactoid reactions have been reported that are suggestive of a causal relationship.

7.1 Prothrombotic Medical Products

Avoid concomitant use of Tranexamic Acid in 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 2-4% and 15-20%, 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.

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

There are limited data concerning the use of tranexamic acid in pediatric patients with hemophilia who are undergoing tooth extraction. The limited data suggest that there are no significant pharmacokinetic differences between adult and pediatric patients.

8.5 Geriatric Use

Clinical studies of tranexamic acid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Reduce the dosage of Tranexamic Acid in Sodium Chloride Injection in patients with renal impairment, based on the patient's serum creatinine [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

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 μmol/L) and 1 with high affinity (Kd = 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.

12.2 Pharmacodynamics

Tranexamic acid in concentrations of 1 mg/mL and 10 mg/mL prolongs the thrombin time. An antifibrinolytic concentration of tranexamic acid remains in different tissues for about 17 hours, and in the serum, up to seven or eight hours.

Tranexamic acid in concentrations up to 10 mg/mL blood has no influence on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood from healthy subjects.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Tranexamic acid was not carcinogenic in a 2-year study in rats and mice at oral doses up to 3 and 5.3 g/kg/day, which are approximately 12 and 11 times the maximum recommended human dose based on body surface area, respectively. Tranexamic acid was not genotoxic in the reverse mutation bacterial (Ames) test, and in vitro and in vivo cytogenetic test.

In a fertility and early embryonic development study, tranexamic acid was administered to male rats as 0.3% and 1% of drug in diet (average doses of 222 and 856 mg/kg/day) or to female rats at dose levels of 0.3% and 1.2% of drug in diet. Tranexamic acid had no effect on fertility or reproductive function of male or female rats at dose multiples of 4 or 5 times the maximum recommended human dose based on body surface area, respectively.

13.2 Animal Toxicology and/or Pharmacology

Nonclinical studies have shown a retinal toxicity associated with tranexamic acid. Toxicity is characterized by retinal atrophy commencing with changes to the retinal pigmented epithelium and progressing to retinal detachment in cats. The toxicity appears to be dose related, and changes are partially reversible at lower doses. Effects were observed in dogs at oral doses of 800 mg/kg/day and higher (multiple of 11 times the maximum human dose based on body surface area), and in cats at 250 mg/kg/day for 14 days (multiple of 1.6 times the maximum human dose based on body surface area). Some fully reversible changes in pigmentation were observed in cats at doses of 125 mg/kg/day (multiple of 0.8 times the maximum human dose based on body surface area). Studies suggest that the underlying mechanism may be related to a transient retinal ischemia at high exposures, linked to the known sympathomimetic effect of high plasma exposures of tranexamic acid.

Thromboembolic Risk

•

Inform patients that Tranexamic Acid in Sodium Chloride Injection may increase the risk of venous and arterial thrombosis or thromboembolism and to contact their healthcare provider for any signs or symptoms suggestive of thromboembolism.

•

Advise patients using hormonal contraception that combined use with Tranexamic Acid in Sodium Chloride Injection may increase the risk for thromboembolic adverse reactions and to use effective alternative (nonhormonal) contraception during therapy with Tranexamic Acid in Sodium Chloride Injection [see Warnings and Precautions (5.1), Drug Interactions (7.1), Use in Specific Populations (8.3)].

Seizures

Inform patients that Tranexamic Acid in Sodium Chloride Injection may cause seizures and to contact their healthcare provider for any signs or symptoms suggestive of seizures [see Warnings and Precautions (5.2)].

Hypersensitivity Reactions

Inform patients that Tranexamic Acid in Sodium Chloride Injection may cause hypersensitivity reactions and to contact their healthcare provider for any signs or symptoms of hypersensitivity reactions [see Warnings and Precautions (5.3)].

Visual Disturbances

Inform patients that Tranexamic Acid in Sodium Chloride Injection can cause visual disturbance and that they should report any eye symptoms or change in their vision to their healthcare provider and to follow-up with an ophthalmologist for a complete ophthalmologic evaluation, including dilated retinal examination of the retina [see Warnings and Precautions (5.4)].

Risk of Driving and Operating Machinery

Inform patients that Tranexamic Acid in Sodium Chloride Injection may cause dizziness, and that the patient should be cautioned about driving, operating machinery, or performing hazardous tasks while taking Tranexamic Acid in Sodium Chloride Injection [see Warnings and Precautions (5.5)].

Manufactured for:

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

Made in Norway
451837