Tranexamic Acid: Package Insert and Label Information (Page 2 of 4)

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 IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

Tranexamic acid USP tablets are not recommended in patients taking either Factor IX 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)].

8 USE IN SPECIFIC POPULATIONS

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)].

10 OVERDOSAGE

There are no known cases of intentional overdose with tranexamic acid USP tablets and no subjects in the clinical program took more than 2 times the prescribed amount of tranexamic acid USP tablets in a 24-hour period (>7800 mg/day). However, cases of overdose of tranexamic acid have been reported. Based on these reports, symptoms of overdose may include gastrointestinal (nausea, vomiting, diarrhea); hypotensive (e.g., orthostatic symptoms); thromboembolic (arterial, venous, embolic); visual impairment; mental status changes; myoclonus; or rash. No specific information is available on the treatment of overdose with tranexamic acid USP tablets. In the event of overdose, employ the usual supportive measures (e.g., clinical monitoring and supportive therapy) as dictated by the patient’s clinical status.

11 DESCRIPTION

Tranexamic acid USP tablets is an antifibrinolytic drug administered orally. The chemical name is trans-4-aminomethyl-cyclohexanecarboxylic acid. The structural formula is:

Chemical Structure

Tranexamic acid is a white crystalline powder. It is freely soluble in water and in glacial acetic acid and is very slightly soluble in ethanol and practically insoluble in ether. The molecular formula is C 8 H 15 N0 2 and the molecular weight is 157.2.

Tranexamic acid USP tablets are provided as white oval-shaped tablets and are not scored. Each tablet is debossed with the marking “FP650.” The active ingredient in each tablet is 650 mg tranexamic acid. The inactive ingredients contained in each tablet are: microcrystalline cellulose, colloidal silicon dioxide, pregelatinized corn starch, povidone, hypromellose, stearic acid, and magnesium stearate.

12 CLINICAL PHARMACOLOGY

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 (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.

12.2 Pharmacodynamics

Tranexamic acid, at in vitro concentrations of 25 — 100 μM, reduces by 20 — 60% the maximal rate of plasmin lysis of fibrin catalyzed by tissue plasminogen activator (tPA).

Elevated concentrations of endometrial, uterine, and menstrual blood tPA are observed in women with heavy menstrual bleeding (HMB) compared to women with normal menstrual blood loss. The effect of tranexamic acid on lowering endometrial tPA activity and menstrual fluid fibrinolysis is observed in women with HMB receiving tranexamic acid total oral doses of 2-3 g/day for 5 days.

In healthy subjects, tranexamic acid at blood concentrations less than 10 mg/mL has no effect on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood. Tranexamic acid, however, at blood concentrations of 1 and 10 mg/mL prolongs the thrombin time.

Cardiac Electrophysiology

The effect of tranexamic acid USP tablets on QT interval was evaluated in a randomized, single-dose, 4-way crossover study in 48 healthy females aged 18 to 49 years. Subjects received (1) tranexamic acid USP tablets 1300 mg (2) tranexamic acid USP tablets 3900 mg (three times the maximum recommended single dose), (3) moxifloxacin 400 mg, and (4) placebo. There was no significant increase in the corrected QT interval at any time up to 24 hours after the administration of either dose of tranexamic acid USP tablets. Moxifloxacin, the active control, was associated with a maximum 14.1 msec mean increase in corrected QT interval (moxifloxacin – placebo) at 3 hours after administration.

12.3 Pharmacokinetics

Absorption

After a single oral administration of 1300 mg of tranexamic acid USP tablets, the peak plasma concentration (C max ) occurred at approximately 3 hours (T max ). The absolute bioavailability of tranexamic acid USP tablets in women aged 18-49 is approximately 45%. Following multiple oral doses (1300 mg tablets three times daily) administration of tranexamic acid USP tablets for 5 days, the mean C max increased by approximately 19% and the mean area under the plasma concentration-time curve (AUC) remained unchanged, compared to a single oral dose administration (1300 mg ). Plasma concentrations reached steady state at the 5 th dose of tranexamic acid USP tablets on Day 2.

The mean plasma pharmacokinetic parameters of tranexamic acid determined in 19 healthy women following a single (1300 mg ) and multiple (1300 mg tablets three times daily for 5 days) oral dose of tranexamic acid USP tablets are shown in Table 3.

Table 3. Mean (CV%) Pharmacokinetic Parameters Following a Single (1300 mg) and Multiple Dose (1300 mg three times daily for 5 days) Oral Administration of tranexamic acid USP tablets in 19 Healthy Women under Fasting Conditions
Parameter Arithmetic Mean (CV%)
Single dose Multiple dose
C max = maximum concentration
AUC tldc = area under the drug concentration curve from time 0 to time of last determinable concentration
AUC inf = area under the drug concentration curve from time 0 to infinity
T max = time to maximum concentration
t 1/2 = terminal elimination half-life
a AUC 0-tau (mcg·h/mL) = area under the drug concentration curve from time 0 to 8 hours
b Data presented as median (range)
C max (mcg/mL) 13.83 (32.14) 16.41 (26.19)
AUC tldc (mcg∙h/mL) 77.96 (31.14) 77.67 a (29.39)
AUC inf (mcg∙h/mL) 80.19 (30.43)
T max (h) b 2.5 (1 – 5) 2.5 (2 – 3.5)
t 1/2 (h) 11.08 (16.94)

Effect of food: Tranexamic acid USP tablets may be administered with or without food. A single dose administration (1300 mg ) of tranexamic acid USP tablets with food increased both C max and AUC by 7% and 16%, respectively.

Distribution

Tranexamic acid is 3% bound to plasma proteins with no apparent binding to albumin. Tranexamic acid is distributed with an initial volume of distribution of 0.18 L/kg and steady-state apparent volume of distribution of 0.39 L/kg.

Tranexamic acid crosses 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.

Tranexamic acid concentration in cerebrospinal fluid is about one tenth of the plasma concentration.

The drug passes into the aqueous humor of the eye achieving a concentration of approximately one tenth of plasma concentrations.

Elimination

Most elimination post intravenous administration occurred during the first 10 hours, giving an apparent elimination half-life of approximately 2 hours. The mean terminal half-life of tranexamic acid is approximately 11 hours. Plasma clearance of tranexamic acid is 110-116 mL/min.

Metabolism

A small fraction of the tranexamic acid is metabolized.

Excretion

Tranexamic acid is eliminated by urinary excretion primarily via glomerular filtration with more than 95% of the dose excreted unchanged. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10 mg/kg.

Specific Populations

Pediatric Patients
Tranexamic acid USP tablets are indicated for females of reproductive age (not approved for use in premenarcheal girls).
In a randomized, single dose, two-way crossover study of two dose levels (650 mg and 1,300 mg), pharmacokinetics of tranexamic acid was evaluated in 20 female adolescents (12 to 16 years of age) with heavy menstrual bleeding. The C max and AUC values after a single oral dose of 650 mg in the adolescent females were 32 – 36% less than those after a single oral dose of 1,300 mg in the adolescent females. The C max and AUC values after a single oral dose of 1300 mg in the adolescent females were 20 – 25% less than those in the adult females given the same dose in a separate study. [See Use in Specific Populations (8.4) ]

Patients with Renal Impairment The effect of renal impairment on the disposition of tranexamic acid USP tablets has not been evaluated. Urinary excretion following a single intravenous injection of tranexamic acid declines as renal function decreases. Following a single 10 mg/kg intravenous injection of tranexamic acid in 28 patients, the 24-hour urinary fractions of tranexamic acid with serum creatinine concentrations 1.4 – 2.8, 2.8 – 5.7, and greater than 5.7 mg/dL were 51, 39, and 19%, respectively. The 24-hour tranexamic acid plasma concentrations for these patients demonstrated a direct relationship to the degree of renal impairment. Therefore, a lower dosage is needed in patients with renal impairment [see Dosage and Administration (2.2)].

Patients with Hepatic Impairment

The effect of hepatic impairment on the disposition of tranexamic acid USP tablets has not been evaluated. One percent and 0.5 percent of an oral dose are excreted as a dicarboxylic acid and acetylated metabolite, respectively. 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 impairment.

Drug Interactions Studies

No drug-drug interaction studies were conducted with tranexamic acid USP tablets.

All-Trans Retinoic Acid (Oral Tretinoin)

In a study involving 28 patients with acute promyelocytic leukemia who were given either orally administered (1) all-trans retinoic acid plus intravenously administered tranexamic acid, (2) all-trans retinoic acid plus chemotherapy, or (3) all-trans retinoic acid plus tranexamic acid plus chemotherapy, all 4 patients who were given all-trans retinoic acid plus tranexamic acid died, with 3 of the 4 deaths due to thrombotic complications. The procoagulant effect of all-trans retinoic acid may have been exacerbated by concomitant use of tranexamic acid. Therefore, tranexamic acid USP tablets is not recommended in patients with acute promyelocytic leukemia taking all-trans retinoic acid [see Warnings and Precautions (5.1) and Drug Interactions (7.4)].

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