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

7 DRUG INTERACTIONS

No drug-drug interaction studies were conducted with Tranexamic acid tablets.

7.1 Hormonal Contraceptives

Because Tranexamic acid tablets are antifibrinolytic, concomitant use of hormonal contraception and Tranexamic acid tablets may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. Women using hormonal contraception should use Tranexamic acid tablets only if there is a strong medical need and the benefit of treatment will outweigh the potential increased risk of a thrombotic event [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3) ].

7.2 Tissue Plasminogen Activators

Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both Tranexamic acid tablets and tissue plasminogen activators. Therefore, exercise caution if a woman taking Tranexamic acid tablets therapy requires tissue plasminogen activators.

7.3 Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

Tranexamic acid tablets are not recommended for women 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) and Clinical Pharmacology(12.3)].

7.4 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 Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3) ].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

(Category B)

Tranexamic acid tablets are not indicated for use in pregnant women. Reproduction studies have been performed in mice, rats and rabbits and have revealed no evidence of impaired fertility or harm to the fetus due to tranexamic acid. However, tranexamic acid is known to cross the placenta and appears in cord blood at concentrations approximately equal to the maternal concentration. There are no adequate and well-controlled studies in pregnant women [see Nonclinical Toxicology ( 13.1) ].

An embryo-fetal developmental toxicity study in rats and a perinatal developmental toxicity study in rats were conducted using tranexamic acid. No adverse effects were observed in either study at doses up to 4 times the recommended human oral dose of 3900 mg/day based on mg/m2 (actual animal dose 1500 mg/kg/day).

8.3 Nursing Mothers

Tranexamic acid is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentration. Tranexamic acid tablets should be used during lactation only if clearly needed.

8.4 Pediatric Use

Tranexamic acid tablets are indicated for women of reproductive age and are not intended for use in premenarcheal girls. Tranexamic acid tablets have not been studied in adolescents under age 18 with heavy menstrual bleeding.

8.5 Geriatric Use

Tranexamic acid tablets are indicated for women of reproductive age and are not intended for use by postmenopausal women.

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of Tranexamic acid 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, dosage adjustment in patient with renal impairment is needed [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 tablets has not been studied. Because only a small fraction of the drug is metabolized, dosage adjustment in patients with hepatic impairment is not needed [see Clinical Pharmacology ( 12.3) ].

10 OVERDOSAGE

There are no known cases of intentional overdose with Tranexamic acid tablets and no subjects in the clinical program took more than 2 times the prescribed amount of Tranexamic acid 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 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 tablets are an antifibrinolytic drug. The chemical name is trans-4-aminomethyl-cyclohexanecarboxylic acid. The structural formula is:

Structural Formula for Tranexamic Acid

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 C8 H15 N02 and the molecular weight is 157.2.

Tranexamic acid tablets are provided as white to off-white, oval-shaped, film coated tablets, debossed with “WPI 3720” on one side of the tablet. The active ingredient in each tablet is 650 mg tranexamic acid. The inactive ingredients contained in each tablet are: colloidal silicon dioxide, copovidone, crospovidone, eudragit, glyceryl behenate, lactose monohydrate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and triethyl citrate.

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 (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, 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 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 tablets 1300 mg (two 650 mg tablets), (2) Tranexamic acid tablets 3900 mg (six 650 mg tablets; three times the 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 tablets. Moxifloxacin, the active control, was associated with a maximum 14.11 msec mean increase in corrected QT interval (moxifloxacin – placebo) at 3 hours after administration.

12.3 Pharmacokinetics

Absorption

After a single oral administration of two 650 mg tablets of Tranexamic acid tablets, the peak plasma concentration (Cmax ) occurred at approximately 3 hours (Tmax ). The absolute bioavailability of Tranexamic acid tablets in women aged 18-49 is approximately 45%. Following multiple oral doses (two 650 mg tablets three times daily) administration of Tranexamic acid tablets for 5 days, the mean Cmax increased by approximately 19% and the mean area under the plasma concentration-time curve (AUC) remained unchanged, compared to a single oral dose administration (two 650 mg tablets). Plasma concentrations reached steady state at the 5th dose of Tranexamic acid tablets on Day 2.

The mean plasma pharmacokinetic parameters of tranexamic acid determined in 19 healthy women following a single (two 650 mg tablets) and multiple (two 650 mg tablets three times daily for 5 days) oral dose of Tranexamic acid tablets are shown in Table 3.

Table 3. Mean (CV%) Pharmacokinetic Parameters Following a Single (two 650 mg tablets) and Multiple Oral Dose (two 650 mg tablets three time daily for 5 days) Administration of Tranexamic Acid Tablets in 19 Healthy Women under Fasting Conditions
Parameter Arithmetic Mean (CV%)
Single dose Multiple dose
Cmax (mcg/mL) 13.83 (32.14) 16.41 (26.19)
AUCtldc (mcg•h/mL) 77.96 (31.14) 77.67 a (29.39)
AUCinf (mcg•h/mL) 80.19 (30.43) -
Tmax (h)b 2.5 (1 – 5) 2.5 (2 – 3.5)
t1/2 (h) 11.08 (16.94) -

Cmax = maximum concentration

AUCtldc = area under the drug concentration curve from time 0 to time of last determinable concentration

AUCinf = area under the drug concentration curve from time 0 to infinity

Tmax = time to maximum concentration t1/2 = terminal elimination half-life

a AUC0-tau (mcg•h/mL) = area under the drug concentration curve from time 0 to 8 hours

b Data presented as median (range)

Effect of food: Tranexamic acid tablets may be administered without regard to meals. A single dose administration (two 650 mg tablets) of Tranexamic acid tablets with food increased both Cmax 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.

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. 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 tablets is approximately 11 hours. Plasma clearance of tranexamic acid is 110-116 mL/min.

Specific Populations

Pregnancy (Category B)

Tranexamic acid tablets are not indicated for use in pregnant women. Tranexamic acid is known to cross the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. There are no adequate and well-controlled studies in pregnant women [see Use in Specific Populations ( 8.1) ].

Nursing Mothers

Tranexamic acid is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentrations. Tranexamic acid tablets should be used during lactation only if clearly needed [see Use in Specific Populations ( 8.3) ].

Pediatric Use

Tranexamic acid tablets are indicated for women of reproductive age and are not intended for use in premenarcheal girls. Tranexamic acid tablets have not been studied in adolescents under age 18 with heavy menstrual bleeding.

Geriatric Use

Tranexamic acid tablets are indicated for women of reproductive age and are not intended for use by postmenopausal women.

Renal Impairment

The effect of renal impairment on the disposition of Tranexamic acid 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, dose adjustment is needed in patients with renal impairment [see Dosage and Administration ( 2.2) ].

Hepatic Impairment

The effect of hepatic impairment on the disposition of Tranexamic acid 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, no dose adjustment is needed in patients with hepatic impairment.

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