Actions of Tranexamic Acid in details
Pharmacology: Pharmacodynamics: Tranexamic Acid is a competitive inhibitor of plasminogen activation, and at much higher concentrations, a noncompetitive inhibitor of plasmin, ie, actions similar to aminocaproic acid. Tranexamic Acid is about 10 times more potent in vitro than aminocaproic acid.
Tranexamic Acid binds more strongly than aminocaproic acid to both the strong and weak receptor sites of the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. Tranexamic Acid in a concentration of 1 mg/mL does not aggregate platelets in vitro.
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 normal subjects. However, Tranexamic Acid in concentrations of 10 mg/mL and 1 mg/mL blood prolongs the thrombin time.
Pharmacokinetics: The plasma protein-binding of Tranexamic Acid is about 3% at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen. Tranexamic Acid does not bind to serum albumin.
After an IV dose of 1 g, the plasma concentration time curve shows a triexponential decay with a t½ of about 2 hrs for the terminal elimination phase. The initial volume of distribution is about 9-12 L. Urinary excretion via glomerular filtration is the main route of elimination. Overall renal clearance is equal to overall plasma clearance (110-116 mL/min) and >95% of the dose is excreted in the urine as the unchanged drug. Excretion of Tranexamic Acid is about 90% at 24 hrs after IV administration of 10 mg/kg body weight.
An anti-fibrinolytic concentration of Tranexamic Acid remains in different tissues for about 17 hrs, and in the serum, up to 7 or 8 hrs.
Tranexamic Acid passes through the placenta. The concentration in cord blood after an IV injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood.
Tranexamic Acid diffuses rapidly into joint fluid and the synovial membrane. In the joint fluid the same concentration is obtained as in the serum. The biological t½ of Tranexamic Acid in the joint fluid is about 3 hrs.
The concentration of Tranexamic Acid in a number of other tissues is lower than in blood. In breast milk, the concentration is about 1/100 of the serum peak concentration. Tranexamic Acid concentration in cerebrospinal fluid is about 1/10 of that of the plasma. The drug passes into the aqueous humor, the concentration being about 1/10 of the plasma concentration.
Tranexamic Acid has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration.
Toxicology: Preclinical Safety Data: An increased incidence of leukemia in male mice receiving Tranexamic Acid in food at a concentration of 4.8% (equivalent to doses as high as 5 g/kg/day) may have been related to treatment. Female mice were not included in this experiment.
Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in 1 strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver. No mutagenic activity has been demonstrated in several in vitro and in vivo genotoxicity testing systems.
In published, preclinical animal studies, epileptic activities were induced by topical application of Tranexamic Acid to the cortex of anesthetized cats. Similarly, IV infusion of high doses (500-600 mg/kg) of Tranexamic Acid induced seizure-like activity in conscious cats. Severe hind limb spasms developed into generalized convulsions in a rat model following application of Tranexamic Acid to the lumbar spinal cord. Tranexamic Acid within a fibrin sealant similarly induced limb spasms and convulsions in this rat model. Fibrin sealant containing Tranexamic Acid evoked generalized seizures in rats following application to the cerebral cortex of anesthetized rats. Central nervous system hyperexcitability may be the result of antagonism of γ-aminobutyric acidA receptors by Tranexamic Acid.
How should I take Tranexamic Acid?
Take Tranexamic Acid only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.
Do not take Tranexamic Acid when you do not have your period. You should wait until your monthly period has started before taking Tranexamic Acid.
Tranexamic Acid comes with a patient information insert. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.
You may take Tranexamic Acid with or without food.
Swallow the tablet whole with liquids. Do not break, crush, or chew it.
Dosing
The dose of Tranexamic Acid will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Tranexamic Acid. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For oral dosage form (tablets):
- To treat heavy menstrual bleeding:
- Adults—Two tablets (650 milligrams per tablet) three times a day in the morning, afternoon, and evening. The tablets should not be taken more than 5 days in a row for each monthly period.
- Children—Use and dose must be determined by your doctor.
- To treat heavy menstrual bleeding:
Missed Dose
If you miss a dose of Tranexamic Acid, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
If you take a dose that is late, wait at least 6 hours before you take your next dose.
Storage
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Tranexamic Acid administration
Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Tranexamic Acid is injected into a vein through an IV just before your tooth is pulled. You may need to keep using the medication for up to 8 days afterward.
You may be shown how to use an IV at home. Do not self-inject Tranexamic Acid if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.
To be sure this medication is not causing harmful effects, your vision may need to be tested while you are using Tranexamic Acid. Follow your doctor's instructions.
Store this medication at room temperature away from moisture and heat.
Tranexamic Acid pharmacology
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.
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.
Pharmacokinetics
Absorption
After a single oral administration of two 650 mg tablets of Tranexamic Acid, 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.
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.
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.
Pediatric Use
Tranexamic Acid Tablets are indicated for women of reproductive age and are not intended for use in premenarcheal girls.
In a randomized, single dose, two-way crossover study of two dose levels (650 mg and 1,300 mg [two 650 mg tablets]), pharmacokinetics of Tranexamic Acid was evaluated in 20 female adolescents (12 to 16 years of age) with heavy menstrual bleeding. The Cmax 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 Cmax 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.
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.
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.
Drug Interactions
No drug-drug interaction studies were conducted with Tranexamic Acid Tablets.
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. For this reason, concomitant use of Tranexamic Acid Tablets with combination hormonal contraceptives is contraindicated
Factor IX Complex Concentrates or Anti-inhibitor Coagulant Concentrates
Tranexamic Acid 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.
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 patient taking Tranexamic Acid Tablets therapy requires tissue plasminogen activators.
All-Trans Retinoic Acid (Oral Tretinoin)
In a study involving 28 patients with acute promyelocytic leukemia who were given either orally administered all-trans retinoic acid plus intravenously administered Tranexamic Acid, all-trans retinoic acid plus chemotherapy, or 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. It appears that the procoagulant effect of all-trans retinoic acid may be exacerbated by concomitant use of Tranexamic Acid. Therefore, exercise caution when prescribing Tranexamic Acid Tablets to patients with acute promyelocytic leukemia taking all-trans retinoic acid.
References
- DailyMed. "TRANEXAMIC ACID: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Tranexamic Acid: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Tranexamic acid: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
