Tranexamic acid - instructions for use, dose, side effects, contraindications

Antifibrinolytic agent, is a competitive (at high concentrations - noncompetitive) inhibitor of plasminogen activation and its transformation into plasmin protease. Has a local and systemic hemostatic effect in bleeding associated with increased fibrinolysis (platelet pathology, menorrhagia). Also tranexamic acid by suppressing the formation of kinins and other active peptides involved in allergic and inflammatory reactions, has anti-allergic and anti-inflammatory effects. In the experimental studies, the own analgesic activity of tranexamic acid and its potentiating effect on the analgesic activity of opioid analgesics have been confirmed.

Tranexamic acid at a concentration of 1 mg / ml does not aggregate platelets in vitro, in a concentration of up to 10 mg / ml of blood does not affect the number of platelets,the time of blood coagulation or various coagulation factors in whole blood or citrated blood in a healthy person. On the other hand, tranexamic acid both in the concentration of 1 mg / ml blood, and 10 mg / ml blood extends thrombin time.

Pharmacokinetics:

It is distributed in tissues relatively evenly (with the exception of cerebrospinal fluid, where the concentration is 1/10 of the plasma one). Penetrates through the placental barrier (the concentration in the cord blood after administration to a woman at a dose of 10 mg / kg can be quite high, about 30 μg / ml fetal serum) and the blood-brain barrier (GEB), excreted in breast milk (reaching approximately 1% of the concentration in the plasma mother). It is found in seminal fluid, where it reduces fibrinolytic activity, but does not affect the migratory motility of spermatozoa. Tranexamic acid quickly diffuses into the joint fluid and through the synovial membranes, in the joint fluid is found at the same concentration as in the blood serum. The biological half-life of the joint fluid is about 3 hours.

Initial volume of distribution V_d - 9-12 liters.

Binding to plasma proteins (profibrinolysin) is less than 3%.

In blood, about 3% is associated with a protein (plasminogen).

Antifibrinolytic concentration in various tissues persists for 17 hours, in plasma - up to 7-8 hours.

Metabolized to a small extent. The area under the concentration / time curve (AUC) has a three-phase form with a half-life (T_1/2) in the terminal phase equal to 2 hours. The total renal clearance is equal to the plasma clearance (7 l / h). It is excreted by the kidneys (the main way is glomerular filtration), more than 95% unchanged during the first 12 hours. After intravenous administration at a dose of 10 mg / kg for 24 hours by glomerular filtration, about 90% of tranexamic acid is excreted. Two metabolites of tranexamic acid have been identified: N-acetylated and deaminated derivatives.

With impaired renal function, there is a risk of cumulation of tranexamic acid.

Indications:

Prevention and treatment of bleeding caused by generalized or local fibrinolysis in adults and children aged 1 year and older.

Tranexamic acid preparations are used in the following situations:

- Treatment of bleeding caused by generalized or local fibrinolysis,such as: menorrhagia and metrorrhagia; gastrointestinal bleeding; bleeding after surgical interventions on the prostate and bladder;

- Prevention and treatment of bleeding during surgery in the nasal cavity, mouth and pharynx (adenoidectomy, tonsillectomy, tooth extraction); with thoracic, abdominal and other large surgical interventions (including cardiosurgery operations); at gynecological operations;

- Treatment of obstetric-gynecological bleeding;

- Treatment of bleeding caused by the use of fibrinolytic drugs.

Contraindications:

Hypersensitivity to tranexamic acid.

Severe chronic renal failure (glomerular filtration rate [GFR] less than 30 mg / ml / 1.73 m²) due to the risk of cumulation.

Venous or arterial thrombosis at present or in the anamnesis (deep vein thrombosis of the legs, pulmonary embolism, thrombosis of the intracranial vessels, etc.) with the impossibility of simultaneous therapy with anticoagulants.

Fibrinolysis due to consumption coagulopathy (hypocoagulation stage of the syndrome of disseminatedintravascular coagulation [DVS-syndrome]).

Cramps in the anamnesis.

Acquired violation of color vision.

Subarachnoid hemorrhage (due to the risk of developing cerebral edema, ischemia and cerebral infarction).

Treatment of menorrhagia in patients under the age of 16 years (no experience is available).

Age younger than 1 year (no experience of use).

Carefully:

Tranexamic acid should be used with caution in the following situations:

Hematuria caused by diseases of the kidney parenchyma, and bleeding from the upper urinary tract (risk of secondary mechanical obstruction of the urinary tract with a clot of blood with the development of anuria).

Patients with a high risk of thrombosis (history of thromboembolic events or family history of thromboembolic disease, verified diagnosis of thrombophilia).

Patients taking combined oral contraceptives (due to an increased risk of venous thromboembolic complications and arterial thrombosis).

Simultaneous use of preparations of clotting factors II, VII, IX and X in combination [prothrombin complex] or anti-inhibitory coagulantcomplex.

Patients receiving anticoagulant therapy (limited experience).

Pregnancy and lactation:

In preclinical studies tranexamic acid had no teratogenic effects on animals. Adequate and strictly controlled studies of the efficacy and safety of the use of tranexamic acid preparations in pregnant women have not been conducted. Tranexamic acid penetrates the placenta and can be contained in cord blood in a concentration close to that of the mother.

Because studies of reproductive function in animals do not always allow predicting reactions in humans, tranexamic acid should be used during pregnancy only in case of emergency.

Tranexamic acid penetrates into breast milk (the concentration of the drug in milk is about 1% of the concentration in the blood plasma of the mother). The development of antifibrinolytic effect in an infant is unlikely. Nevertheless, caution should be exercised when using tranexamic acid in nursing mothers.

Dosing and Administration:

Intravenous drip or jet slowly; rate of administration of 1 ml / min (50 mg / min).You should avoid rapid intravenous injection!

Adult patients:

- Treatment of menorrhagia and metrorrhagia, gastrointestinal bleeding: 500 mg (2 ampoules 5 ml) 2-3 times a day from the time of bleeding to its stop;

- Treatment of bleeding after surgical interventions on the prostate and bladder: 1000 mg (4 ampoules 5 ml) 3 times a day from the time of bleeding to its stop;

- Treatment of bleeding due to generalized fibrinolysis: 15 mg / kg body weight every 6-8 hours from the time of bleeding to its stop;

- Treatment of bleeding due to local fibrinolysis: 500 mg (2 ampoules 5 ml) 2-3 times a day from the moment of development of bleeding to its stop;

- Prevention and treatment of bleeding:

with surgical interventions in the nasal cavity, mouth and pharynx: 10-15 mg / kg body weight every 6-8 hours until bleeding stops;
with thoracic, abdominal and other large surgical interventions: 15 mg / kg of body weight every 6-8 hours until bleeding stops;
at cardiosurgical operations: a loading dose of 15 mg / kg after the induction of anesthesia before the onset of surgery,then intravenous infusion at a rate of 4.5 mg / kg / hour throughout the operation; it is recommended to administer tranexamic acid in a dose of 0.6 mg / kg in the device of artificial circulation;
at gynecological operations: 10-15 mg / kg of body weight every 6-8 hours until bleeding stops;

- Treatment of obstetric-gynecological bleeding: 15 mg / kg of body weight every 6-8 hours from the time of bleeding to its stop;

- Treatment of bleeding caused by the use of fibrinolytic drugs: 10 mg / kg body weight every 6-8 hours from the time of bleeding to its stop.

In case of long (more than 48 hours) long-term haemostatic therapy, the use of tranexamic acid preparations in the tablet dosage form is recommended.

Children over 1 year old:

The experience of using tranexamic acid drugs in children is limited. The recommended dose of the drug for treatment of bleeding caused by local and generalized fibrinolysis is 20 mg / kg / day.

Use of the drug in specific patient groups:

Impaired renal function

In patients with mild and moderate impairment of the excretory function of the kidneysit is necessary to correct the dose and the frequency of administration of tranexamic acid:

Concentration of serum creatinine

Glomerular filtration rate (GFR)

Dose tranexamic acid

Multiplicity introduction of

120-249 μmol / l

(1.36-2.82 mg / dL)

60-89 ml / min / 1.73 m²

15 mg / kg body weight

2 times a day

250-500 μmol / l

(2.83-5.66 mg / dL)

30-59 ml / min / 1.73 m²

15 mg / kg body weight

1 time per day

Impaired liver function

In patients with impaired liver function, dose adjustment is not required.

Elderly age

In elderly patients, in the absence of renal failure, dose adjustment is not required.

Side effects:

The incidence of adverse drug reactions is determined according to the WHO classification: very often (> 1/10), often (> 1/100, ≤1 / 10), infrequently (> 1/1000, ≤1 / 100), rarely (> 1/10000, ≤1 / 1000), very rarely (less than 1/10000), the frequency is unknown (can not be determined from available data).

Disorders from the organs of the gastrointestinal tract: often - nausea, vomiting, diarrhea (symptoms disappear when the dose decreases);

Disturbances from the skin and subcutaneous tissues: rarely - skin allergic reactions, incl. allergic dermatitis;

Disorders from the side of the organ of vision: rarely - visual impairment, incl.violation of color perception, thrombosis of the vessels of the retina;

Vascular disorders: rarely - thromboembolic complications, marked decrease in blood pressure (usually due to excessively rapid intravenous administration); very rarely - arterial and venous thrombosis of different localization; frequency unknown - acute myocardial infarction, cerebral artery thrombosis, carotid thrombosis, stroke, deep vein thrombosis of the legs, pulmonary embolism, renal artery thrombosis with cortical necrosis and acute renal failure, coronary artery occlusion, central artery vein and retinal veins );

Immune system disorders: very rarely - reactions hypersensitivity, incl. anaphylactic shock;

Impaired nervous system: rarely - dizziness, convulsions.

Overdose:

Cases of overdose of a solution of tranexamic acid have not been described. There are limited data on overdose of tablets of tranexamic acid (one case of ingestion of 37 g of tranexamic acid is reported).

Symptoms: dizziness, headache, nausea, vomiting, diarrhea, orthostatic symptoms (including dizziness when going from horizontal to vertical position), orthostatic arterial hypotension. In predisposed patients, the risk of thrombosis increases.

Treatment: antidote is unknown. If suspected overdose of tranexamic acid, hospitalization is necessary. It is recommended ingestion or parenteral administration of a large amount of fluid to enhance renal excretion, forced diuresis, control of the amount of urine released. In some cases, the use of anticoagulants may be justified.

Interaction:

Special clinical studies on the interaction of tranexamic acid with other drugs have not been conducted.

Tranexamic acid prevents the development of the pharmacological effect of fibrinolytic (thrombolytic) drugs. Combined oral contraceptives increase the risk of venous thromboembolic complications and arterial thrombosis (in particular, ischemic stroke and myocardial infarction).The experience of using tranexamic acid in women taking combined oral contraceptives is not available. Because the tranexamic acid has antifibrinolytic effect, simultaneous application with combined oral contraceptives may lead to an additional increase in the risk of thrombotic complications.

Simultaneous use of tranexamic acid with preparations of coagulation factors II, VII, IX and X in combination [prothrombin complex] or anti-inhibitory coagulant complex increases the risk of thrombosis. Possible increased risk of thrombotic complications (in particular, myocardial infarction) with the simultaneous use of tranexamic acid with hydrochlorothiazide, desmopressin, ampicillin-sulbactam, ranitidine and nitroglycerin.

When combined with hemostatic drugs, activation of thrombosis is possible.

Pharmaceutical drug interactions:

Tranexamic acid solution compatible with the majority of infusion solutions (0.9% sodium chloride solution, Ringer's solution, 5% dextrose solution, solutions of amino acids, dextrans).The tranexamic acid solution is compatible with unfractionated heparin.

A solution of tranexamic acid is pharmaceutically incompatible with urokinase, norepinephrine, dipyridamole, diazepam.

A solution of tranexamic acid should not be mixed with solutions of antibiotics (penicillins, tetracyclines) and blood preparations.

Special instructions:

Before and during the treatment with tranexamic acid preparations, an ophthalmologist should be consulted (visual acuity, color vision, eye fundus condition). When there are visual impairments against the background of treatment with tranexamic acid, the drug should be discarded.

Tranexamic acid preparations should be used with caution in hematuria caused by kidney parenchyma diseases, since intravascular precipitation of fibrin is often observed in these conditions, which can exacerbate kidney damage. In addition, in cases of massive bleeding of any etiology from the upper urinary tract, antifibrinolytic therapy increases the risk of blood clots in the renal pelvis and / or ureter and, accordingly, the risk of secondary mechanical obstruction of the urinary tract and the development of anuria.

Although clinical studies have not revealed a significant increase in the incidence of thrombosis, the risk of thrombotic complications can not be completely ruled out. The cases of development of venous and arterial thrombosis and thromboembolism in patients receiving tranexamic acid are described. In addition, cases of occlusion of the central artery of the retina and the central vein of the retina have been reported. In several patients, with intravenous tranexamic acid, intracranial thrombosis developed. Accordingly, in patients with a high risk of thrombosis (thromboembolic complications in the anamnesis, cases of thromboembolism in relatives, verified diagnosis of thrombophilia), tranexamic acid should be used only in case of emergency and under strict medical supervision. Before the application of tranexamic acid, a check should be carried out to determine the risk factors for thromboembolic complications.

The presence of blood in the cavities, for example, in the pleural cavity, joint cavities and urinary tract (including in the renal pelvis and in the bladder) can lead to the formation of an "insoluble clot" due to extravascularcoagulation, and such a clot can be resistant to physiological fibrinolysis. Patients with irregular menstrual bleeding should not be prescribed tranexamic acid until the cause of dysmenorrhea is established. If the amount of menstrual bleeding is inadequately reduced with treatment with tranexamic acid, alternative treatment should be considered.

The efficacy and safety of tranexamic acid preparations for the treatment of menorrhagia in patients younger than 16 years of age have not been established.

Care should be taken if tranexamic acid is used in women who simultaneously take combined oral contraceptives, in connection with an increased risk of thrombosis (see section "Interaction with other drugs"),

In patients with DIC syndrome who need treatment with tranexamic acid, therapy should be performed under the close supervision of a physician with experience in the treatment of this disease.

In connection with the lack of adequate clinical studies, the simultaneous use of tranexamic acid with anticoagulants should be carried out under the close supervision of a specialist,who has experience in the treatment of blood clotting disorders.

Effect on the ability to drive transp. cf. and fur:

The ability of tranexamic acid to influence the speed of psychomotor reactions and the ability to control transport or other mechanical means has not been studied. Tranexamic acid preparations can cause dizziness and visual impairment and, accordingly, can affect the ability to engage in potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Solution for intravenous administration, 50 mg / ml.

Packaging:

5 ml per ampoule of neutral glass or glass of the first hydrolytic class with a break point or a ring of fracture.

By 5 ampoules in a plastic pallet or contour mesh packaging.

For 1, 2, 10 plastic pallets or 1, 2, 10 contour mesh packages together with instructions for use in a pack of cardboard.

For 10 ampoules together with instructions for use in a pack of cardboard.

20, 50 or 100 plastic pallets or 20, 50 or 100 contour packs with 10, 25 or 50 instructions for use in a carton box box (for hospitals)

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004103

Date of registration:25.01.2017

Expiration Date:25.01.2022

The owner of the registration certificate:TRIVIUM-XXI, LLC TRIVIUM-XXI, LLC Russia

Manufacturer: & nbsp

Armavir Biofactory, FKP

Information update date: & nbsp28.02.2017

Illustrated instructions

Instructions

Tranexamic acid (Tranexamic acid)