TRANEXAMIC ACID-ZDOROVYA

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRANEXAMIC ACID-ZDOROVYE (TRANEXAMIC ACID-ZDOROVYE)

Composition:

Active substance: tranexamic acid;

1 ml of the preparation contains 100 mg of tranexamic acid;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or almost colorless solution.

Pharmacotherapeutic group. Antihemorrhagic agents, antifibrinolytic amino acids. Inhibitors of fibrinolysis. ATC code B02A A02.

Pharmacological Properties

Pharmacodynamics

Tranexamic acid exerts an antihemorrhagic effect by inhibiting the fibrinolytic activity of plasmin. A complex is formed involving tranexamic acid and plasminogen; tranexamic acid binds to plasminogen during its conversion involving plasmin. The activity of the tranexamic acid–plasmin complex on fibrin is lower than that of plasmin alone.

In vitro study data have shown that high doses of tranexamic acid reduce the activity of this complex.

Pediatric population. Children aged 1 year and older

Twelve studies on efficacy in pediatric cardiac surgery involving 1073 children have been described in the scientific literature, of which 631 patients received tranexamic acid. Most of these were evaluated in comparison with a placebo control group. The study population was heterogeneous with respect to age, type of surgical procedure, and dosing. Study results indicate that tranexamic acid reduces blood loss and decreases the need for blood product transfusions in pediatric cardiac surgery involving cardiopulmonary bypass (CPB) during high-bleeding-risk procedures, particularly in cyanotic patients or those undergoing repeat surgery. The most appropriate dosing regimen has been found to be:

− Initial dose (loading dose): bolus infusion of 10 mg/kg administered after induction of anesthesia and prior to skin incision;

− continuous infusion at 10 mg/kg/hour or injection into the CPB pump adapter at a dose adjusted for the specific surgical procedure or body weight-based dose of 10 mg/kg, or administration into the CPB pump adapter and a final bolus injection of 10 mg/kg at the end of the surgical procedure involving CPB.

Some data suggest that continuous infusion may be preferable, as it maintains therapeutic plasma concentrations throughout the surgery. No specific dose-response studies have been conducted in children.

Pharmacokinetics

Absorption. Maximum plasma concentration (Cmax) of tranexamic acid is rapidly achieved following short-term intravenous infusion, after which plasma concentrations decline in a multi-exponential manner.

Distribution. At therapeutic plasma levels, the protein binding of tranexamic acid to plasma proteins is approximately 3%; this binding is believed to be entirely attributable to binding to plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is approximately 9 to 12 liters.

Tranexamic acid crosses the placental barrier. After intravenous administration of 10 mg/kg in pregnant women, serum concentrations range from 10–53 μg/mL, while concentrations in umbilical cord blood range from 4–31 μg/mL. Tranexamic acid rapidly penetrates into synovial fluid and synovial membrane tissues. After intravenous administration of 10 mg/kg in patients undergoing knee surgery, concentrations in joint fluid were similar to those in serum. Concentrations of tranexamic acid in other tissues and fluids are proportional to those observed in blood (in breast milk – approximately 1/100, in cerebrospinal fluid – approximately 1/10, in intraocular fluid – approximately 1/10). Tranexamic acid has been detected in seminal fluid, where it inhibits fibrinolytic activity but has almost no effect on sperm motility.

Elimination. The drug is primarily excreted unchanged in urine. Renal excretion via glomerular filtration is the main elimination pathway.

Renal clearance is practically equivalent to plasma clearance (110–116 mL/min). Approximately 90% of tranexamic acid is excreted within the first 24 hours after intravenous administration of a 10 mg/kg dose. The elimination half-life of tranexamic acid is approximately 3 hours.

Special patient groups. Plasma concentrations increase in patients with renal impairment. No specific pharmacokinetic studies have been conducted in children.

Clinical characteristics.

Indications.

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

Specific indications include:

• Bleeding due to increased systemic or local fibrinolysis, such as:
  • Menorrhagia and metrorrhagia;
  • Gastrointestinal bleeding;
  • Hemorrhagic disorders of the urinary tract occurring following surgery on the prostate gland or due to surgical interventions or procedures on the urinary tract;
• Otorhinolaryngological (ENT) surgeries (adenoidectomy, tonsillectomy, tooth extraction);

− Gynecological surgeries or complications in obstetric practice;

− Thoracic, abdominal, and other major surgical procedures, e.g., cardiovascular surgery;

− Control of bleeding associated with administration of a fibrinolytic medicinal product.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• Acute venous or arterial thrombosis (see section "Special precautions");
• Fibrinolytic states secondary to coagulopathy due to exhaustion, except in cases of excessive activation of the fibrinolytic system during acute severe bleeding (see section "Special precautions");
• Severe renal insufficiency (risk of accumulation);
• History of seizures;
• Intrathecal and intraventricular injection of the drug, intracerebral administration (risk of cerebral edema and seizures).

Interaction with other medicinal products and other types of interactions.

Interaction studies have not been conducted.

Concomitant use with anticoagulants should be performed under strict supervision of a physician experienced in this field.

Medicinal products affecting hemostasis should be prescribed cautiously to patients receiving tranexamic acid.

There is a theoretical risk of increased thrombotic potential when used concomitantly with estrogens.

The antifibrinolytic effect of the drug may be inhibited by thrombolytics.

Special precautions for use.

The following recommendations should be strictly observed:

• Intravenous injections should be administered very slowly;
• Intramuscular administration of tranexamic acid is not allowed.

Seizures
Cases of seizures associated with tranexamic acid treatment have been reported. Most of these cases were reported after intravenous administration of high-dose tranexamic acid during coronary artery bypass graft (CABG) surgery. When recommended low doses of tranexamic acid are used, the incidence of postoperative seizures is similar to that in patients who did not receive tranexamic acid.

Visual disturbances
Visual disorders, including reduced visual acuity, blurred vision, and color vision disturbances, may occur during treatment with this drug. If such symptoms occur, treatment should be discontinued. Regular ophthalmological examinations (including assessment of eyes, visual acuity, color vision, fundus, and visual fields) are recommended during continuous long-term use of tranexamic acid injection solution. If pathological ophthalmological changes are present, especially retinal disorders, the physician should, after consultation with a specialist, determine the necessity of long-term use of tranexamic acid injection solution on an individual basis.

Hematuria
In cases of hematuria originating from the upper urinary tract, there is a risk of urethral obstruction.

Thromboembolic complications
Risk factors for thromboembolic complications should be considered before initiating tranexamic acid. Tranexamic acid injection solution should be administered only under strict medical indication, after consultation with a specialist experienced in hemostasis, and under close medical supervision in patients with a history of thromboembolic disorders or a family history of such conditions (patients at high risk of thrombophilia) (see section "Contraindications").

Due to an increased risk of thrombosis, the drug should be used with caution in patients taking oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").

Disseminated intravascular coagulation (DIC)
In most cases, patients with disseminated intravascular coagulation (DIC) should not receive this drug (see section "Contraindications"). Use of tranexamic acid should be limited to patients with predominant activation of the fibrinolytic system in cases of acute severe bleeding.

Typically, the hematological profile is characterized as follows: shortened euglobulin fibrinolysis time; prolonged prothrombin time; decreased plasma levels of fibrinogen, factors V and VIII, plasminogen, fibrinolysin, and α2-macroglobulin; normal plasma levels of P and P-complex, i.e., factors II (prothrombin), VIII, and X; elevated plasma levels of fibrinogen degradation products; normal platelet count.

The above assumes that the underlying pathological condition does not alter the various parameters of this profile. In such acute cases, a single dose of 1 g of tranexamic acid is usually sufficient to stop bleeding. The use of tranexamic acid in DIC should only be considered if hematological laboratory facilities and expertise are available.

Use during pregnancy or breastfeeding.

Women of reproductive age
Women of reproductive age should use a reliable method of contraception during treatment.

Pregnancy
There is insufficient clinical data on the use of tranexamic acid in pregnant women.
Although animal studies do not indicate teratogenic effects, the drug is not recommended during the first trimester of pregnancy.

Limited clinical data on the use of tranexamic acid in various hemorrhagic conditions during the second and third trimesters do not demonstrate harmful effects on the fetus. Tranexamic acid should be used during pregnancy only when the expected benefit to the mother outweighs the potential risk to the fetus.

Period of breastfeeding
Tranexamic acid passes into breast milk; therefore, breastfeeding is not recommended.

Fertility
There are no clinical data on the effect of tranexamic acid on fertility.

Ability to affect reaction speed when driving or operating machinery.
Studies on the effect on the ability to drive or operate machinery have not been conducted.

Method of Administration and Dosage

The method of administration is strictly limited to slow intravenous injection or infusion.

Adults
Unless otherwise indicated, the following doses are recommended:

Standard treatment for local fibrinolysis:

From 0.5 g to 1 g of tranexamic acid administered by slow intravenous injection or infusion (= 1 ml/min) 2 or 3 times daily.

Standard treatment for generalized fibrinolysis:

1 g of tranexamic acid administered by slow intravenous injection or infusion (= 1 ml/min) every 6–8 hours, equivalent to 15 mg/kg body weight.

Renal impairment

The use of tranexamic acid is contraindicated in patients with severe renal impairment (see section "Contraindications"). For patients with mild or moderate renal impairment, the dosage of tranexamic acid should be reduced according to serum creatinine levels:

Hepatic impairment.

Dose adjustment is not required for patients with hepatic impairment.

Elderly patients.

Dose reduction is not necessary in the absence of renal impairment.

Children.

For children aged 1 year and older, use is recommended according to current approved therapeutic indications as described in the section "Indications," with a dosage of approximately 20 mg/kg/day. Data on efficacy, dosing, and safety are limited.

The efficacy, dosing, and safety of tranexamic acid in children who have undergone cardiac surgery have not been fully established.

Overdose.

No cases of overdose have been reported.

Signs and symptoms may include dizziness, headache, hypotension, and seizures. Seizures usually occur more frequently with increasing dose.

In case of overdose, supportive therapy should be administered.

Adverse reactions.

The adverse reactions are listed in the table below according to system organ classification and frequency of occurrence. Within each frequency group, adverse reactions are presented in order of decreasing severity.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Incompatibility.

This medicinal product should not be added to blood for transfusion or to injectable solutions of penicillin.

Packaging. 5 ml or 10 ml in vials, pack of 5 (5×1), pack of 10 (5×2) in blisters in a cardboard box, pack of 5, pack of 10 in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's address and place of business.

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.