Skytran

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SCAITRAN (SKYTRAN)

Composition:

Active substance: tranexamic acid;

1 ml of solution contains 100 mg of tranexamic acid;

Excipients: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antihemorrhagic agents, antifibrinolytic amino acids. Fibrinolysis inhibitors. ATC code B02A A02.

Pharmacological Properties

Pharmacodynamics

Tranexamic acid exerts an antihemorrhagic effect by inhibiting the fibrinolytic activity of plasmin.

Tranexamic acid forms a complex with plasminogen; it binds to plasminogen during its conversion to plasmin.

The activity of the tranexamic acid–plasmin complex against fibrin is lower than that of free plasmin.

In vitro studies have shown that high doses of tranexamic acid reduce complement activity.

Children

Children aged 1 year and older

Literature data identified 12 efficacy studies in pediatric cardiac surgery involving 1073 children, of whom 631 received tranexamic acid. Most of these studies were placebo-controlled. The study population was heterogeneous in terms of age, types of surgery, and dosing regimens. Study results with tranexamic acid indicate reduced blood loss and decreased need for blood products in pediatric cardiac surgery with cardiopulmonary bypass, where there is a high risk of bleeding, particularly in cyanotic patients or those undergoing repeat surgery.

The most commonly used dosing regimen:

• Initial bolus dose of 10 mg/kg body weight administered after induction of anesthesia and before skin incision;
• Continuous infusion of 10 mg/kg body weight/hour, or administration into the cardiopulmonary bypass circuit at a dose adjusted to the cardiopulmonary bypass procedure, or according to patient body weight at 10 mg/kg body weight, or according to the priming volume of the cardiopulmonary bypass circuit, with the final dose of 10 mg/kg body weight administered at the end of cardiopulmonary bypass use.

Although studies have been conducted in a limited number of patients, available data suggest that continuous infusion is preferable, as it maintains therapeutic plasma concentrations throughout the entire surgical procedure.

In children, specific dose-effect or pharmacokinetic studies have not been conducted.

Pharmacokinetics

Absorption

Peak plasma concentrations of tranexamic acid are rapidly achieved after short intravenous infusion, after which plasma concentrations decline in a multi-exponential manner.

Distribution

Protein binding of tranexamic acid to plasma proteins is approximately 3% at therapeutic plasma levels and is likely entirely explained by its 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 placenta. After intravenous injection at a dose of 10 mg/kg body weight in 12 pregnant women, serum concentrations of tranexamic acid ranged from 10–53 µg/mL, while in umbilical cord blood they ranged from 4–31 µg/mL. Tranexamic acid rapidly penetrates into joint fluid and synovial membrane. After intravenous injection at a dose of 10 mg/kg body weight in 17 patients undergoing knee surgery, concentrations in joint fluid were similar to those in corresponding serum samples. Concentrations of tranexamic acid in certain other tissues are a fraction of those observed in blood (breast milk – 0.01; cerebrospinal fluid – 0.1; intraocular fluid – 0.1). Tranexamic acid has been detected in semen, where it suppresses fibrinolytic activity but does not affect sperm migration.

Elimination

Tranexamic acid is primarily excreted unchanged in urine. Renal elimination via glomerular filtration is the main route of elimination. Renal clearance equals plasma clearance (110–116 mL/min). Excretion of tranexamic acid amounts to approximately 90% within the first 24 hours after intravenous administration of a 10 mg/kg body weight dose. The elimination half-life of tranexamic acid is approximately 3 hours.

Other special patient populations

Plasma concentrations increase in patients with renal impairment.

No specific pharmacokinetic studies have been conducted in children.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on standard safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive and developmental toxicity studies. Epileptogenic activity was observed in animals following intraperitoneal administration of tranexamic acid.

Clinical characteristics.

Indications.

Tranexamic acid is indicated in adults and children aged 1 year and older for the prevention and treatment of hemorrhages due to systemic or local fibrinolysis.

Specific indications include:

• hemorrhages caused by systemic or local fibrinolysis, such as:
  • menorrhagia and metrorrhagia;
  • gastrointestinal bleeding;
  • hemorrhagic disorders of urination, additionally during surgery on the prostate or surgical procedures affecting the urinary tract;
• ear, nose and throat surgery (adenoidectomy, tonsillectomy, dental interventions);
• gynecological surgery or obstetric complications;
• thoracic and abdominal surgery and other major surgical procedures, such as cardiovascular surgery;
• control of hemorrhages due to administration of a fibrinolytic agent.

Contraindications.

Hypersensitivity to the active substance of the medicinal product.

Acute venous or arterial thrombosis (see section "Special precautions").

Fibrinolytic states following consumption coagulopathy, except those where predominant activation of the fibrinolytic system occurs with acute severe bleeding (see section "Special precautions").

Severe renal impairment (risk of accumulation).

History of seizures.

Intracerebral and intraventricular administration, intramedullary administration (risk of cerebral edema and seizures).

Interaction with other medicinal products and other forms of interaction.

No interaction studies have been conducted. Concomitant treatment 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 who have received tranexamic acid. There is a risk of increased thrombotic potential, for example with estrogens. Alternatively, the antifibrinolytic effect of the drug may be antagonized by thrombolytic agents.

Special precautions for use.

When using the medicinal product, the indications and method of administration must be strictly observed:

• Intravenous injections or infusions should be administered very slowly (maximum 1 mL/min);
• tranexamic acid must not be administered intramuscularly.

Seizures

Cases of seizures have been reported during the use of tranexamic acid. In coronary artery surgery, most cases of seizures were reported after intravenous administration of high doses of tranexamic acid. When lower recommended doses of tranexamic acid were used, the incidence of postoperative seizures was similar to that in untreated patients.

Visual disturbances

Possible visual disturbances should be considered, including blurred vision, visual clouding, and impaired color vision. If such disturbances occur, treatment should be discontinued. During prolonged continuous use of tranexamic acid, regular ophthalmological examinations (eye examination including visual acuity, color vision, fundoscopy, and visual field testing) should be scheduled. When prescribing the drug to patients with pre-existing ophthalmological pathology, especially retinal disorders, the physician should decide, in consultation with a specialist, on the duration of tranexamic acid treatment in each individual case.

Hematuria

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

Thromboembolic disorders

Before administering tranexamic acid, risk factors for thromboembolic disease should be considered. Tranexamic acid should be administered only under strict medical indications and after consultation with a physician experienced in hemostasis, and under close medical supervision, to patients with a history of thromboembolic disorders or those with a family history of increased incidence of thromboembolic disorders (patients at high risk of thrombophilia) (see section "Contraindications").

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

Disseminated intravascular coagulation (DIC)

Patients with DIC should generally not be treated with tranexamic acid (see section "Contraindications"). If tranexamic acid is used, it should be restricted only to patients in whom activation of the fibrinolytic system predominates during acute, severe bleeding. Typically, the hematological profile includes: shortened euglobulin clot lysis time; prolonged prothrombin time; decreased plasma levels of fibrinogen, factors V and VIII, plasminogen, and alpha-2-macroglobulin; normal levels of plasma factors II (prothrombin), VIII, and X; elevated levels of plasma fibrin and fibrinogen degradation products; and normal platelet count. The above profile suggests that the underlying disease state itself does not alter the various components of this profile. In such acute cases, a single dose of 1 g of tranexamic acid is often sufficient to control bleeding. Administration of tranexamic acid in DIC syndrome should be considered only when appropriate hematological laboratory facilities are available and under expert supervision.

The medicinal product is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment.

Pregnancy

There is limited data on the use of tranexamic acid in pregnant women. Although animal studies do not indicate teratogenic effects, as a precautionary measure, tranexamic acid 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 of pregnancy have not shown any harmful effects on the fetus. Tranexamic acid should be used during pregnancy only if the expected benefit outweighs the potential risk.

Breastfeeding period

Tranexamic acid is excreted in breast milk; therefore, breastfeeding should be discontinued during treatment with this medicinal product.

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 ability to drive or operate machinery have not been conducted.

Method of Administration and Dosage

Dosage

Adults

Unless otherwise indicated, the following doses are recommended:

1. Standard treatment for local fibrinolysis:

0.5 g (1 vial of 5 ml) to 1 g (2 vials of 5 ml) of tranexamic acid administered slowly intravenously as an injection or infusion (approximately 1 ml/min) 2–3 times daily.

2. Standard treatment for systemic fibrinolysis:

1 g (2 vials of 5 ml) of tranexamic acid administered slowly intravenously as an injection or infusion (approximately 1 ml/min) every 6–8 hours, equivalent to 15 mg/kg body weight.

Renal Impairment

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

Liver Function Impairment

Dose adjustment is not required in patients with impaired liver function.

Children

For children aged 1 year and older, use as indicated (see section "Indications"), with a dosage of approximately 20 mg/kg/day. However, data on efficacy, safety, and dosing characteristics in children for the specified indications are limited.

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

Elderly Patients

Dosage reduction is not necessary if there is no evidence of renal impairment.

Administration Method

Administration is strictly limited to slow intravenous injection or infusion at a rate not exceeding 1 mL/min.

The medicinal product may be mixed with most infusion solutions, such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and dextran solutions. Heparin may be added to the preparation.

Tranexamic acid should not be administered intramuscularly.

Intravenous Injection: tranexamatic acid should be administered by slow bolus injection over at least 5 minutes.

Intravenous Infusion: tranexamic acid should be mixed directly with the following injection/infusion solutions: sodium chloride 0.9%, injection solution; Ringer's injection solution; dextrose, 5% injection solution; dextrin-40 in dextrose 5% injection solution; dextrin-40 in sodium chloride 0.9% injection solution; amino acid solution.

Children

The maximum single dose for children aged 1 year and older is 10 mg/kg body weight. The maximum daily dose is 20 mg/kg body weight.

Overdose

No cases of overdose have been reported.

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

Treatment of overdose should be supportive.

Side effects

The side effects reported in clinical trials and post-marketing experience are listed below by system organ classes. Within each organ system, side effects are categorized by frequency. Within each frequency group, side effects are presented in order of decreasing severity. The frequency of occurrence is classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (frequency cannot be estimated from available data).

Immune system disorders

Frequency not known: hypersensitivity reactions, including anaphylaxis.

Nervous system disorders

Frequency not known: convulsions, particularly with incorrect use (see sections "Contraindications" and "Special precautions for use").

Eye disorders

Frequency not known: visual disturbances, including color vision abnormalities.

Cardiovascular system disorders

Frequency not known: general malaise with hypotension, with or without loss of consciousness (usually following too rapid intravenous injection; exception – after oral administration). Arterial or venous thrombosis at any site.

Gastrointestinal disorders

Common: diarrhea, vomiting, nausea.

Skin and subcutaneous tissue disorders

Uncommon: allergic dermatitis.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 30 °C. Keep out of reach of children.

Incompatibility.

The medicinal product should not be mixed with blood for transfusion or with solutions containing penicillin.

Packaging. 5 ml in ampoules, 4 ampoules per blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. Mankind Pharma Limited.

Manufacturer's address and location of its business operations.

Village Kishanpura, P.O. Jamniwala, Tehsil Paonta Sahib, District Sirmour 173025, Himachal Pradesh, India.