Tranaar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRANAAR (TRANAAR)

Composition:

Active substance: tranexamic acid;

1 ml of solution contains 100 mg of tranexamic acid;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

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; this complex is converted into 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 one year and older

Literature data identified 12 studies on efficacy in pediatric cardiac surgery involving 1073 children, of whom 631 patients 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 demonstrate 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 reoperation. The most commonly used dosing regimen is:

• 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 procedure or patient body weight (10 mg/kg body weight), or according to the priming volume of the cardiopulmonary bypass circuit, with a final dose of 10 mg/kg body weight administered at the end of cardiopulmonary bypass use.

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

No specific dose-effect or pharmacokinetic studies have been conducted in children.

Pharmacokinetics

Absorption

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

Distribution

Protein binding of tranexamic acid to plasma proteins is approximately 3% at therapeutic plasma levels and is likely entirely due to 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 concentrations in umbilical cord blood 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 several 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 inhibits fibrinolytic activity but does not affect sperm migration (motility).

Elimination

Tranexamic acid is primarily excreted unchanged in urine. Renal elimination occurs mainly via glomerular filtration. Renal clearance equals plasma clearance (110–116 mL/min). Excretion of tranexamic acid is 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

Carcinogenicity and mutagenicity

Standard studies with tranexamic acid have not shown evidence of carcinogenic or mutagenic potential.

Reproductive toxicity

In reproductive toxicity studies (fertility and early embryonic development, embryofetal development, and pre- and postnatal studies), tranexamic acid did not exert adverse effects on reproductive parameters in mice, rats, and rabbits at clinically relevant doses.

General toxicity

In nonclinical studies, retinal toxicity of tranexamic acid was observed. The observed toxicity was characterized by retinal atrophy, beginning with changes in the retinal pigment epithelium and progressing to retinal detachment in cats. The toxicity was dose-dependent, and changes were partially reversible at lower doses. Effects (some fully reversible) were observed in cats at clinically relevant doses, while in dogs effects occurred only at doses multiple times higher than clinical doses. Studies suggest that the primary mechanism may involve transient retinal ischemia induced by high doses, related to the known sympathomimetic effect of high plasma levels of tranexamic acid. The clinical relevance of these findings is unknown.

Epileptogenic activity was observed in animals following intrathecal administration of tranexamic acid.

Clinical characteristics.

Indications.

Tranexamic acid is indicated in adults and children aged one year and older for the prevention and treatment of bleeding due to general or local fibrinolysis.

Specific indications include:

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

Contraindications.

Hypersensitivity to the active substance.

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

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

History of seizure disorders.

Intrathecal, epidural, intraventricular, and intracerebral injection (risk of cerebral edema leading to seizures and fatal outcome).

Interaction with other medicinal products and other types of interactions.

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 with caution to patients who have received tranexamic acid. When used concomitantly with hormonal contraceptives, there is a risk of increased thrombotic potential. Furthermore, the antifibrinolytic effect of the medicinal product may be antagonized by the use of thrombolytics.

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.

Risk of medication errors due to incorrect route of administration

Tranaar is intended for intravenous use only. Intrathecal, epidural, intraventricular, and intracerebral administration of Tranaar is contraindicated (see section "Contraindications"). Serious adverse reactions, including fatal cases, have been reported when tranexamic acid was inadvertently administered intrathecally. These reactions included severe back, buttock, and lower limb pain, myoclonus, generalized seizures, and arrhythmias.

Care must be taken to ensure the correct route of administration of Tranaar. Healthcare professionals should be aware of the potential for confusion between Tranaar and other injectable medicinal products, which may lead to accidental intrathecal administration of Tranaar. This includes, in particular, injectable medicinal products intended for intrathecal use that may be used during the same procedure as tranexamic acid.

Syringes containing tranexamic acid must be clearly labeled indicating the intravenous route of administration.

Seizures

Cases of seizures in association with tranexamic acid treatment have been reported. In coronary artery surgery, most cases of seizures occurred after intravenous administration of high doses of tranexamic acid. When recommended lower doses of tranexamic acid are used, the frequency of postoperative seizures is similar to that in untreated patients.

Visual disturbances

Possible visual disturbances, including blurred vision, visual impairment, and impaired color vision, should be monitored. If such disturbances occur, treatment should be discontinued. Regular ophthalmological examinations (eye examination including visual acuity, color vision, fundoscopy, and visual field testing) are recommended during prolonged continuous use of tranexamic acid. In patients with pre-existing ophthalmological pathology, particularly retinal disorders, the physician should consult with a specialist to determine the necessity of prolonged tranexamic acid use in each individual case.

Hematuria

In cases of hematuria involving the upper urinary tract, there may be a risk of urethral obstruction.

Without appropriate treatment, urinary tract obstruction may lead to serious consequences such as renal failure, urinary tract infection, hydronephrosis, and anuria. Therefore, careful monitoring is recommended for patients with hematuria or at risk of hematuria from the upper urinary tract.

Thromboembolic disorders

Risk factors for thromboembolic disease should be considered before administering tranexamic acid. Tranexamic acid should be administered only under strict medical indications and under close medical supervision after consultation with a physician experienced in hemostasis for 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 receiving 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 is characterized by: shortened euglobulin clot lysis time; prolonged prothrombin time; decreased plasma levels of fibrinogen, factors V and VIII, plasminogen, and alpha-2-macroglobulin; normal plasma levels of prothrombin (P) and P-complex (i.e., factors II, VIII, and X); increased levels of fibrinogen degradation products in plasma; and normal platelet count. The above profile suggests that the underlying disease state itself does not modify the various elements 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 and qualified specialists are available.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Pregnancy

Available data from published studies, case series, and reports on the use of tranexamic acid in pregnant women during the second and third trimesters of pregnancy and during delivery do not indicate an association between the use of the medicinal product and an increased risk of miscarriage or adverse outcomes for the mother or fetus. Cases of fetal structural abnormalities resulting in neonatal death have been reported following maternal use of tranexamic acid during conception or in the first trimester of pregnancy; however, due to the influence of other concomitant factors, the risk of serious congenital malformations associated with the use of tranexamic acid during pregnancy has not been established.

Animal studies do not indicate direct or indirect harmful effects on reproductive toxicity (see section "Preclinical safety data").

Tranexamic acid crosses the placenta. The concentration in umbilical cord blood after intravenous administration of 10 mg/kg to pregnant women is approximately 30 mg/L, which is as high as in maternal blood.

Thirteen clinical studies have reported functional problems in the fetus and/or newborn, such as low Apgar scores, neonatal sepsis, and cephalohematoma, and nine clinical studies have discussed growth changes, including low birth weight and preterm delivery at 22–36 weeks of gestation in fetuses and infants exposed to tranexamic acid in utero.

When deciding on the use of tranexamic acid during pregnancy, the potential risk of tranexamic acid to the fetus and the clinical necessity of tranexamic acid for the mother should always be considered; a precise risk-benefit assessment should be decisive in the treating physician's decision.

Breastfeeding period

Published literature reports the passage of tranexamic acid into breast milk. Data on the effects of tranexamic acid on the breastfed infant or on milk production are limited.

The benefits of breastfeeding for the infant's development and health should be weighed against the mother's clinical need for tranexamic acid and any potential adverse effects of tranexamic acid or the mother's underlying condition on the breastfed infant. Due to limited data, a definitive assessment of the use of tranexamic acid during breastfeeding has not been established.

Fertility

There are no clinical data on the effect of tranexamic acid on fertility. In animal studies, tranexamic acid did not affect fertility in males or females at clinically relevant doses (see section "Preclinical safety data").

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted on the ability to drive or operate machinery.

Method of Administration and Dosage

Dosage

Adults

If not otherwise established, the following doses are recommended:

1. Standard treatment of local fibrinolysis:

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

2. Standard treatment of systemic fibrinolysis:

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

Renal Function Impairment

For patients with mild to moderate renal impairment, the dosage of tranexamic acid should be reduced according to serum creatinine levels:

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment.

Elderly patients

Dosage reduction is not necessary in the absence of evidence of renal insufficiency.

Method of administration

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 medicinal product.

Tranexamic acid must not be administered intramuscularly.

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

TRANEXAMIC ACID MUST BE ADMINISTERED INTRAVENOUSLY ONLY and must not be administered intrathecally or epidurally (see sections "Contraindications" and "Special precautions for use").

To reduce the risk of fatal medication errors due to incorrect route of administration of tranexamic acid, it is strongly recommended to label syringes containing tranexamic acid (see sections "Contraindications" and "Special precautions for use").

Children

In children aged one year and older, for currently approved indications as stated in the section "Indications", the dosage is within the range of 20 mg/kg body weight/day. However, data on efficacy, dosage, and safety for these indications are limited.

The efficacy, dosage, and safety of tranexamic acid in children who have undergone cardiac surgery have not been fully established. Current data are limited and described in the section "Pharmacodynamics".

Overdose

No cases of overdose have been reported.

Signs and symptoms may include dizziness, headache, hypotension, and seizures. Seizures have been shown to occur more frequently with increasing dose.

Treatment of overdose should be supportive.

Adverse reactions.

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

Immune system disorders

Frequency not known: hypersensitivity reactions, including anaphylaxis.

Nervous system disorders

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

Eye disorders

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

Cardiovascular system disorders

Frequency not known: general malaise with hypotension, with or without loss of consciousness (usually after 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. Do not freeze.

Incompatibilities. Tranexamic acid for injection must not be added to blood for transfusion or to injectable solutions containing penicillin-group medicinal products.

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

Prescription category. Prescription only.

Manufacturer. Mankind Pharma Limited.

Manufacturer's address and site of operations.
Village Kishanpura, P.O. Jamniwala, Tehsil Paonta Sahib, District Sirmour 173025, Himachal Pradesh, India.