Neotranex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEOTRANEX

Composition:

Active substance: 5 ml of solution contains 500 mg of tranexamic acid;

Excipients: concentrated hydrochloric acid (for pH adjustment to 6.5–7.5), water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Antihemorrhagic agents. Fibrinolysis inhibitors. Amino acids. Tranexamic acid.

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 studies have shown that high doses of tranexamic acid reduce the activity of this complex.

Pediatric population (children aged 1 year and older)

Twelve efficacy studies in pediatric cardiac surgery involving 1073 children have been described in the scientific literature, of which 631 patients received tranexamic acid. Most of these patients were evaluated in comparison with a placebo control group. The study population was heterogeneous with respect to age, type of surgical procedure, and dosing regimen. Study results indicate that the use of tranexamic acid reduces blood loss and the need for blood products in pediatric cardiac surgery involving cardiopulmonary bypass (CPB), particularly in high-bleeding-risk procedures, especially in "cyanotic" patients (with significant circulatory impairment) or patients undergoing reoperation. The most appropriate dosing regimen identified is as follows:

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

− Continuous administration via infusion at 10 mg/kg/hour, or injection into the cardiopulmonary bypass pump adapter at a dose adjusted for the specific surgical procedure or calculated according to patient body weight (10 mg/kg), or administration into the cardiopulmonary bypass pump adapter followed by 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 or pharmacokinetic studies have been conducted in children.

Pharmacokinetics

Absorption

Maximum plasma concentration of tranexamic acid is rapidly achieved after 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 considered to be entirely attributable to binding with plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is approximately 9 to 12 L. Tranexamic acid crosses the placenta. After intravenous administration of 10 mg/kg in pregnant women, the concentration of tranexamic acid in maternal serum ranges from 10 to 53 µg/mL, while in umbilical cord blood it ranges from 4 to 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 synovial fluid were similar to those in serum. Concentrations of tranexamic acid in other tissues and fluids are proportional to those in blood (in breast milk – one hundredth, in cerebrospinal fluid – one tenth, in aqueous humor of the eye – one tenth). Tranexamic acid has been detected in semen, where it inhibits fibrinolytic activity but has almost no effect on sperm motility.

Elimination

The drug is primarily excreted in urine as unchanged compound. Renal excretion via glomerular filtration is the main elimination pathway. Renal clearance is almost 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 are increased in patients with renal impairment. No specific pharmacokinetic studies have been conducted in children.

Clinical characteristics.

Indications.

Bleeding or risk of bleeding due to enhanced fibrinolysis, either generalized or local, in adults and children aged 1 year and older.

Specific indications include:

− bleeding caused by increased systemic or local fibrinolysis, such as:

− menorrhagia and metrorrhagia;

− gastrointestinal bleeding;

− hemorrhagic disorders of the urinary tract occurring following surgical intervention on the prostate gland or due to surgical procedures or interventions on the urinary tract;

− otorhinolaryngological (adenoidectomy, tonsillectomy) and dental (tooth extraction) surgical procedures;

− gynecological surgeries or complications in obstetric practice;

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

− control of hemorrhage associated with administration of a fibrinolytic medicinal product.

Contraindications.

Hypersensitivity to tranexamic acid and components of the medicinal product. Acute venous or arterial thrombosis. Fibrinolytic states with acute severe bleeding due to administration of anticoagulant agents, except for medicinal products that predominantly activate the fibrinolytic system. Severe renal insufficiency (risk of drug accumulation). History of seizures. Intrathecal and intraventricular injection, intracerebral administration (risk of cerebral edema with subsequent development of seizures).

Interaction with other medicinal products and other forms of interaction.

Drug interaction studies have not been conducted. Concomitant (simultaneous) use of anticoagulants should be performed under strict supervision of a physician experienced in this therapeutic area. Medicinal products affecting hemostasis should be used with caution in patients who have received treatment with tranexamic acid. In such cases, there is a risk of thrombosis, for example, when using estrogens. In addition, the antifibrinolytic effect of the drug may be antagonized by thrombolytics. Heparins may be added during intravenous infusion.

Special precautions for use

Strict adherence to the specified indications and method of administration is required:

− Intravenous injections should be administered very slowly;

− tranexamic acid must not be administered intramuscularly.

Seizures. Cases of seizures associated with tranexamic acid treatment have been reported in patients. During aortocoronary bypass surgery (ACBS), most of these cases occurred after intravenous administration of high doses of tranexamic acid. When recommended low doses of tranexamic acid are used, the incidence of postoperative seizures is the same as in patients who did not receive this medicinal product.

Visual disturbances. The possibility of ophthalmological complications, including visual disturbances, worsening of vision, and color vision disorders, should be considered. In such cases, treatment should be discontinued. With continuous long-term use of tranexamic acid (injections), regular ophthalmological examinations (including visual acuity, color vision, fundoscopy, visual field testing, etc.) should be scheduled. In the presence of, or if ophthalmological abnormalities develop—particularly those related to retinal disorders—after appropriate specialist consultation, the physician must individually assess the necessity and feasibility of long-term tranexamic acid (injection) therapy in each specific case.

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

Thromboembolic complications. Risk factors for thromboembolic complications should be evaluated before prescribing tranexamic acid. Patients with a history of thromboembolic disease or those with a family history indicating risk of thromboembolic complications (patients at high risk of thrombophilia) should receive tranexamic acid (injection solution) only when there are clear, life-threatening indications. Treatment should be initiated only after consultation with a specialist experienced in hemostasis and must be conducted under strict medical supervision.

Due to the increased risk of thrombosis, tranexamic acid should be administered cautiously to patients taking oral contraceptives.

Disseminated intravascular coagulation (DIC). Patients with DIC syndrome generally should not receive treatment with tranexamic acid. If use of tranexamic acid is considered necessary, it should be prescribed only in cases of predominant activation of the fibrinolytic system associated with acute, severe bleeding. The characteristic hematological profile in these conditions includes: shortened euglobulin clot lysis time; prolonged prothrombin time; decreased plasma levels of fibrinogen, factors V and VIII, plasminogen, fibrinolysin, and α-2-macroglobulin; normal plasma levels of P and P-complex (i.e., factors II [prothrombin], VIII, and X); elevated plasma levels of fibrinogen degradation products; and normal platelet count. The above profile implies that various components may not change independently in the presence of the underlying disease. In such acute cases, a single dose of 1 g of tranexamic acid is often sufficient to control bleeding. The use of tranexamic acid in patients with DIC should only be considered when appropriate hematological laboratory support and clinical experience are available.

Use during pregnancy or breastfeeding.

Women of reproductive age should use effective contraceptive methods during treatment.

There is insufficient clinical data on the use of tranexamic acid in pregnant women.

As a precautionary measure, tranexamic acid is not recommended during the first trimester of pregnancy.

There are only limited clinical data on the use of tranexamic acid in various hemorrhagic conditions during the second and third trimesters of pregnancy, which do not indicate a harmful effect on the fetus. Tranexamic acid may be used during pregnancy only if the expected therapeutic benefit outweighs the potential risk.

Tranexamic acid passes into breast milk. Therefore, breastfeeding is not recommended.

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

Ability to influence reaction rate while driving or operating machinery.

No studies have been conducted to evaluate the effect of tranexamic acid on the ability to drive or operate machinery.

Method of Administration and Dosage

Neotranex should be administered intravenously (by infusion or bolus injection).

Adults.

In cases of generalized fibrinolysis, tranexamic acid should be administered intravenously slowly at a dose of 1 g (2 vials of 5 ml) or 15 mg/kg body weight every 6–8 hours; the administration rate should be 1 ml/min.

In cases of local fibrinolysis, the recommended dose is 500 mg (1 vial of 5 ml) to 1 g (2 vials of 5 ml) of the drug administered intravenously slowly (approximately 1 ml/min), 2–3 times daily.

Dosing for patients with renal impairment.

In patients with renal insufficiency, the use of tranexamic acid is contraindicated in cases of severe renal impairment. For patients with mild or moderate renal impairment, the dosage of tranexamic acid should be reduced according to serum creatinine levels:

Dosing in patients with hepatic impairment

Dose adjustment is not required in patients with hepatic impairment.

Use in 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 specific dosing regimens in children for the indicated conditions are limited.

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

Use in elderly patients

Dose adjustment is generally not required unless there are signs of renal impairment.

Route of administration

Administration must strictly follow a defined regimen – slow intravenous injection (bolus) or infusion.

Tranexamic acid must not be administered intramuscularly.

Intravenous injection: tranexamic 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: 0.9% sodium chloride injection; Ringer's injection solution; 5% dextrose injection; dextrin-40 in 5% dextrose injection; dextrin-40 in 0.9% sodium chloride injection for injection; 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

Cases of overdose have not been reported.

Symptoms of overdose may include dizziness, headache, hypotension, and seizures (convulsions). Seizures have been shown to occur more frequently with higher infusion rates and are characteristic of increased dosage.

Treatment of overdose is symptomatic.

Adverse reactions

The adverse reactions listed below are systematized according to the MedDRA classification (primary system organ classes). Within each organ system class, adverse reactions are ranked by frequency. Within each frequency group, reactions are listed in decreasing order of occurrence. Frequency was defined as follows: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); frequency not known (cannot be estimated from available data).

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Incompatibility.

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

Packaging.

5 ampoules in a blister pack, 1 pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

BIOINDUSTRIA LABORATORIO ITALIANO MEDICINALI S.P.A.

Manufacturer's address and location of business activity.

Via degli Ammoggiati 2/6 – 15067 Novi Ligure (AL), Italy.