Maxitran

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Maxitran® (Maxitran)

Composition:

Active substance: tranexamic acid;

1 ml of injection 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. 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 forms involving tranexamic acid and plasminogen; tranexamic acid binds to plasminogen during conversion involving plasmin. The activity of the complex of tranexamic acid and plasmin 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 studies on efficacy in pediatric cardiac surgery, involving 1073 children, have been described in the scientific literature; of these, 631 patients received tranexamic acid. Most were evaluated in comparison with a placebo control group. The study population was heterogeneous with respect to age, type of surgical intervention, and dosing. Results from studies on the use of tranexamic acid indicate reduced blood loss and decreased 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 repeat surgery. The most appropriate dosing regimen identified appears to be:

• Initial dose (loading dose) – bolus infusion of 10 mg/kg administered after induction of anesthesia and before skin incision;
• continuous infusion at 10 mg/kg/h or intravenous injection into the CPB 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 CPB pump adapter and a final 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.

Peak 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 believed 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 serum ranges from 10–53 µg/mL, while in umbilical cord blood it ranges 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 synovial 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 – 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 virtually 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 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 body weight 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.

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 as a result of surgical intervention on the prostate gland or due to surgical procedures or interventions on the urinary tract;
• Otolaryngological (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 the active substance or to any of the excipients. Acute venous or arterial thrombosis. Fibrinolytic states with acute severe bleeding due to administration of anticoagulant agents, except for agents that predominantly activate the fibrinolytic system. Severe renal insufficiency (risk of drug accumulation). History of seizures. Intrathecal, intraventricular, and intracerebral injection (risk of cerebral edema followed by 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. Furthermore, the antifibrinolytic effect of the drug may be antagonized by thrombolytics. Heparins may be added during intravenous infusion.

Special precautions for use.

The specified indications and method of administration must be strictly observed:

• Intravenous injections should be administered very slowly;
• tranexamic acid must not be administered intramuscularly.

Seizures: Seizures associated with tranexamic acid treatment have been reported in patients. During coronary artery bypass graft (CABG) surgery, most of these cases occurred after intravenous administration of high-dose 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: Possible ophthalmological complications should be carefully monitored, including visual disturbances, decreased vision, and impaired color vision. Treatment should be discontinued in such cases. With continuous prolonged administration of tranexamic acid (injections), regular ophthalmological examinations (including visual acuity, color vision, fundoscopy, visual field testing, etc.) should be scheduled. In the presence or development of pathological ophthalmological changes, particularly retinal disorders, the physician, after appropriate specialist consultation, must individually assess the necessity and feasibility of long-term tranexamic acid (injections) 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. Tranexamic acid (injection solution) should be administered to patients with a history of thromboembolic disorders or to those with a family history indicating risk of thromboembolic complications (patients at high risk of thrombophilia) only when there are clear life-threatening indications. Treatment should be initiated only after consultation with a specialist experienced in hemostasis and conducted under strict medical supervision.

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

Disseminated intravascular coagulation (DIC): Patients with DIC syndrome generally should not receive treatment with tranexamic acid. If the use of tranexamic acid is 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 elements of this profile cannot change independently due to the underlying disease itself. In such acute cases, a single dose of 1 g of tranexamic acid is often sufficient to stop bleeding. The use of tranexamic acid in patients with DIC syndrome should only be considered when appropriate hematological laboratory facilities 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 speed when driving or operating machinery.

Studies evaluating the effect on the ability to drive or operate machinery are lacking.

Method of administration and dosage.

Maxitran® is administered intravenously (by drip or bolus injection).

Adults.

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

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

Dosing for patients with renal impairment.

In cases of renal insufficiency, tranexamic acid is contraindicated in patients with 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 impaired liver function.

Use in children

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

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

Use in elderly patients

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

Route of administration

Administration is strictly limited to slow intravenous injection or infusion.

Tranexamic acid should 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 immediately before use 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

Maximum single dose for children aged 1 year and older is 10 mg/kg body weight. 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 when doses are increased.

Treatment of overdose is symptomatic.

Adverse reactions

The adverse reactions listed below are classified according to the MedDRA system organ class. Within each system organ class, adverse reactions are ranked by frequency. Within each frequency group, reactions are listed in decreasing order of incidence. Frequency has been defined as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); frequency not known (cannot be estimated based on available data).

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.

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, 5 ampoules (5×1) in a cassette in a cardboard pack.

Or 5 ml in ampoules, 10 ampoules (5×2) in cassettes in a cardboard pack.

Prescription status.

By prescription only.

Manufacturer.

MICROCHEM LLC (responsible for batch release, excluding control/testing of the batch)

HALYCHPHARM JSC (responsible for manufacturing and control/testing of the batch, excluding batch release)

Manufacturer's address and place of business.

Ukraine, 01013, Kyiv, Budynstustriyi St., 5 (MICROCHEM LLC).

Ukraine, 79024, Lviv region, Lviv city, Opryshkovska St., 6/8 (HALYCHPHARM JSC).

Marketing authorization holder.

MICROCHEM LLC.

Address of the marketing authorization holder.

Ukraine, 01013, Kyiv, Budynstustriyi St., 5.