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. Inhibitors of fibrinolysis. 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 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 were evaluated in comparison with a placebo control group. The study population was heterogeneous with respect to age, type of surgical intervention, and dosing. Study results on the use of tranexamic acid indicate reduced blood loss and decreased need for blood products in pediatric cardiac surgery involving cardiopulmonary bypass (CPB) during high-risk bleeding procedures, particularly in "cyanotic" patients (with significant circulatory impairment) or patients undergoing reoperation. The most appropriate dosing regimen identified appears to be as follows:

• Initial dose (loading dose) – a bolus infusion of 10 mg/kg administered after induction of anesthesia and before skin incision;
• continuous infusion at 10 mg/kg/hour or intermittent 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 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 with 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 administration of 10 mg/kg in pregnant women, serum concentrations of tranexamic acid range from 10–53 mcg/mL, while concentrations in umbilical cord blood range from 4–31 mcg/mL. Tranexamic acid rapidly penetrates into joint fluid and synovial membrane tissues. After intravenous injection of 10 mg/kg in patients undergoing knee surgery, concentrations in joint fluid are similar to those in blood 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 migration (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 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 following surgical intervention on the prostate or as a result of surgery or procedures 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 the active substance or to any of the excipients of the medicinal product. 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 impairment (risk of drug accumulation). History of seizures. Intrathecal, intraventricular, or intracerebral administration (risk of cerebral edema with subsequent development of seizures).

Interaction with other medicinal products and other forms of interactions.

Drug interaction studies have not been conducted. Concomitant (simultaneous) use of anticoagulants should be performed under strict supervision of a physician experienced in this area of therapy. 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 estrogens are used. 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 aortic coronary bypass surgery (CABG), 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: Possible ophthalmological complications, including visual disturbances, deterioration of vision, and color vision disturbances, should be carefully monitored. Treatment should be discontinued in such cases. Regular ophthalmological examinations (including assessment of visual acuity, color vision, fundus, visual fields, etc.) should be scheduled during continuous long-term administration of tranexamic acid (injections). In the presence of, or if pathological ophthalmological changes develop—particularly those related to retinal disorders—after appropriate specialist consultation, the physician must individually determine 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 disorders or those with a family history indicating a 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 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 the 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 stop bleeding. The use of tranexamic acid in patients with DIC should only be considered when appropriate hematological laboratory capabilities 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, the use of tranexamic acid during the first trimester of pregnancy is not recommended.

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 affect reaction speed when operating vehicles or machinery.

Studies evaluating the effect of tranexamic acid on the ability to drive vehicles or operate machinery have not been conducted.

Method of administration and dosage.

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

Adults.

In 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.

In local fibrinolysis, the recommended initial dose 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 in patients with renal impairment.

In patients with renal insufficiency, the use of tranexamic acid is contraindicated in those 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 hepatic dysfunction.

Use in children.

For children aged 1 year and older, use is indicated as specified in the section "Indications". The recommended dosage is approximately 20 mg/kg/day. However, data on efficacy, safety, and specific dosing considerations for use in children for the specified indications are limited.

The efficacy, dosing specifics, 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 specific regimen – slow intravenous injection/infusion.

Tranexamic acid should not be administered intramuscularly.

Intravenous injection: tranexamic acid should be administered as a 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.

Cases of overdose have not been reported.

Symptoms of overdose may include dizziness, headache, hypotension, and convulsions. Convulsions have been shown to occur more frequently with higher infusion rates and are characteristic with increased doses.

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 listed in order of frequency. Within each frequency group, reactions are ranked in decreasing order of occurrence. Frequency has been defined as follows: very common (<u>> 1/10); common (<u>> 1/100 to < 1/10); uncommon (<u>> 1/1000 to < 1/100); frequency not known (cannot be estimated from 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.

Injectable tranexamic acid must not be added to blood intended 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.

Prescription only.

Manufacturer.

Private joint-stock company "Lekhim-Kharkiv" (responsible for manufacturing and control/testing of the batch, excluding batch release).

SCIENTIFIC-PRODUCTION FIRM "MIKROKHEM" LLC (responsible for batch release, excluding control/testing of the batch).

Manufacturer's address and place of business.

36 Severin Pototskoho Street, Kharkiv, Kharkiv region, 61115, Ukraine (Private joint-stock company "Lekhim-Kharkiv").

33 Lenin Street, Rubizhne, Luhansk region, 93000, Ukraine (SCIENTIFIC-PRODUCTION FIRM "MIKROKHEM" LLC).

Marketing Authorization Holder.

SCIENTIFIC-PRODUCTION FIRM "MIKROKHEM" LLC.

Address of the Marketing Authorization Holder.

33 Lenin Street, Rubizhne, Luhansk region, 93000, Ukraine.

Adverse events related to the use of this medicinal product should be reported by calling: + 38 (050) 309-83-54 (24/7).