4.1. Therapeutic indications

Prevention and treatment of haemorrhages due to general or local fibrinolysis in adults and children from one year.

Specific indications include:

- Haemorrhage caused by general or local fibrinolysis such as:

- Menorrhagia and metrorrhagia,

- Gastrointestinal bleeding,

- Haemorrhagic urinary disorders, further to prostate surgery or surgical procedures affecting the urinary tract,

- Ear Nose Throat surgery (adenoidectomy, tonsillectomy, dental extractions),

- Gynaecological surgery or disorders of obstetric origin,

- Thoracic and abdominal surgery and other major surgical intervention such as cardiovascular surgery,

- Management of haemorrhage due to the administration of a fibrinolytic agent.

4.2. Posology and method of administration

Posology

Adults

Unless otherwise prescribed, the following doses are recommended:

1. Standard treatment of local fibrinolysis:

0.5 g (1 ampoule of 5 mL) to 1 g (1 ampoule of 10 mL or 2 ampoules of 5 mL) tranexamic acid by slow intravenous injection (= 1 mL/minute) two to three times daily

2. Standard treatment of general fibrinolysis:

1 g (1 ampoule of 10 mL or 2 ampoules of 5 mL) tranexamic acid by slow intravenous injection (= 1 mL/minute) every 6 to 8 hours, equivalent to 15 mg/kg body weight (BW)

Renal impairment

In renal insufficiency leading to a risk of accumulation, the use of tranexamic acid is contra-indicated in patients with severe renal impairment (see section 4.3). For patients with mild to moderate renal impairment, the dosage of tranexamic acid should be reduced according to the serum creatinine level:

Serum creatinine

Dose IV

Administration

μmol/l

mg/10 ml

120 to 249

1.35 to 2.82

10 mg/kg BW

Every 12 hours

250 to 500

2.82 to 5.65

10 mg/kg BW

Every 24 hours

> 500

> 5.65

5 mg/kg BW

Every 24 hours

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment.

Paediatric Population

In children from 1 year, for current approved indications as described in section 4.1, the dosage is in the region of 20 mg/kg/day. However, data on efficacy, posology and safety for these indications are limited.

The efficacy, posology and safety of tranexamic acid in children undergoing cardiac surgery have not been fully established. Currently available data is limited and is described in section 5.1.

Elderly

No reduction in dosage is necessary unless there is evidence of renal failure.

Method of administration

The administration is strictly limited to slow intravenous injection (see section 6.6) of maximum 1 ml per minute.

TRANEXAMIC ACID MUST ONLY BE ADMINISTERED INTRAVENOUSLY and must not be administered intrathecally or epidurally (see sections 4.3 and 4.4).

IN ORDER TO REDUCE THE RISK OF FATAL MEDICATION ERRORS DUE TO INCORRECT ROUTE OF ADMINISTRATION OF TRANEXAMIC ACID, IT IS STRONGLY RECOMMENDED TO LABEL THE SYRINGES CONTAINING TRANEXAMIC ACID (see sections 4.3, 4.4 and 6.6).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Acute venous or arterial thrombosis (see section 4.4).

Fibrinolytic conditions following consumption coagulopathy except in those with predominant activation of the fibrinolytic system with acute severe bleeding (see section 4.4).

Severe renal impairment (risk of accumulation).

History of convulsions.

Intrathecal, epidural, intraventricular injection and intracerebral application (risk of cerebral oedema and convulsions and death).

4.4. Special warnings and precautions for use

The indications and method of administration indicated above should be followed strictly:

• Intravenous injections should be given very slowly (maximum 1 ml per minute).

• Tranexamic acid should not be administered by the intramuscular route.

Risk of medication errors due to incorrect route of administration

Tranexamic acid is for intravenous use only. Intrathecal, epidural, intraventricular and intracerebral use of tranexamic acid is contraindicated (see section 4.3). Serious adverse reactions including fatal events have been reported when tranexamic acid was inadvertently administered intrathecally. These events have included severe back, gluteal and lower limb pain, myoclonus and generalised seizures, and cardiac arrhythmias.

Care should be exercised to ensure the correct route of administration of tranexamic acid. Healthcare professionals should be aware of the potential for confusion of tranexamic acid with other injectables which could result in inadvertent intrathecal administration of tranexamic acid. This includes in particular intrathecally administered injectables that may be used during the same procedure as tranexamic acid.

Syringes containing tranexamic acid should be clearly labelled with the intravenous route of administration.

Convulsions

Cases of convulsions have been reported in association with tranexamic acid treatment. In coronary artery bypass graft (CABG) surgery, most of these cases were reported following intravenous (IV) injection of tranexamic acid in high doses. With the use of the recommended lower doses of tranexamic acid, the incidence of post-operative seizures was the same as that in untreated patients.

Visual disturbances

Attention should be paid to possible visual disturbances including visual impairment, vision blurred, impaired colour vision and if necessary, the treatment should be discontinued. With continuous long-term use of tranexamic acid solution for injection, regular ophthalmologic examinations (eye examinations including visual acuity, colour vision, fundus, visual field etc.) are indicated. With pathological ophthalmic changes, particularly with diseases of the retina, the physician must decide after consulting a specialist on the necessity for the long-term use of tranexamic acid solution for injection in each individual case.

Haematuria

In case of haematuria from the upper urinary tract, there is a risk for urethral obstruction at the lower levels of the tract.

If left untreated, urinary obstruction may lead to serious consequences such as renal insufficiency, urinary tract infection, hydronephrosis, and anuria. Therefore, close monitoring is recommended for those patients with haematuria or risk of haematuria from the upper urinary tract.

Thromboembolic events

Before use of tranexamic acid, risk factors of thromboembolic disease should be considered. In patients with a history of thromboembolic diseases or in those with increased incidence of thromboembolic events in their family history (patients with a high risk of thrombophilia), Tranexamic acid solution for injection should only be administered if there is a strong medical indication after consulting a physician experienced in hemostaseology and under strict medical supervision (see section 4.3).

Tranexamic acid should be administered with care in patients using hormonal contraceptives because of the increased risk of thrombosis (see section 4.5).

Disseminated intravascular coagulation

Patients with disseminated intravascular coagulation (DIC) should in most cases not be treated with tranexamic acid (see section 4.3). If tranexamic acid is given it must be restricted to those in whom there is predominant activation of the fibrinolytic system with acute severe bleeding. Characteristically, the haematological profile approximates to the following: reduced euglobulin clot lysis time; prolonged prothrombin time; reduced plasma levels of fibrinogen, factors V and VIII, plasminogen fibrinolysin and alpha-2 macroglobulin; normal plasma levels of P and P complex; i.e. factors II (prothrombin), VIII and X; increased plasma levels of fibrinogen degradation products; a normal platelet count. The foregoing presumes that the underlying disease state does not of itself modify the various elements in this profile. In such acute cases a single dose of 1 g tranexamic acid is frequently sufficient to control bleeding. Administration of tranexamic acid in DIC should be considered only when appropriate haematological laboratory facilities and expertise are available.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Simultaneous treatment with anticoagulants must take place under the strict supervision of a physician experienced in this field. Medicinal products that act on haemostasis should be given with caution to patients treated with tranexamic acid. There is a risk of increased thrombus-formation potential during concomitant use with hormonal contraception. Alternatively, the antifibrinolytic action of the drug may be antagonised with thrombolytic drugs.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment (see sections 4.4 and 4.5).

Pregnancy

Available data from published studies, case series and case reports with tranexamic acid use in pregnant women in the second and third trimester and at the time of delivery have not clarified whether there is a drug-associated risk of miscarriage or adverse maternal or foetal outcomes. There are cases of foetal structural abnormalities that resulted in death of the newborn following administration of tranexamic acid to the mother during conception or the first trimester of pregnancy; however, due to other confounding factors the risk of major birth defects with use of tranexamic acid during pregnancy is not clear.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Tranexamic acid passes through the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood.

There were 13 clinical studies that described foetal and/or neonatal functional issues such as low Apgar score, neonatal sepsis, cephalohematoma and 9 clinical studies that discussed alterations to growth including low birth weight and preterm birth at 22‑36 weeks of gestation in foetuses and infants exposed to tranexamic acid in‑utero.

For decisions regarding the use of tranexamic acid during pregnancy, the potential risk of tranexamic acid administration on the foetus should always be considered along with the mother's clinical need for tranexamic acid; an accurate risk-benefit evaluation should drive the treating physician's decision.

Breastfeeding

Published literature reports the presence of tranexamic acid in human milk. There are limited data on the effects of tranexamic acid on the breast-fed child or the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for tranexamic acid and any potential adverse effects on the breast-fed child from tranexamic acid or from the underlying maternal condition.

Due to limited data, no final assessment can be established on the use of tranexamic acid during breast‑feeding.

Fertility

There is no clinical data on the effects of tranexamic acid on fertility. In animal studies, tranexamic acid did not affect male or female fertility at clinically relevant doses (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies have been performed on the ability to drive and use machines.

4.8. Undesirable effects

The ADRs reported from clinical studies and post-marketing experience are listed below according to system organ class.

Tabulated list of adverse reactions

Adverse reactions reported are presented in table below. Adverse reactions are listed according to MedDRA primary system organ class. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined 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) and very rare (<1/10,000) and frequency not known (cannot be estimated from the available data).

MedDRA System Organ Class

Frequency category

Common

(≥ 1/100 to <1/10)

Uncommon

(≥ 1/1,000 to <1/100)

Frequency not known

(cannot be estimated from the available data)

Immune system disorders

- Hypersensitivity reactions including anaphylaxis

Nervous system disorders

- Convulsions particularly in case of misuse (refer to sections 4.3 and 4.4)

Eye disorders

- Visual disturbances including impaired colour vision

Vascular disorders

- Malaise with hypotension, with or without loss of consciousness (generally following a too fast intravenous injection, exceptionally after oral administration)

- Arterial or venous thrombosis at any sites

Gastrointestinal disorders

- Diarrhoea

- Vomiting

- Nausea

Skin and subcutaneous tissue disorders

- Dermatitis allergic

- Fixed drug eruption

Renal and urinary disorders

- Acute renal cortical necrosis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported.

Signs and symptoms may include dizziness, headache, hypotension, and convulsions. It has been shown that convulsions tend to occur at higher frequency with increasing dose.

Management of overdose should be supportive.