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 BW

Patients with renal impairment

In renal insufficiency leading to a risk of accumulation, the use of tranexamic acid is contraindicated 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

Patients with 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 are limited and are 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 or infusion (see section 6.6) of maximum 1ml 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 its 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 or infusions should be given very slowly (maximum 1ml 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 include 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 (i.v.) 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, 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 in each individual case.

Haematuria

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

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 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 receiving oral 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 1g 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.

Sodium content

This medicinal product contains less than 1mmol sodium (23mg) per dose i.e. essentially “sodium-free”.

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 theoretical risk of increased thrombus-formation potential, such as with oestrogens. Alternatively, the antifibrinolytic action of the drug may be antagonised with thrombolytic drugs.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential have to use effective contraception during treatment.

Pregnancy

There is insufficient clinical data on the use of tranexamic acid in pregnant women. As a result, although studies in animals do not indicate teratogenic effects, as precaution for use, tranexamic acid is not recommended during the first trimester of pregnancy.

Limited clinical data of the use of tranexamic acid in different clinical haemorrhagic settings during the second and third trimesters did not identify deleterious effect for the foetus. Tranexamic acid should be used throughout pregnancy only if the expected benefit justifies the potential risk.

Breast-feeding

Tranexamic acid is excreted in human milk. Therefore, breast-feeding is not recommended.

Fertility

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

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 the table below. Adverse reactions are listed according to MedDRA primary system organ class. Within each system organ class, adverse reactions are ranked by frequency. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequencies were defined as follows:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), not known (can not be estimated from the available data).

MedDRA

System Organ Class

Frequency

Undesirable Effects

Skin and subcutaneous tissue disorders

Uncommon

Dermatitis allergic

Not known

Fixed drug eruption

Gastrointestinal disorders

Common

Diarrhoea

Vomiting

Nausea

Nervous system disorders

Not known

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

Eye disorders

Not known

Visual disturbances including impaired colour vision

Vascular disorders

Not known

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

Arterial or venous embolism at any sites

Immune system disorders

Not known

Hypersensitivity reactions including anaphylaxis

Renal and urinary disorders

Not known

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.