CYKLOKAPRON 500 MG SOLUTION FOR INJECTION - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 mL ampoule contains 500 mg tranexamic acid.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection/infusion.

Clear, colourless solution with pH of 6.5– 8.0.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Tranexamic acid is indicated in adults and children from one year in prevention and treatment of haemorrhages due to general or local fibrinolysis.

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. CLINICAL PARTICULARS

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 or infusion (= 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 or infusion (= 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 contraindicated in patient 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:

Hepatic impairment

No dose adjustment is required in patient 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 1 mL per minute.

4. CLINICAL PARTICULARS

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

4.

CLINICAL PARTICULARS

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 1 mL per minute).

Tranexamic acid should not be administered by the intramuscular rou­te.

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, 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 haemostaseology 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 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

4.7.   Effects on ability to drive and use machines

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antihaemorrhagics, Antifibrinolytics, Aminoacids ATC code: B02AA02

Tranexamic acid exerts an anti haemorrhagic activity by inhibiting the fibrinolytic properties of plasmin.

A complex involving tranexamic acid, plasminogen is constituted; the tranexamic acid being linked to plasminogen when transformed into plasmin.

The activity of the tranexamic acid-plasmin complex on the activity on fibrin is lower than the activity of free plasmin alone.

In vitro studies showed that high tranexamic dosages decreased the activity of complement.

Paediatric population

In children over one year old

Literature review identified 12 efficacy studies in paediatric cardiac surgery which have included 1073 children, 631 having received tranexamic acid. Most of them were controlled versus placebo. Studied population was heterogenic in terms of age, surgery types, dosing schedules. Study results with tranexamic acid suggest reduced blood loss and reduced blood product requirements in paediatric cardiac surgery under cardiopulmonary bypass (CPB) where there is a high risk of haemorrhage, especially in cyanotic patients or patients undergoing repeat surgery.The most adapted dosing schedule appeared to be:

– first bolus of 10 mg/kg after induction of anaesthesia and prior to skin incision,

– continuous infusion of 10 mg/kg/h or injection into the CPB pump prime at a dose adapted on the CPB procedure, either according to a patient weight with a dose of 10 mg/kg dose, either according to CPB pump prime volume, last injection of 10 mg/kg at the end of CPB.

While studied in very few patients, the limited data suggest that continuous infusion is preferable, since it would maintain therapeutic plasma concentration throughout surgery.

No specific dose-effect study or PK study has been conducted in children.

5. PHARMACOLOGICAL PROPERTIES

5.2 Pharmacokinetic properties

Absorption

Peak plasma concentrations of tranexamic acid are obtained rapidly after a short intravenous infusion after which plasma concentrations decline in a multi-exponential manner.

Distribution

The plasma protein binding of tranexamic acid is about 3% at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is about 9 to 12 litres.

Tranexamic acid passes through the placenta. Following administration of an intravenous injection of 10 mg/kg to 12 pregnant women, the concentration of tranexamic acid in serum ranged 10–53 microgram/mL while that in cord blood ranged 4–31 microgram/mL. Tranexamic acid diffuses rapidly into joint fluid and the synovial membrane. Following administration of an intravenous injection of 10 mg/kg to 17 patients undergoing knee surgery, concentrations in the joint fluids were similar to those seen in corresponding serum samples. The concentration of tranexamic acid in a number of other tissues is a fraction of that observed in the blood (breast milk, one hundredth; cerebrospinal fluid, one tenth; aqueous humor, one tenth). Tranexamic acid has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration.

Elimination

It is excreted mainly in the urine as unchanged drug. Urinary excretion via glomerular filtration is the main route of elimination. Renal clearance is equal to plasma clearance (110 to 116 mL/min). Excretion of tranexamic acid is about 90% within the first 24 hours after intravenous administration of 10 mg/kg body weight. Elimination half-life of tranexamic acid is approximately 3 hours.

Other special populations

Plasma concentrations increase in patients with renal failure.

No specific pharmacokinetic study has been conducted in children.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Epileptogenic activity has been observed in animals with intrathecal use of tranexamic acid.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections.

6. PHARMACEUTICAL PARTICULARS

6.2 Incompati­bilities

This medicinal product should not be mixed with blood for transfusion or with solutions containing penicillin.

6. PHARMACEUTICAL PARTICULARS

6.3 Shelf life

3 years

After first opening: the solution for injection/infusion is for single use only. Unused solution must be discarded.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Do not freeze.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

6.6   Special precautions for disposal and other handling

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited

Ramsgate Road

Sandwich

CT13 9NJ

UK

8. MARKETING AUTHORISATION NUMBER(S)

PL 00057/0952

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

9thFebruary 1987