Exacyl

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:

- 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.

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) Exacyl 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) Exacyl by slow intravenous injection (= 1 ml/minute) every 6 to 8 hours, equivalent to 15 mg/kg BW

Renal impairment

In renal insufficiency leading to a risk of accumulation, the use of Exacyl is contraindicated in patients with severe renal impairment. For patients with mild to moderate renal impairment, the dosage of Exacyl should be reduced according to the serum creatinine level:

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment.

Paediatric Population:

The efficacy, posology and safety of Exacyl in children undergoing cardiac surgery have not been fully established.

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.

Acute venous or arterial thrombosis.

Fibrinolytic conditions following consumption coagulopathy except in those with predominant activation of the fibrinolytic system with acute severe bleeding.

Severe renal impairment (risk of accumulation).

History of convulsions

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

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

- Intravenous injections should be given very slowly.

- Exacyl should not be administered by the intramuscular route.

Convulsions

Cases of convulsions have been reported in association with Exacyl treatment.In coronary artery bypass graft (CABG) surgery, most of these cases were reported following intravenous (i.v.) injection of Exacyl in high doses. With the use of the recommended lower doses of TXA, 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 TXA 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 TXA solution for injection 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 TXA, 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), Exacyl 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.

Exacyl should be administered with care in patients receiving oral contraceptives because of the increased risk of thrombosis.

Disseminated intravascular coagulation

Patients with disseminated intravascular coagulation (DIC) should in most cases not be treated with Exacyl. If Exacyl 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 Exacyl is frequently sufficient to control bleeding. Administration of Exacyl in DIC should be considered only when appropriate haematological laboratory facilities and expertise are available.

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

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. 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 (cannot be estimated from the available data).

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

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.

Pharmacotherapeutic group: Antihemorrhagics, Antifibrinolytics, Aminoacids

ATC code: B02AA02

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

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

The activity of the Exacyl-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 Exacyl. Most of them were controlled versus placebo. Studied population was heterogenic in terms of age, surgery types, dosing schedules. Study results with Exacyl 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.

Absorption

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

Distribution

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

Exacyl passes through the placenta. Following administration of an intravenous injection of 10 mg/kg to 12 pregnant women, the concentration of Exacyl in serum ranged 10-53 μg/mL while that in cord blood ranged 4-31 μg/mL. Exacyl 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 Exacyl 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). Exacyl has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration.

Excretion

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 Exacyl is about 90% within the first 24 hours after intravenous administration of 10 mg/kg body weight. Elimination half-life of Exacyl is approximately 3 hours.

Special populations

Plasma concentrations increase in patients with renal failure.

No specific PK study has been conducted in children.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Epileptogenic activity has been observed in animals with intrathecal use of Exacyl.

Exacyl solution for injection should not be added to blood for transfusion, or to injections containing penicillin.

The product is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.