Cyklokapron Injection

Active ingredient: Tranexamic Acid Ph.Eur 500 mg

Ampoules containing 5ml colourless solution

Local fibrinolysis

For short term use in prophylaxis and treatment in patients at high risk of per - and post-operative haemorrhage following:

a) prostatectomy

b) conisation of the cervix

c) surgical procedures and dental extractions in haemophiliacs

General fibrinolysis

a) haemorrhagic complications in association with thrombolytic therapy.

b) Haemorrhage associated with disseminated intravascular coagulation with predominant activation of the fibrinolytic system.

Route of administration: by slow intravenous injection.

Local fibrinolysis: the recommended standard dose is 5-10ml (500-1000mg) by slow intravenous injection (1 ml/min), three times daily. Following an initial intravenous injection, subsequent treatment may proceed by intravenous infusion. Following addition to a suitable diluent (see Section 4.5), Cyklokapron may be administered at a rate of 25-50 mg/kg body wt/day.

Children:

In children, 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.

Injectable solution: 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 patients: No reduction in dosage is necessary unless there is evidence of renal failure.

General fibrinolysis

1 In disseminated intravascular coagulation with predominant activation of the fibrinolytic system, usually a single dose of 10ml (1g) is sufficient to control bleeding.

2 Neutralisation of thrombolytic therapy; 10mg/kg body wt by slow intravenous injection.

• History of venous or arterial thrombosis

• 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

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

• Due to the risk of cerebral oedema and convulsions, intrathecal or intraventricular injection and intracerebral application are contra-indicated. In patients with a history of convulsion, tranexamic acid should not be administered.

• In case of haematuria of renal origin, there is a risk of mechanical anuria due to formation of a ureteral clot.

• In patients with renal insufficiency, because of the risk of accumulation. The dose should be reduced according to the following table:

• In massive haematuria from the upper urinary tract (especially in haemophilia) since, in a few cases, ureteric obstruction has been reported.

• In patients with disseminated intravascular coagulation (DIC) treatment 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 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. The fibrinolytic activity in the blood will be reduced for about 4 hours if renal function is normal. Anticoagulation with heparin should be instigated in order to prevent further fibrin deposition. Administration of Cyklokapron in DIC should be considered only when appropriate haematological laboratory facilities and expertise are available. Cyklokapron must not be administered in DIC with predominant activation of the coagulation system.

• Before use of TXA, risk factors of thromboembolic disease should be investigated.

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

The solution for injection may be mixed with the following solutions: isotonic sodium chloride; isotonic glucose; 20% fructose; 10% invertose; dextran 40; dextran 70; ringer's solution.

Cyklokapron solution for injection may be mixed with Heparin.

Although there is no evidence from animal studies of a teratogenic effect, the usual caution with the use of drugs in pregnancy should be observed.

Tranexamic acid passes into breast milk to a concentration of approximately one hundredth of the concentration in the maternal blood. An antifibrinolytic effect in the infant is unlikely.

None known

Very rare adverse events have been reported :

• Gastro-intestinal disorders: digestive effects such as nausea, vomiting and diarrhoea.

• Cardio-vascular disorders :

• Nervous system disorders: dizziness; convulsions, particularly in case of misuse (see section 4.4 "Precautions and warnings")

• General disorders: hypersensitivity reactions including anaphylaxis

No cases of overdosage have been reported. Symptoms may be nausea, vomiting, orthostatic symptoms and/or hypotension. Maintain a high fluid intake to promote renal excretion.

Tranexamic acid is an antifibrinolytic agent, which competitively inhibits the activation of plasminogen to plasmin.

In children over one year old:

Literature review identified 12 efficacy studies in paediatric cardiac surgery which have included 1073 children, 631 having received TXA. Most of them were controlled versus placebo. Studied population was heterogenic in terms of age, surgery types, dosing schedules. Study results with TXA suggest reduced blood loss and reduced blood product requirements in paediatric cardiac surgery under cardiopulmonary bypass when 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 patient weight with a 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 ATX concentration is obtained immediately after IV administration (500mg). Then concentration decreases until the 6th hour. Elimination half-life is about 3 hours.

Distribution

TXA is delivered in the cell compartment and the cerebrospinal fluid with delay. The distribution volume is about 33% of the body mass.

Elimination

TXA is excreted in urine as unchanged compound. 90% of the administered dose is excreted by the kidney in the twelve first hours after administration (glomerular excretion without tubular reabsorption). Plasma concentrations are increased in patients with renal insufficiency.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

Water for injections

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

3 years.

None.

Type I glass 5ml ampoules packed in outer cardboard carton.

See Section 4.2

Pharmacia Limited

Ramsgate Road

Sandwich

CT13 9NJ

UK

PL 00032/0314

9^th February 1987

July 2010

Company Ref: CK3_0